Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients.

PubMed

Sofou, Kalliopi; de Coo, Irenaeus F M; Ostergaard, Elsebet; Isohanni, Pirjo; Naess, Karin; De Meirleir, Linda; Tzoulis, Charalampos; Uusimaa, Johanna; Lönnqvist, Tuula; Bindoff, Laurence Albert; Tulinius, Már; Darin, Niklas

2018-01-01

Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored. We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients. We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases. We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation. Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

FOLATE AND HUMAN DEVELOPMENT: PREFACE

EPA Science Inventory

Neural tube defects (NTDs) are a complex developmental trait in which several genes, interacting with environmental factors, create the phenotype. In the United States, the rate of NTDs has been reported to range from 4 to 10 per 10,000 live births, and NTDs affect approximately...

Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome-like phenotype and hypogammaglobulinemia.

PubMed

Khandelwal, Kriti D; Ockeloen, Charlotte W; Venselaar, Hanka; Boulanger, Cécile; Brichard, Bénédicte; Sokal, Etienne; Pfundt, Rolph; Rinne, Tuula; van Beusekom, Ellen; Bloemen, Marjon; Vriend, Gerrit; Revencu, Nicole; Carels, Carine E L; van Bokhoven, Hans; Zhou, Huiqing

2017-05-17

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here. © 2017 Wiley Periodicals, Inc.

Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes.

PubMed

Giorgio, Elisa; Brussino, Alessandro; Biamino, Elisa; Belligni, Elga Fabia; Bruselles, Alessandro; Ciolfi, Andrea; Caputo, Viviana; Pizzi, Simone; Calcia, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Mancini, Cecilia; Pozzi, Elisa; Ferrero, Marta; Riberi, Evelise; Borelli, Iolanda; Amoroso, Antonio; Ferrero, Giovanni Battista; Tartaglia, Marco; Brusco, Alfredo

2017-05-01

More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10-15% of intellectual disability (ID). To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth). WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376). Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Steven D; Guss, Adam M; Karpinets, Tatiana V

2011-01-01

Clostridium thermocellum is a thermophilic, obligately anaerobic, Gram-positive bacterium that is a candidate microorganism for converting cellulosic biomass into ethanol through consolidated bioprocessing. Ethanol intolerance is an important metric in terms of process economics, and tolerance has often been described as a complex and likely multigenic trait for which complex gene interactions come into play. Here, we resequence the genome of an ethanol-tolerant mutant, show that the tolerant phenotype is primarily due to a mutated bifunctional acetaldehyde-CoA/alcohol dehydrogenase gene (adhE), hypothesize based on structural analysis that cofactor specificity may be affected, and confirm this hypothesis using enzyme assays. Biochemical assaysmore » confirm a complete loss of NADH-dependent activity with concomitant acquisition of NADPH-dependent activity, which likely affects electron flow in the mutant. The simplicity of the genetic basis for the ethanol-tolerant phenotype observed here informs rational engineering of mutant microbial strains for cellulosic ethanol production.« less

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

PubMed Central

Courcet, Jean- Benoît; Elalaoui, Siham Chafai; Duplomb, Laurence; Tajir, Mariam; Rivière, Jean-Baptiste; Thevenon, Julien; Gigot, Nadège; Marle, Nathalie; Aral, Bernard; Duffourd, Yannis; Sarasin, Alain; Naim, Valeria; Courcet-Degrolard, Emilie; Aubriot-Lorton, Marie- Hélène; Martin, Laurent; Abrid, Jamal Eddin; Thauvin, Christel; Sefiani, Abdelaziz; Vabres, Pierre; Faivre, Laurence

2015-01-01

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer. PMID:25315659

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

PubMed

Courcet, Jean-Benoît; Elalaoui, Siham Chafai; Duplomb, Laurence; Tajir, Mariam; Rivière, Jean-Baptiste; Thevenon, Julien; Gigot, Nadège; Marle, Nathalie; Aral, Bernard; Duffourd, Yannis; Sarasin, Alain; Naim, Valeria; Courcet-Degrolard, Emilie; Aubriot-Lorton, Marie-Hélène; Martin, Laurent; Abrid, Jamal Eddin; Thauvin, Christel; Sefiani, Abdelaziz; Vabres, Pierre; Faivre, Laurence

2015-07-01

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.

graph-GPA: A graphical model for prioritizing GWAS results and investigating pleiotropic architecture.

PubMed

Chung, Dongjun; Kim, Hang J; Zhao, Hongyu

2017-02-01

Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. However, identification of risk variants associated with complex diseases remains challenging as they are often affected by many genetic variants with small or moderate effects. There has been accumulating evidence suggesting that different complex traits share common risk basis, namely pleiotropy. Recently, several statistical methods have been developed to improve statistical power to identify risk variants for complex traits through a joint analysis of multiple GWAS datasets by leveraging pleiotropy. While these methods were shown to improve statistical power for association mapping compared to separate analyses, they are still limited in the number of phenotypes that can be integrated. In order to address this challenge, in this paper, we propose a novel statistical framework, graph-GPA, to integrate a large number of GWAS datasets for multiple phenotypes using a hidden Markov random field approach. Application of graph-GPA to a joint analysis of GWAS datasets for 12 phenotypes shows that graph-GPA improves statistical power to identify risk variants compared to statistical methods based on smaller number of GWAS datasets. In addition, graph-GPA also promotes better understanding of genetic mechanisms shared among phenotypes, which can potentially be useful for the development of improved diagnosis and therapeutics. The R implementation of graph-GPA is currently available at https://dongjunchung.github.io/GGPA/.

Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families

PubMed Central

Fyer, Abby J.; Costa, Ramiro; Haghighi, Fatemeh; Logue, Mark W.; Knowles, James A.; Weissman, Myrna M.; Hodge, Susan E.; Hamilton, Steven P.

2013-01-01

Background The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the DSM IV PD definition. Here we extend this work by conducting exploratory linkage analyses in this same pedigree set using ten additional literature- based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities. Methods Multiply affected families (> 2 individuals with PD) were recruited from clinical and non-clinical sources, evaluated by clinician administered semi-structured interview and subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric 2-point (homogeneity and heterogeneity), multipoint, and non-parametric methods. Empirically based permutations were used to estimate model specific and global (across all phenotypes) p-values. Results The highest score was a 2-point lod (4.27, global p < 0.08) on chromosome 13 (D13S793, 76cM) for the phenotype “specific or social phobia” under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes. Conclusions Though interpretation of findings is limited by sample size and the large number of phenotypes and models analyzed these data suggest a region on chromosome 13 as a potential site for further exploration in relation to risk for specific and social phobias. PMID:22525237

Structural variation within the potato Ve gene locus and correlation with molecular marker analysis

USDA-ARS?s Scientific Manuscript database

The disconnect between single genotype model systems and plant breeding using wide crosses of diverse germplasm is often too great to affect progress in understanding complex phenotypes. Whole genome sequencing allows researchers and breeders to quickly and inexpensively resequence interesting indiv...

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

PubMed Central

Shamseldin, Hanan E.; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S.; Gleeson, Joseph G.; Alkuraya, Fowzan S.

2016-01-01

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. PMID:26708753

Retinal dystrophies, genomic applications in diagnosis and prospects for therapy

PubMed Central

Nash, Benjamin M.; Wright, Dale C.; Grigg, John R.; Bennetts, Bruce

2015-01-01

Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs. PMID:26835369

Untargeted Metabolic Quantitative Trait Loci Analyses Reveal a Relationship between Primary Metabolism and Potato Tuber Quality1[W][OA

PubMed Central

Carreno-Quintero, Natalia; Acharjee, Animesh; Maliepaard, Chris; Bachem, Christian W.B.; Mumm, Roland; Bouwmeester, Harro; Visser, Richard G.F.; Keurentjes, Joost J.B.

2012-01-01

Recent advances in -omics technologies such as transcriptomics, metabolomics, and proteomics along with genotypic profiling have permitted dissection of the genetics of complex traits represented by molecular phenotypes in nonmodel species. To identify the genetic factors underlying variation in primary metabolism in potato (Solanum tuberosum), we have profiled primary metabolite content in a diploid potato mapping population, derived from crosses between S. tuberosum and wild relatives, using gas chromatography-time of flight-mass spectrometry. In total, 139 polar metabolites were detected, of which we identified metabolite quantitative trait loci for approximately 72% of the detected compounds. In order to obtain an insight into the relationships between metabolic traits and classical phenotypic traits, we also analyzed statistical associations between them. The combined analysis of genetic information through quantitative trait locus coincidence and the application of statistical learning methods provide information on putative indicators associated with the alterations in metabolic networks that affect complex phenotypic traits. PMID:22223596

Characterization and classification of zebrafish brain morphology mutants

PubMed Central

Lowery, Laura Anne; De Rienzo, Gianluca; Gutzman, Jennifer H.; Sive, Hazel

2010-01-01

The mechanisms by which the vertebrate brain achieves its three-dimensional structure are clearly complex, requiring the functions of many genes. Using the zebrafish as a model, we have begun to define genes required for brain morphogenesis, including brain ventricle formation, by studying 16 mutants previously identified as having embryonic brain morphology defects. We report the phenotypic characterization of these mutants at several time-points, using brain ventricle dye injection, imaging, and immunohistochemistry with neuronal markers. Most of these mutants display early phenotypes, affecting initial brain shaping, while others show later phenotypes, affecting brain ventricle expansion. In the early phenotype group, we further define four phenotypic classes and corresponding functions required for brain morphogenesis. Although we did not use known genotypes for this classification, basing it solely on phenotypes, many mutants with defects in functionally related genes clustered in a single class. In particular, class 1 mutants show midline separation defects, corresponding to epithelial junction defects; class 2 mutants show reduced brain ventricle size; class 3 mutants show midbrain-hindbrain abnormalities, corresponding to basement membrane defects; and class 4 mutants show absence of ventricle lumen inflation, corresponding to defective ion pumping. Later brain ventricle expansion requires the extracellular matrix, cardiovascular circulation, and transcription/splicing-dependent events. We suggest that these mutants define processes likely to be used during brain morphogenesis throughout the vertebrates. PMID:19051268

Tourette Syndrome: School-Based Interventions for Tics and Associated Conditions

ERIC Educational Resources Information Center

Koutsoklenis, Athanasios; Theodoridou, Zoe

2012-01-01

Tourette syndrome (TS) is a neurological disorder characterized by motor and phonic tics that follow a fluctuating pattern of severity, intensity and frequency. TS is often associated with other conditions such as attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and learning difficulties. This complex phenotype affects the…

Metabolic and Epigenetic Interactions Regulate Vascular Phenotypic Change and Maintenance in Pulmonary Hypertension

DTIC Science & Technology

2016-10-01

Krebs cycle through the generation of alpha-ketoglutarate. However, increased oxidative stress affected oxygen consumption rates at the Complex I...machinery and respiration in PH-Fibs. The difference in endogenous respiration, (i.e., oxygen consumption ) was not statistically different compared...driven through complex I. We found a roughly17% drop in oxygen consumption in PH-Fibs versus Co-Fibs (Figure 3C), which corresponded to the down

A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar Atrophy.

PubMed

Kim, Young Ok; Yun, Misun; Jeong, Jae Ho; Choi, Seong Min; Kim, Seul Kee; Yoon, Woong; Park, Chungoo; Hong, Yeongjin; Woo, Young Jong

2017-11-01

Progressive cerebellar ataxias are rare diseases during childhood, especially under 6 years of age. In a single family, three affected siblings exhibited Friedreich's-ataxia-like phenotypes before 2 years of age. They had progressive cerebellar atrophy, intellectual disability, and scoliosis. Although their phenotypes were similar to those observed in patients with autosomal recessive cerebellar ataxias, other phenotypes (e.g., seizure, movement disorders, ophthalmologic disturbance, cardiomyopathy, and cutaneous disorders) were not noted in this family. Whole-exome sequencing of the family members revealed one potential heterozygous mutation (c.1209delG, NM_181733.2; p.Met403IlefsX3, NP_859422.2) of the gene encoding conserved oligomeric Golgi complex subunit 5 (COG5). The heterozygous deletion at the fifth base in exon 12 of COG5 caused a frameshift and premature stop. Western blotting of COG5 proteins in the skin tissues from an affected proband showed a significantly decreased level of full length COG5 and smaller, aberrant COG5 proteins. We reported a milder form of COG5 defect showing Friedreich's-ataxia-like phenotypes without hypotonia, microcephaly, and short stature that were observed in most patients with COG5 defect. © 2017 The Korean Academy of Medical Sciences.

Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.

PubMed

Dermaut, B; Seneca, S; Dom, L; Smets, K; Ceulemans, L; Smet, J; De Paepe, B; Tousseyn, S; Weckhuysen, S; Gewillig, M; Pals, P; Parizel, P; De Bleecker, J L; Boon, P; De Meirleir, L; De Jonghe, P; Van Coster, R; Van Paesschen, W; Santens, P

2010-01-01

m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.

High- and low-throughput scoring of fat mass and body fat distribution in C. elegans

PubMed Central

Wählby, Carolina; Lee-Conery, Annie; Bray, Mark-Anthony; Kamentsky, Lee; Larkins-Ford, Jonah; Sokolnicki, Katherine L.; Veneskey, Matthew; Michaels, Kerry; Carpenter, Anne E.; O’Rourke, Eyleen J.

2014-01-01

Fat accumulation is a complex phenotype affected by factors such as neuroendocrine signaling, feeding, activity, and reproductive output. Accordingly, the most informative screens for genes and compounds affecting fat accumulation would be those carried out in whole living animals. Caenorhabditis elegans is a well-established and effective model organism, especially for biological processes that involve organ systems and multicellular interactions, such as metabolism. Every cell in the transparent body of C. elegans is visible under a light microscope. Consequently, an accessible and reliable method to visualize worm lipid-droplet fat depots would make C. elegans the only metazoan in which genes affecting not only fat mass but also body fat distribution could be assessed at a genome-wide scale. Here we present a radical improvement in oil red O worm staining together with high-throughput image-based phenotyping. The three-step sample preparation method is robust, formaldehyde-free, and inexpensive, and requires only 15 minutes of hands-on time to process a 96-well plate. Together with our free and user-friendly automated image analysis package, this method enables C. elegans sample preparation and phenotype scoring at a scale that is compatible with genome-wide screens. Thus we present a feasible approach to small-scale phenotyping and large-scale screening for genetic and/or chemical perturbations that lead to alterations in fat quantity and distribution in whole animals. PMID:24784529

Interaction of Hb South Florida (codon 1; GTG-->ATG) and HbE, with beta-thalassemia (IVS1-1; G-->A): expression of different clinical phenotypes.

PubMed

Tan, Jin-Ai Mary Anne; Tan, Kim-Lian; Omar, Khairul Zaman; Chan, Lee-Lee; Wee, Yong-Chui; George, Elizabeth

2009-09-01

Interactions of different hemoglobin variants with thalassemia alleles can result in various clinical phenotypes. HbE-beta-thalassemia generally manifests with severe anemia where individuals exhibit beta-thalassemia major with regular blood transfusions or beta-thalassemia intermedia with periodic blood transfusions. This study presents a unique Malay family with three beta-globin gene defects-HbE, Hb South Florida, and IVS1-1 (G-->A). HbE activates a cryptic splice site that produces non-functional mRNAs. Hb South Florida is a rare beta-hemoglobin variant, and its interactions with other beta-thalassemia alleles have not been reported. IVS1-1 is a Mediterranean mutation that affects mRNA processing giving rise to beta(o)-thalassemia. Fifteen mutations along the beta-globin gene complex were analyzed using the amplification refractory mutation system. Hb South Florida was identified by direct sequencing using genomic DNA. The affected child with HbE/IVS1-1 produced a beta-thalassemia major phenotype. Compound heterozygosity for Hb South Florida/IVS1-1 produced a beta-thalassemia carrier phenotype in the mother.

Effects of paternal phenotype and environmental variability on age and size at maturity in a male dimorphic mite

NASA Astrophysics Data System (ADS)

Smallegange, Isabel M.

2011-04-01

Investigating how the environment affects age and size at maturity of individuals is crucial to understanding how changes in the environment affect population dynamics through the biology of a species. Paternal phenotype, maternal, and offspring environment may crucially influence these traits, but to my knowledge, their combined effects have not yet been tested. Here, I found that in bulb mites ( Rhizoglyphus robini), maternal nutrition, offspring nutrition, and paternal phenotype (males are fighters, able to kill other mites, or benign scramblers) interactively affected offspring age and size at maturity. The largest effect occurred when both maternal and offspring nutrition was poor: in that case offspring from fighter sires required a significantly longer development time than offspring from scrambler sires. Investigating parental effects on the relationship between age and size at maturity revealed no paternal effects, and only for females was its shape influenced by maternal nutrition. Overall, this reaction norm was nonlinear. These non-genetic intergenerational effects may play a complex, yet unexplored role in influencing population fluctuations—possibly explaining why results from field studies often do not match theoretical predictions on maternal effects on population dynamics.

The evolution of phenotypic correlations and ‘developmental memory’

PubMed Central

Watson, Richard A.; Wagner, Günter P.; Pavlicev, Mihaela; Weinreich, Daniel M.; Mills, Rob

2014-01-01

Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution of phenotypes produced by complex developmental systems can be shaped by past selective environments is poorly understood. Here we investigate the evolution of a network of recurrent non-linear ontogenetic interactions, such as a gene regulation network, in various selective scenarios. We find that evolved networks of this type can exhibit several phenomena that are familiar in cognitive learning systems. These include formation of a distributed associative memory that can ‘store’ and ‘recall’ multiple phenotypes that have been selected in the past, recreate complete adult phenotypic patterns accurately from partial or corrupted embryonic phenotypes, and ‘generalise’ (by exploiting evolved developmental modules) to produce new combinations of phenotypic features. We show that these surprising behaviours follow from an equivalence between the action of natural selection on phenotypic correlations and associative learning, well-understood in the context of neural networks. This helps to explain how development facilitates the evolution of high-fitness phenotypes and how this ability changes over evolutionary time. PMID:24351058

Common genetic variation drives molecular heterogeneity in human iPSCs.

PubMed

Kilpinen, Helena; Goncalves, Angela; Leha, Andreas; Afzal, Vackar; Alasoo, Kaur; Ashford, Sofie; Bala, Sendu; Bensaddek, Dalila; Casale, Francesco Paolo; Culley, Oliver J; Danecek, Petr; Faulconbridge, Adam; Harrison, Peter W; Kathuria, Annie; McCarthy, Davis; McCarthy, Shane A; Meleckyte, Ruta; Memari, Yasin; Moens, Nathalie; Soares, Filipa; Mann, Alice; Streeter, Ian; Agu, Chukwuma A; Alderton, Alex; Nelson, Rachel; Harper, Sarah; Patel, Minal; White, Alistair; Patel, Sharad R; Clarke, Laura; Halai, Reena; Kirton, Christopher M; Kolb-Kokocinski, Anja; Beales, Philip; Birney, Ewan; Danovi, Davide; Lamond, Angus I; Ouwehand, Willem H; Vallier, Ludovic; Watt, Fiona M; Durbin, Richard; Stegle, Oliver; Gaffney, Daniel J

2017-06-15

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Common genetic variation drives molecular heterogeneity in human iPSCs

PubMed Central

Leha, Andreas; Afzal, Vackar; Alasoo, Kaur; Ashford, Sofie; Bala, Sendu; Bensaddek, Dalila; Casale, Francesco Paolo; Culley, Oliver J; Danecek, Petr; Faulconbridge, Adam; Harrison, Peter W; Kathuria, Annie; McCarthy, Davis; McCarthy, Shane A; Meleckyte, Ruta; Memari, Yasin; Moens, Nathalie; Soares, Filipa; Mann, Alice; Streeter, Ian; Agu, Chukwuma A; Alderton, Alex; Nelson, Rachel; Harper, Sarah; Patel, Minal; White, Alistair; Patel, Sharad R; Clarke, Laura; Halai, Reena; Kirton, Christopher M; Kolb-Kokocinski, Anja; Beales, Philip; Birney, Ewan; Danovi, Davide; Lamond, Angus I; Ouwehand, Willem H; Vallier, Ludovic; Watt, Fiona M; Durbin, Richard

2017-01-01

Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells. PMID:28489815

Identifying candidate genes affecting developmental time in Drosophila melanogaster: pervasive pleiotropy and gene-by-environment interaction

PubMed Central

Mensch, Julián; Lavagnino, Nicolás; Carreira, Valeria Paula; Massaldi, Ana; Hasson, Esteban; Fanara, Juan José

2008-01-01

Background Understanding the genetic architecture of ecologically relevant adaptive traits requires the contribution of developmental and evolutionary biology. The time to reach the age of reproduction is a complex life history trait commonly known as developmental time. In particular, in holometabolous insects that occupy ephemeral habitats, like fruit flies, the impact of developmental time on fitness is further exaggerated. The present work is one of the first systematic studies of the genetic basis of developmental time, in which we also evaluate the impact of environmental variation on the expression of the trait. Results We analyzed 179 co-isogenic single P[GT1]-element insertion lines of Drosophila melanogaster to identify novel genes affecting developmental time in flies reared at 25°C. Sixty percent of the lines showed a heterochronic phenotype, suggesting that a large number of genes affect this trait. Mutant lines for the genes Merlin and Karl showed the most extreme phenotypes exhibiting a developmental time reduction and increase, respectively, of over 2 days and 4 days relative to the control (a co-isogenic P-element insertion free line). In addition, a subset of 42 lines selected at random from the initial set of 179 lines was screened at 17°C. Interestingly, the gene-by-environment interaction accounted for 52% of total phenotypic variance. Plastic reaction norms were found for a large number of developmental time candidate genes. Conclusion We identified components of several integrated time-dependent pathways affecting egg-to-adult developmental time in Drosophila. At the same time, we also show that many heterochronic phenotypes may arise from changes in genes involved in several developmental mechanisms that do not explicitly control the timing of specific events. We also demonstrate that many developmental time genes have pleiotropic effects on several adult traits and that the action of most of them is sensitive to temperature during development. Taken together, our results stress the need to take into account the effect of environmental variation and the dynamics of gene interactions on the genetic architecture of this complex life-history trait. PMID:18687152

Digest: Context matters: The effects of light environment and female presence on the structure of wolf spider courtship displays.

PubMed

Fialko, Kristina

2018-05-01

Does variation in the environment in which a signal is presented affect the components of a complex, ritualized animal display? Using a signal phenotype network, Rosenthal et al. (2018) found that light and female presence alter the structure of wolf spider courtship displays, providing evidence that complex signaling behaviors may be modified depending on the social and environmental context. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.

Next-generation sequencing to solve complex inherited retinal dystrophy: A case series of multiple genes contributing to disease in extended families.

PubMed

Jones, Kaylie D; Wheaton, Dianna K; Bowne, Sara J; Sullivan, Lori S; Birch, David G; Chen, Rui; Daiger, Stephen P

2017-01-01

With recent availability of next-generation sequencing (NGS), it is becoming more common to pursue disease-targeted panel testing rather than traditional sequential gene-by-gene dideoxy sequencing. In this report, we describe using NGS to identify multiple disease-causing mutations that contribute concurrently or independently to retinal dystrophy in three relatively small families. Family members underwent comprehensive visual function evaluations, and genetic counseling including a detailed family history. A preliminary genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed with retinitis pigmentosa (RP) and had a suspected autosomal dominant pedigree with non-penetrance (n.p.). Family 3 (FAM3) consisted of a large family with a diagnosis of RP and an overall dominant pedigree, but the proband had phenotypically cone-rod dystrophy. Initial genetic analysis was performed on one family member with traditional Sanger single gene sequencing and/or panel-based testing, and ultimately, retinal gene-targeted NGS was required to identify the underlying cause of disease for individuals within the three families. Results obtained in these families necessitated further genetic and clinical testing of additional family members to determine the complex genetic and phenotypic etiology of each family. Genetic testing of FAM1 (n = 4 affected; 1 n.p.) identified a dominant mutation in RP1 (p.Arg677Ter) that was present for two of the four affected individuals but absent in the proband and the presumed non-penetrant individual. Retinal gene-targeted NGS in the fourth affected family member revealed compound heterozygous mutations in USH2A (p. Cys419Phe, p.Glu767Serfs*21). Genetic testing of FAM2 (n = 3 affected; 1 n.p.) identified three retinal dystrophy genes ( PRPH2 , PRPF8 , and USH2A ) with disease-causing mutations in varying combinations among the affected family members. Genetic testing of FAM3 (n = 7 affected) identified a mutation in PRPH2 (p.Pro216Leu) tracking with disease in six of the seven affected individuals. Additional retinal gene-targeted NGS testing determined that the proband also harbored a multiple exon deletion in the CRX gene likely accounting for her cone-rod phenotype; her son harbored only the mutation in CRX , not the familial mutation in PRPH2 . Multiple genes contributing to the retinal dystrophy genotypes within a family were discovered using retinal gene-targeted NGS. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole. Identification of a disease-causing mutation in a proband, even with a clear inheritance pattern in hand, may not be sufficient for targeted, known mutation analysis in other family members.

Dissection of complex adult traits in a mouse synthetic population.

PubMed

Burke, David T; Kozloff, Kenneth M; Chen, Shu; West, Joshua L; Wilkowski, Jodi M; Goldstein, Steven A; Miller, Richard A; Galecki, Andrzej T

2012-08-01

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modest-sized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.

PubMed

Shamseldin, Hanan E; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S; Gleeson, Joseph G; Alkuraya, Fowzan S

2016-01-07

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants

PubMed Central

Zaitlen, Noah A.; Ye, Chun Jimmie; Witte, John S.

2016-01-01

The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature. PMID:27197206

Epilepsy with auditory features

PubMed Central

Licchetta, Laura; Baldassari, Sara; Palombo, Flavia; Menghi, Veronica; D'Aurizio, Romina; Leta, Chiara; Stipa, Carlotta; Boero, Giovanni; d'Orsi, Giuseppe; Magi, Alberto; Scheffer, Ingrid; Seri, Marco; Tinuper, Paolo; Bisulli, Francesca

2015-01-01

Objective: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. Methods: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. Results: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. Conclusions: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence. PMID:27066544

The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications.

PubMed

Gillentine, M A; Berry, L N; Goin-Kochel, R P; Ali, M A; Ge, J; Guffey, D; Rosenfeld, J A; Hannig, V; Bader, P; Proud, M; Shinawi, M; Graham, B H; Lin, A; Lalani, S R; Reynolds, J; Chen, M; Grebe, T; Minard, C G; Stankiewicz, P; Beaudet, A L; Schaaf, C P

2017-03-01

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

Neurocognitive Allied Phenotypes for Schizophrenia and Bipolar Disorder

PubMed Central

Hill, S. Kristian; Harris, Margret S. H.; Herbener, Ellen S.; Pavuluri, Mani; Sweeney, John A.

2008-01-01

Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed. PMID:18448479

Whole genome sequencing of one complex pedigree illustrates challenges with genomic medicine.

PubMed

Fang, Han; Wu, Yiyang; Yang, Hui; Yoon, Margaret; Jiménez-Barrón, Laura T; Mittelman, David; Robison, Reid; Wang, Kai; Lyon, Gholson J

2017-02-23

Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; however, there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants. We illustrate an integrative analysis of WGS and HPO using an extended pedigree, which involves Prader-Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. A comprehensive WGS pipeline was used to ensure reliable detection of genomic variants. Beyond variant filtering, we pursued phenotypic prioritization of candidate genes using Phenolyzer. Regarding PWS, WGS confirmed a 5.5 Mb de novo deletion of the parental allele at 15q11.2 to 15q13.1. Phenolyzer successfully returned the diagnosis of PWS, and pinpointed clinically relevant genes in the deletion. Further, Phenolyzer revealed how each of the genes is linked with the phenotypes represented by HPO terms. For HH, WGS identified a known disease variant (p.C282Y) in HFE of an affected female. Analysis of HPO terms alone fails to provide a correct diagnosis, but Phenolyzer successfully revealed the phenotype-genotype relationship using a disease-centric approach. Finally, Phenolyzer also revealed the complexity behind dysautonomia-like symptoms, and seven variants that might be associated with the phenotypes were identified by manual filtering based on a dominant inheritance model. The integration of WGS and HPO can inform comprehensive molecular diagnosis for patients, eliminate false positives and reveal novel insights into undiagnosed diseases. Due to extreme heterogeneity and insufficient knowledge of human diseases, it is also important that phenotypic and genomic data are standardized and shared simultaneously.

Novel autosomal dominant mandibulofacial dysostosis with ptosis: clinical description and exclusion of TCOF1

PubMed Central

Hedera, P; Toriello, H; Petty, E

2002-01-01

Methods: Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype. Results: Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal. Conclusions: We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype. PMID:12114479

Extent of QTL Reuse During Repeated Phenotypic Divergence of Sympatric Threespine Stickleback.

PubMed

Conte, Gina L; Arnegard, Matthew E; Best, Jacob; Chan, Yingguang Frank; Jones, Felicity C; Kingsley, David M; Schluter, Dolph; Peichel, Catherine L

2015-11-01

How predictable is the genetic basis of phenotypic adaptation? Answering this question begins by estimating the repeatability of adaptation at the genetic level. Here, we provide a comprehensive estimate of the repeatability of the genetic basis of adaptive phenotypic evolution in a natural system. We used quantitative trait locus (QTL) mapping to discover genomic regions controlling a large number of morphological traits that have diverged in parallel between pairs of threespine stickleback (Gasterosteus aculeatus species complex) in Paxton and Priest lakes, British Columbia. We found that nearly half of QTL affected the same traits in the same direction in both species pairs. Another 40% influenced a parallel phenotypic trait in one lake but not the other. The remaining 10% of QTL had phenotypic effects in opposite directions in the two species pairs. Similarity in the proportional contributions of all QTL to parallel trait differences was about 0.4. Surprisingly, QTL reuse was unrelated to phenotypic effect size. Our results indicate that repeated use of the same genomic regions is a pervasive feature of parallel phenotypic adaptation, at least in sticklebacks. Identifying the causes of this pattern would aid prediction of the genetic basis of phenotypic evolution. Copyright © 2015 by the Genetics Society of America.

A targeted genetic modifier screen links the SWI2/SNF2 protein domino to growth and autophagy genes in Drosophila melanogaster.

PubMed

Kwon, Matt Hyoung; Callaway, Heather; Zhong, Jim; Yedvobnick, Barry

2013-05-20

Targeted genetic studies can facilitate phenotypic analyses and provide important insights into development and other complex processes. The SWI2/SNF2 DNA-dependent ATPase Domino (Dom) of Drosophila melanogaster, a component of the Tip60 acetyltransferase complex, has been associated with a wide spectrum of cellular processes at multiple developmental stages. These include hematopoiesis, cell proliferation, homeotic gene regulation, histone exchange during DNA repair, and Notch signaling. To explore the wider gene network associated with Dom action, we used RNAi directed against domino (dom) to mediate loss-of-function at the wing margin, a tissue that is readily scored for phenotypic changes. Dom RNAi driven through GAL4-UAS elicited dominant wing nicking that responded phenotypically to the dose of dom and other loci known to function with dom. We screened for phenotypic modifiers of this wing phenotype among 2500 transpositions of the EP P element and found both enhancers and suppressors. Several classes of modifier were obtained, including those encoding transcription factors, RNA regulatory proteins, and factors that regulate cell growth, proliferation and autophagy, a lysosomal degradation pathway that affects cell growth under conditions of starvation and stress. Our analysis is consistent with prior studies, suggesting that Dom acts pleiotropically as a positive effector of Notch signaling and a repressor of proliferation. This genetic system should facilitate screens for additional loci associated with Dom function, and complement biochemical approaches to their regulatory activity.

Large-scale image-based profiling of single-cell phenotypes in arrayed CRISPR-Cas9 gene perturbation screens.

PubMed

de Groot, Reinoud; Lüthi, Joel; Lindsay, Helen; Holtackers, René; Pelkmans, Lucas

2018-01-23

High-content imaging using automated microscopy and computer vision allows multivariate profiling of single-cell phenotypes. Here, we present methods for the application of the CISPR-Cas9 system in large-scale, image-based, gene perturbation experiments. We show that CRISPR-Cas9-mediated gene perturbation can be achieved in human tissue culture cells in a timeframe that is compatible with image-based phenotyping. We developed a pipeline to construct a large-scale arrayed library of 2,281 sequence-verified CRISPR-Cas9 targeting plasmids and profiled this library for genes affecting cellular morphology and the subcellular localization of components of the nuclear pore complex (NPC). We conceived a machine-learning method that harnesses genetic heterogeneity to score gene perturbations and identify phenotypically perturbed cells for in-depth characterization of gene perturbation effects. This approach enables genome-scale image-based multivariate gene perturbation profiling using CRISPR-Cas9. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities.

PubMed

Dansault, Anouk; David, Gabriel; Schwartz, Claire; Jaliffa, Carolina; Vieira, Véronique; de la Houssaye, Guillaume; Bigot, Karine; Catin, Françise; Tattu, Laurent; Chopin, Catherine; Halimi, Philippe; Roche, Olivier; Van Regemorter, Nicole; Munier, Francis; Schorderet, Daniel; Dufier, Jean-Louis; Marsac, Cécile; Ricquier, Daniel; Menasche, Maurice; Penfornis, Alfred; Abitbol, Marc

2007-04-02

The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic remains to be demonstrated. Two previously known heterozygous mutations of the PAX6 gene sequence were also detected in patients affected by aniridia: a de novo previously known nucleotide change, g.972C>T (Q179X), in exon 8, leading to a stop codon and a heterozygous g.555C>A (C40X) recurrent nonsense mutation in exon 5. No mutations were found in patients with Peters' anomaly. We identified three mutations associated with aniridia phenotypes (Q179X, C40X, and V48fsX53). The three other mutations reported here cause non-aniridia ocular phenotypes associated in some cases with neurological anomalies. The IVS2+9G>A nucleotide change was detected in a patient with a microphthalmia phenotype. The L46P mutation was detected in a family with microphthalmia, cataract, and nystagmus. This mutation is located in the DNA-binding paired-domain and the crystallographic representations of this mutation show that this mutation may affect the helix-turn-helix motif, and as a consequence the DNA-binding properties of the resulting mutated protein. Ser74 is located in the PAX6 PD linker region, essential for DNA recognition and DNA binding, and the side chain of the Ser74 contributes to DNA recognition by the linker domain through direct contacts. Crystallographic representations show that the S74G mutation results in no side chain and therefore perturbs the DNA-binding properties of PAX6. This study highlights the severity and diversity of the consequences of PAX6 mutations that appeared to result from the complexity of the PAX6 gene structure, and the numerous possibilities for DNA binding. This study emphasizes the fact that neurodevelopmental abnormalities may be caused by PAX6 mutations. The neuro-developmental abnormalities caused by PAX6 mutations are probably still overlooked in the current clinical examinations performed throughout the world in patients affected by PAX6 mutations.

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities

PubMed Central

Dansault, Anouk; David, Gabriel; Schwartz, Claire; Jaliffa, Carolina; Vieira, Véronique; de la Houssaye, Guillaume; Bigot, Karine; Catin, Françise; Tattu, Laurent; Chopin, Catherine; Halimi, Philippe; Roche, Olivier; Van Regemorter, Nicole; Munier, Francis; Schorderet, Daniel; Dufier, Jean-Louis; Marsac, Cécile; Ricquier, Daniel; Menasche, Maurice; Penfornis, Alfred

2007-01-01

Purpose The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. Methods Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. Results Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic remains to be demonstrated. Two previously known heterozygous mutations of the PAX6 gene sequence were also detected in patients affected by aniridia: a de novo previously known nucleotide change, g.972C>T (Q179X), in exon 8, leading to a stop codon and a heterozygous g.555C>A (C40X) recurrent nonsense mutation in exon 5. No mutations were found in patients with Peters' anomaly. Conclusions We identified three mutations associated with aniridia phenotypes (Q179X, C40X, and V48fsX53). The three other mutations reported here cause non-aniridia ocular phenotypes associated in some cases with neurological anomalies. The IVS2+9G>A nucleotide change was detected in a patient with a microphthalmia phenotype. The L46P mutation was detected in a family with microphthalmia, cataract, and nystagmus. This mutation is located in the DNA-binding paired-domain and the crystallographic representations of this mutation show that this mutation may affect the helix-turn-helix motif, and as a consequence the DNA-binding properties of the resulting mutated protein. Ser74 is located in the PAX6 PD linker region, essential for DNA recognition and DNA binding, and the side chain of the Ser74 contributes to DNA recognition by the linker domain through direct contacts. Crystallographic representations show that the S74G mutation results in no side chain and therefore perturbs the DNA-binding properties of PAX6. This study highlights the severity and diversity of the consequences of PAX6 mutations that appeared to result from the complexity of the PAX6 gene structure, and the numerous possibilities for DNA binding. This study emphasizes the fact that neurodevelopmental abnormalities may be caused by PAX6 mutations. The neuro-developmental abnormalities caused by PAX6 mutations are probably still overlooked in the current clinical examinations performed throughout the world in patients affected by PAX6 mutations. PMID:17417613

Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes.

PubMed

Torraco, Alessandra; Ardissone, Anna; Invernizzi, Federica; Rizza, Teresa; Fiermonte, Giuseppe; Niceta, Marcello; Zanetti, Nadia; Martinelli, Diego; Vozza, Angelo; Verrigni, Daniela; Di Nottia, Michela; Lamantea, Eleonora; Diodato, Daria; Tartaglia, Marco; Dionisi-Vici, Carlo; Moroni, Isabella; Farina, Laura; Bertini, Enrico; Ghezzi, Daniele; Carrozzo, Rosalba

2017-01-01

Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.

Genetic constraints on wing pattern variation in Lycaeides butterflies: A case study on mapping complex, multifaceted traits in structured populations.

PubMed

Lucas, Lauren K; Nice, Chris C; Gompert, Zachariah

2018-03-13

Patterns of phenotypic variation within and among species can be shaped and constrained by trait genetic architecture. This is particularly true for complex traits, such as butterfly wing patterns, that consist of multiple elements. Understanding the genetics of complex trait variation across species boundaries is difficult, as it necessitates mapping in structured populations and can involve many loci with small or variable phenotypic effects. Here, we investigate the genetic architecture of complex wing pattern variation in Lycaeides butterflies as a case study of mapping multivariate traits in wild populations that include multiple nominal species or groups. We identify conserved modules of integrated wing pattern elements within populations and species. We show that trait covariances within modules have a genetic basis and thus represent genetic constraints that can channel evolution. Consistent with this, we find evidence that evolutionary changes in wing patterns among populations and species occur in the directions of genetic covariances within these groups. Thus, we show that genetic constraints affect patterns of biological diversity (wing pattern) in Lycaeides, and we provide an analytical template for similar work in other systems. © 2018 John Wiley & Sons Ltd.

A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers

PubMed Central

Ji, Fei; Lee, Dayoung; Mendell, Nancy Role

2005-01-01

Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait. PMID:16451570

A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers.

PubMed

Ji, Fei; Lee, Dayoung; Mendell, Nancy Role

2005-12-30

Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait.

FISHER'S GEOMETRIC MODEL WITH A MOVING OPTIMUM

PubMed Central

Matuszewski, Sebastian; Hermisson, Joachim; Kopp, Michael

2014-01-01

Fisher's geometric model has been widely used to study the effects of pleiotropy and organismic complexity on phenotypic adaptation. Here, we study a version of Fisher's model in which a population adapts to a gradually moving optimum. Key parameters are the rate of environmental change, the dimensionality of phenotype space, and the patterns of mutational and selectional correlations. We focus on the distribution of adaptive substitutions, that is, the multivariate distribution of the phenotypic effects of fixed beneficial mutations. Our main results are based on an “adaptive-walk approximation,” which is checked against individual-based simulations. We find that (1) the distribution of adaptive substitutions is strongly affected by the ecological dynamics and largely depends on a single composite parameter γ, which scales the rate of environmental change by the “adaptive potential” of the population; (2) the distribution of adaptive substitution reflects the shape of the fitness landscape if the environment changes slowly, whereas it mirrors the distribution of new mutations if the environment changes fast; (3) in contrast to classical models of adaptation assuming a constant optimum, with a moving optimum, more complex organisms evolve via larger adaptive steps. PMID:24898080

Obstructive Sleep Apnea Syndrome: From Phenotype to Genetic Basis

PubMed Central

Casale, M; Pappacena, M; Rinaldi, V; Bressi, F; Baptista, P; Salvinelli, F

2009-01-01

Obstructive sleep apnea syndrome (OSAS) is a complex chronic clinical syndrome, characterized by snoring, periodic apnea, hypoxemia during sleep, and daytime hypersomnolence. It affects 4-5% of the general population. Racial studies and chromosomal mapping, familial studies and twin studies have provided evidence for the possible link between the OSAS and genetic factors and also most of the risk factors involved in the pathogenesis of OSAS are largely genetically determined. A percentage of 35-40% of its variance can be attributed to genetic factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAS phenotype. Although the role of specific genes that influence the development of OSAS has not yet been identified, current researches, especially in animal model, suggest that several genetic systems may be important. In this chapter, we will first define the OSAS phenotype, the pathogenesis and the risk factors involved in the OSAS that may be inherited, then, we will review the current progress in the genetics of OSAS and suggest a few future perspectives in the development of therapeutic agents for this complex disease entity. PMID:19794884

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants.

PubMed

Uricchio, Lawrence H; Zaitlen, Noah A; Ye, Chun Jimmie; Witte, John S; Hernandez, Ryan D

2016-07-01

The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature. © 2016 Uricchio et al.; Published by Cold Spring Harbor Laboratory Press.

The genotype-phenotype map of an evolving digital organism.

PubMed

Fortuna, Miguel A; Zaman, Luis; Ofria, Charles; Wagner, Andreas

2017-02-01

To understand how evolving systems bring forth novel and useful phenotypes, it is essential to understand the relationship between genotypic and phenotypic change. Artificial evolving systems can help us understand whether the genotype-phenotype maps of natural evolving systems are highly unusual, and it may help create evolvable artificial systems. Here we characterize the genotype-phenotype map of digital organisms in Avida, a platform for digital evolution. We consider digital organisms from a vast space of 10141 genotypes (instruction sequences), which can form 512 different phenotypes. These phenotypes are distinguished by different Boolean logic functions they can compute, as well as by the complexity of these functions. We observe several properties with parallels in natural systems, such as connected genotype networks and asymmetric phenotypic transitions. The likely common cause is robustness to genotypic change. We describe an intriguing tension between phenotypic complexity and evolvability that may have implications for biological evolution. On the one hand, genotypic change is more likely to yield novel phenotypes in more complex organisms. On the other hand, the total number of novel phenotypes reachable through genotypic change is highest for organisms with simple phenotypes. Artificial evolving systems can help us study aspects of biological evolvability that are not accessible in vastly more complex natural systems. They can also help identify properties, such as robustness, that are required for both human-designed artificial systems and synthetic biological systems to be evolvable.

The genotype-phenotype map of an evolving digital organism

PubMed Central

Zaman, Luis; Wagner, Andreas

2017-01-01

To understand how evolving systems bring forth novel and useful phenotypes, it is essential to understand the relationship between genotypic and phenotypic change. Artificial evolving systems can help us understand whether the genotype-phenotype maps of natural evolving systems are highly unusual, and it may help create evolvable artificial systems. Here we characterize the genotype-phenotype map of digital organisms in Avida, a platform for digital evolution. We consider digital organisms from a vast space of 10141 genotypes (instruction sequences), which can form 512 different phenotypes. These phenotypes are distinguished by different Boolean logic functions they can compute, as well as by the complexity of these functions. We observe several properties with parallels in natural systems, such as connected genotype networks and asymmetric phenotypic transitions. The likely common cause is robustness to genotypic change. We describe an intriguing tension between phenotypic complexity and evolvability that may have implications for biological evolution. On the one hand, genotypic change is more likely to yield novel phenotypes in more complex organisms. On the other hand, the total number of novel phenotypes reachable through genotypic change is highest for organisms with simple phenotypes. Artificial evolving systems can help us study aspects of biological evolvability that are not accessible in vastly more complex natural systems. They can also help identify properties, such as robustness, that are required for both human-designed artificial systems and synthetic biological systems to be evolvable. PMID:28241039

A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome

PubMed Central

Alves, Leandro Ucela; Pardono, Eliete; Otto, Paulo A.; Mingroni Netto, Regina Célia

2015-01-01

Ectrodactyly – ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292) is a rare disorder determined by mutations in the TP63 gene. Most cases of EEC syndrome are associated to mutations in the DNA binding domain (DBD) region of the p63 protein. Here we report on a three-generation Brazilian family with three individuals (mother, son and grandfather) affected by EEC syndrome, determined by a novel mutation c.1037C > G (p.Ala346Gly). The disorder in this family exhibits a broad spectrum of phenotypes: two individuals were personally examined, one presenting the complete constellation of EEC syndrome manifestations and the other presenting an intermediate phenotype; the third affected, a deceased individual not examined personally and referred to by his daughter, exhibited only the split-hand/foot malformation (SHFM). Our findings contribute to elucidate the complex phenotype-genotype correlations in EEC syndrome and other related TP63-mutation syndromes. The possibility of the mutation c.1037C > G being related both to acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and SHFM is also raised by the findings here reported. PMID:25983622

Integration of Network Biology and Imaging to Study Cancer Phenotypes and Responses.

PubMed

Tian, Ye; Wang, Sean S; Zhang, Zhen; Rodriguez, Olga C; Petricoin, Emanuel; Shih, Ie-Ming; Chan, Daniel; Avantaggiati, Maria; Yu, Guoqiang; Ye, Shaozhen; Clarke, Robert; Wang, Chao; Zhang, Bai; Wang, Yue; Albanese, Chris

2014-01-01

Ever growing "omics" data and continuously accumulated biological knowledge provide an unprecedented opportunity to identify molecular biomarkers and their interactions that are responsible for cancer phenotypes that can be accurately defined by clinical measurements such as in vivo imaging. Since signaling or regulatory networks are dynamic and context-specific, systematic efforts to characterize such structural alterations must effectively distinguish significant network rewiring from random background fluctuations. Here we introduced a novel integration of network biology and imaging to study cancer phenotypes and responses to treatments at the molecular systems level. Specifically, Differential Dependence Network (DDN) analysis was used to detect statistically significant topological rewiring in molecular networks between two phenotypic conditions, and in vivo Magnetic Resonance Imaging (MRI) was used to more accurately define phenotypic sample groups for such differential analysis. We applied DDN to analyze two distinct phenotypic groups of breast cancer and study how genomic instability affects the molecular network topologies in high-grade ovarian cancer. Further, FDA-approved arsenic trioxide (ATO) and the ND2-SmoA1 mouse model of Medulloblastoma (MB) were used to extend our analyses of combined MRI and Reverse Phase Protein Microarray (RPMA) data to assess tumor responses to ATO and to uncover the complexity of therapeutic molecular biology.

Genotypic Complexity of Fisher’s Geometric Model

PubMed Central

Hwang, Sungmin; Park, Su-Chan; Krug, Joachim

2017-01-01

Fisher’s geometric model was originally introduced to argue that complex adaptations must occur in small steps because of pleiotropic constraints. When supplemented with the assumption of additivity of mutational effects on phenotypic traits, it provides a simple mechanism for the emergence of genotypic epistasis from the nonlinear mapping of phenotypes to fitness. Of particular interest is the occurrence of reciprocal sign epistasis, which is a necessary condition for multipeaked genotypic fitness landscapes. Here we compute the probability that a pair of randomly chosen mutations interacts sign epistatically, which is found to decrease with increasing phenotypic dimension n, and varies nonmonotonically with the distance from the phenotypic optimum. We then derive expressions for the mean number of fitness maxima in genotypic landscapes comprised of all combinations of L random mutations. This number increases exponentially with L, and the corresponding growth rate is used as a measure of the complexity of the landscape. The dependence of the complexity on the model parameters is found to be surprisingly rich, and three distinct phases characterized by different landscape structures are identified. Our analysis shows that the phenotypic dimension, which is often referred to as phenotypic complexity, does not generally correlate with the complexity of fitness landscapes and that even organisms with a single phenotypic trait can have complex landscapes. Our results further inform the interpretation of experiments where the parameters of Fisher’s model have been inferred from data, and help to elucidate which features of empirical fitness landscapes can be described by this model. PMID:28450460

A Homozygous Nme7 Mutation Is Associated with Situs Inversus Totalis.

PubMed

Reish, Orit; Aspit, Liam; Zouella, Arielle; Roth, Yehudah; Polak-Charcon, Sylvie; Baboushkin, Tatiana; Benyamini, Lilach; Scheetz, Todd E; Mussaffi, Huda; Sheffield, Val C; Parvari, Ruti

2016-08-01

We investigated the cause of situs inversus totalis (SIT) in two siblings from a consanguineous family. Genotyping and whole-exome analysis revealed a homozygous change in NME7, resulting in deletion of an exon causing an in-frame deletion of 34 amino acids located in the second NDK domain of the protein and segregated with the defective lateralization in the family. NME7 is an important developmental gene, and NME7 protein is a component of the γ-tubulin ring complex. This mutation is predicted to affect the interaction of NME7 protein with this complex as it deletes the amino acids crucial for the binding. SIT associated with homozygous deletion in our patients is in line with Nme7(-/-) mutant mice phenotypes consisting of congenital hydrocephalus and SIT, indicating a novel human laterality patterning role for NME7. Further cases are required to elaborate the full human phenotype associated with NME7 mutations. © 2016 WILEY PERIODICALS, INC.

Regulation of pH During Amelogenesis.

PubMed

Lacruz, Rodrigo S; Nanci, Antonio; Kurtz, Ira; Wright, J Timothy; Paine, Michael L

2010-02-01

During amelogenesis, extracellular matrix proteins interact with growing hydroxyapatite crystals to create one of the most architecturally complex biological tissues. The process of enamel formation is a unique biomineralizing system characterized first by an increase in crystallite length during the secretory phase of amelogenesis, followed by a vast increase in crystallite width and thickness in the later maturation phase when organic complexes are enzymatically removed. Crystal growth is modulated by changes in the pH of the enamel microenvironment that is critical for proper enamel biomineralization. Whereas the genetic bases for most abnormal enamel phenotypes (amelogenesis imperfecta) are generally associated with mutations to enamel matrix specific genes, mutations to genes involved in pH regulation may result in severely affected enamel structure, highlighting the importance of pH regulation for normal enamel development. This review summarizes the intra- and extracellular mechanisms employed by the enamel-forming cells, ameloblasts, to maintain pH homeostasis and, also, discusses the enamel phenotypes associated with disruptions to genes involved in pH regulation.

Early developmental gene enhancers affect subcortical volumes in the adult human brain.

PubMed

Becker, Martin; Guadalupe, Tulio; Franke, Barbara; Hibar, Derrek P; Renteria, Miguel E; Stein, Jason L; Thompson, Paul M; Francks, Clyde; Vernes, Sonja C; Fisher, Simon E

2016-05-01

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish.

PubMed

Signore, Iskra A; Jerez, Carolina; Figueroa, Diego; Suazo, José; Marcelain, Katherine; Cerda, Oscar; Colombo Flores, Alicia

2016-10-01

Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814-830, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Adrenal cortex expression quantitative trait loci in a German Holstein × Charolais cross.

PubMed

Brand, Bodo; Scheinhardt, Markus O; Friedrich, Juliane; Zimmer, Daisy; Reinsch, Norbert; Ponsuksili, Siriluck; Schwerin, Manfred; Ziegler, Andreas

2016-10-06

The importance of the adrenal gland in regard to lactation and reproduction in cattle has been recognized early. Caused by interest in animal welfare and the impact of stress on economically important traits in farm animals the adrenal gland and its function within the stress response is of increasing interest. However, the molecular mechanisms and pathways involved in stress-related effects on economically important traits in farm animals are not fully understood. Gene expression is an important mechanism underlying complex traits, and genetic variants affecting the transcript abundance are thought to influence the manifestation of an expressed phenotype. We therefore investigated the genetic background of adrenocortical gene expression by applying an adaptive linear rank test to identify genome-wide expression quantitative trait loci (eQTL) for adrenal cortex transcripts in cattle. A total of 10,986 adrenal cortex transcripts and 37,204 single nucleotide polymorphisms (SNPs) were analysed in 145 F2 cows of a Charolais × German Holstein cross. We identified 505 SNPs that were associated with the abundance of 129 transcripts, comprising 482 cis effects and 17 trans effects. These SNPs were located on all chromosomes but X, 16, 24 and 28. Associated genes are mainly involved in molecular and cellular functions comprising free radical scavenging, cellular compromise, cell morphology and lipid metabolism, including genes such as CYP27A1 and LHCGR that have been shown to affect economically important traits in cattle. In this study we showed that adrenocortical eQTL affect the expression of genes known to contribute to the phenotypic manifestation in cattle. Furthermore, some of the identified genes and related molecular pathways were previously shown to contribute to the phenotypic variation of behaviour, temperament and growth at the onset of puberty in the same population investigated here. We conclude that eQTL analysis appears to be a useful approach providing insight into the molecular and genetic background of complex traits in cattle and will help to understand molecular networks involved.

Phenotypes and enviromental factors: their influence in PCOS.

PubMed

Diamanti-Kandarakis, Evanthia; Christakou, Charikleia; Marinakis, Evangelos

2012-01-01

Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals.

The lavender plumage colour in Japanese quail is associated with a complex mutation in the region of MLPH that is related to differences in growth, feed consumption and body temperature

PubMed Central

2012-01-01

Background The lavender phenotype in quail is a dilution of both eumelanin and phaeomelanin in feathers that produces a blue-grey colour on a wild-type feather pattern background. It has been previously demonstrated by intergeneric hybridization that the lavender mutation in quail is homologous to the same phenotype in chicken, which is caused by a single base-pair change in exon 1 of MLPH. Results In this study, we have shown that a mutation of MLPH is also associated with feather colour dilution in quail, but that the mutational event is extremely different. In this species, the lavender phenotype is associated with a non-lethal complex mutation involving three consecutive overlapping chromosomal changes (two inversions and one deletion) that have consequences on the genomic organization of four genes (MLPH and the neighbouring PRLH, RAB17 and LRRFIP1). The deletion of PRLH has no effect on the level of circulating prolactin. Lavender birds have lighter body weight, lower body temperature and increased feed consumption and residual feed intake than wild-type plumage quail, indicating that this complex mutation is affecting the metabolism and the regulation of homeothermy. Conclusions An extensive overlapping chromosome rearrangement was associated with a non-pathological Mendelian trait and minor, non deleterious effects in the lavender Japanese quail which is a natural knockout for PRLH. PMID:22937744

Good Epidemiologic Practice in Retinitis Pigmentosa: From Phenotyping to Biobanking

PubMed Central

Chizzolini, Marzio; Galan, Alessandro; Milan, Elisabeth; Sebastiani, Adolfo; Costagliola, Ciro; Parmeggiani, Francesco

2011-01-01

Inherited retinal dystrophies, such as retinitis pigmentosa (RP), include a group of relatively rare hereditary diseases caused by mutations in genes that code for proteins involved in the maintenance and function of the photoreceptor cells (cones and rods). The different forms of RP consist of progressive neurodegenerative disorders which are generally related to various and severe limitations of visual performances. In the course of typical RP (rod-cone dystrophy), the affected individuals first experience night-blindness and/or visual field constriction (secondary to rod dysfunctions), followed by variable alterations of the central vision (due to cone damages). On the other hand, during the atypical form of RP (cone-rod dystrophy), the cone’s functionalities are prevalently disrupted in comparison with the rod’s ones. The basic diagnosis of RP relies upon the documentation of unremitting loss in photoreceptor activity by electroretinogram and/or visual field testing. The prevalence of all RP typologies is variably reported in about one case for each 3000-5000 individuals, with a total of about two millions of affected persons worldwide. The inherited retinal dystrophies are sometimes the epiphenomenon of a complex framework (syndromic RP), but more often they represent an isolated disorder (about 85-90 % of cases). Although 200 causative RP mutations have been hitherto detected in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the analyzed patients with RP. Not only the RP genotypes are very heterogeneous, but also the patients with the same mutation can be affected by different phenotypic manifestations. RP can be inherited as autosomal dominant, autosomal recessive or X-linked trait, and many sporadic forms are diagnosed in patients with no affected relatives. Dissecting the clinico-genetic complexity of RP has become an attainable objective by means of large-scale research projects, in which the collaboration between ophthalmologists, geneticists, and epidemiologists becomes a crucial aspect. In the present review, the main issues regarding clinical phenotyping and epidemiologic criticisms of RP are focused, especially highlighting the importance of both standardization of the diagnostic protocols and appropriateness of the disease’s registration systems. PMID:22131871

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

PubMed

Horvath, Rita; Hudson, Gavin; Ferrari, Gianfrancesco; Fütterer, Nancy; Ahola, Sofia; Lamantea, Eleonora; Prokisch, Holger; Lochmüller, Hanns; McFarland, Robert; Ramesh, V; Klopstock, Thomas; Freisinger, Peter; Salvi, Fabrizio; Mayr, Johannes A; Santer, Rene; Tesarova, Marketa; Zeman, Jiri; Udd, Bjarne; Taylor, Robert W; Turnbull, Douglass; Hanna, Michael; Fialho, Doreen; Suomalainen, Anu; Zeviani, Massimo; Chinnery, Patrick F

2006-07-01

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Rearing environment influences boldness and prey acquisition behavior, and brain and lens development of bull trout

USGS Publications Warehouse

Brignon, William R.; Pike, Martin M.; Ebbesson, Lars O.E.; Schaller, Howard A.; Peterson, James T.; Schreck, Carl B.

2018-01-01

Animals reared in barren captive environments exhibit different developmental trajectories and behaviors than wild counterparts. Hence, the captive phenotypes may influence the success of reintroduction and recovery programs for threatened and endangered species. We collected wild bull trout embryos from the Metolius River Basin, Oregon and reared them in differing environments to better understand how captivity affects the bull trout Salvelinus confluentusphenotype. We compared the boldness and prey acquisition behaviors and development of the brain and eye lens of bull trout reared in conventional barren and more structurally complex captive environments with that of wild fish. Wild fish and captive reared fish from complex habitats exhibited a greater level of boldness and prey acquisition ability, than fish reared in conventional captive environments. In addition, the eye lens of conventionally reared bull trout was larger than complex reared captive fish or same age wild fish. Interestingly, we detected wild fish had a smaller relative cerebellum than either captive reared treatment. Our results suggest that rearing fish in more complex captive environments can create a more wild-like phenotype than conventional rearing practices. A better understanding of the effects of captivity on the development and behavior of bull trout can inform rearing and reintroduction programs though prediction of the performance of released individuals.

Genetic and Genomic Analysis of a Fat Mass Trait with Complex Inheritance Reveals Marked Sex Specificity

PubMed Central

Wang, Hui; Drake, Thomas A; Lusis, Aldons J

2006-01-01

The integration of expression profiling with linkage analysis has increasingly been used to identify genes underlying complex phenotypes. The effects of gender on the regulation of many physiological traits are well documented; however, “genetical genomic” analyses have not yet addressed the degree to which their conclusions are affected by sex. We constructed and densely genotyped a large F2 intercross derived from the inbred mouse strains C57BL/6J and C3H/HeJ on an apolipoprotein E null (ApoE−/−) background. This BXH.ApoE−/− population recapitulates several “metabolic syndrome” phenotypes. The cross consists of 334 animals of both sexes, allowing us to specifically test for the dependence of linkage on sex. We detected several thousand liver gene expression quantitative trait loci, a significant proportion of which are sex-biased. We used these analyses to dissect the genetics of gonadal fat mass, a complex trait with sex-specific regulation. We present evidence for a remarkably high degree of sex-dependence on both the cis and trans regulation of gene expression. We demonstrate how these analyses can be applied to the study of the genetics underlying gonadal fat mass, a complex trait showing significantly female-biased heritability. These data have implications on the potential effects of sex on the genetic regulation of other complex traits. PMID:16462940

Chemical genomics: characterizing target pathways for bioactive compounds using the endomembrane trafficking network.

PubMed

Rodriguez-Furlán, Cecilia; Hicks, Glenn R; Norambuena, Lorena

2014-01-01

The plant endomembrane trafficking system is a highly complex set of processes. This complexity presents a challenge for its study. Classical plant genetics often struggles with loss-of-function lethality and gene redundancy. Chemical genomics allows overcoming many of these issues by using small molecules of natural or synthetic origin to inhibit specific trafficking proteins thereby affecting the processes in a tunable and reversible manner. Bioactive chemicals identified by high-throughput phenotype screens must be characterized in detail starting with understanding of the specific trafficking pathways affected. Here, we describe approaches to characterize bioactive compounds that perturb vesicle trafficking. This should equip researchers with practical knowledge on how to identify endomembrane-specific trafficking pathways that may be perturbed by specific compounds and will help to eventually identify molecular targets for these small molecules.

Complex Roads from Genotype to Phenotype in Dilated Cardiomyopathy: Scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

PubMed

Bondue, Antoine; Arbustini, Eloisa; Bianco, Anna M; Ciccarelli, Michele; Dawson, Dana; De Rosa, Matteo; Hamdani, Nazha; Hilfiker-Kleiner, Denise; Meder, Benjamin; Leite Moreira, Adelino; Thum, Thomas; Gabriele Tocchetti, Carlo; Varricchi, Gilda; Van der Velden, Jolanda; Walsh, Roddy; Heymans, Stephane

2018-05-23

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance -malignancy of the mutated gene- but also on epigenetics, age, toxic factors, pregnancy and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN) or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

PubMed

Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

2017-03-01

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

RNAi pathways contribute to developmental history-dependent phenotypic plasticity in C. elegans

PubMed Central

Hall, Sarah E.; Chirn, Gung-Wei; Lau, Nelson C.; Sengupta, Piali

2013-01-01

Early environmental experiences profoundly influence adult phenotypes through complex mechanisms that are poorly understood. We previously showed that adult Caenorhabditis elegans that transiently passed through the stress-induced dauer larval stage (post-dauer adults) exhibit significant changes in gene expression profiles, chromatin states, and life history traits when compared with adults that bypassed the dauer stage (control adults). These wild-type, isogenic animals of equivalent developmental stages exhibit different signatures of molecular marks that reflect their distinct developmental trajectories. To gain insight into the mechanisms that contribute to these developmental history-dependent phenotypes, we profiled small RNAs from post-dauer and control adults by deep sequencing. RNA interference (RNAi) pathways are known to regulate genome-wide gene expression both at the chromatin and post-transcriptional level. By quantifying changes in endogenous small interfering RNA (endo-siRNA) levels in post-dauer as compared with control animals, our analyses identified a subset of genes that are likely targets of developmental history-dependent reprogramming through a complex RNAi-mediated mechanism. Mutations in specific endo-siRNA pathways affect expected gene expression and chromatin state changes for a subset of genes in post-dauer animals, as well as disrupt their increased brood size phenotype. We also find that both chromatin state and endo-siRNA distribution in dauers are unique, and suggest that remodeling in dauers provides a template for the subsequent establishment of adult post-dauer profiles. Our results indicate a role for endo-siRNA pathways as a contributing mechanism to early experience-dependent phenotypic plasticity in adults, and describe how developmental history can program adult physiology and behavior via epigenetic mechanisms. PMID:23329696

Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

PubMed Central

Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian; Daga, Ankana; LeBerre, Tamara Basta; Matejas, Verena; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T.; Gipson, Patrick E.; Hsu, Chyong-Hsin; Kari, Jameela A.; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okasha; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A.; Tsai, Wen-Hui; Tsai, Jeng-Daw; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wolf, Matthias T.F.; Wong, Sik-Nin; Poduri, Annapurna; Truglio, Gessica; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Calleweart, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

2018-01-01

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID:28805828

RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans

PubMed Central

Shamseldin, Hanan; Alazami, Anas M.; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A. Micheil; Parboosingh, Jillian S.; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P.; Alkuraya, Fowzan S.

2015-01-01

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963∗] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. PMID:26608784

Arabidopsis ILITHYIA protein is necessary for proper chloroplast biogenesis and root development independent of eIF2α phosphorylation.

PubMed

Faus, I; Niñoles, R; Kesari, V; Llabata, P; Tam, E; Nebauer, S G; Santiago, J; Hauser, M T; Gadea, J

One of the main mechanisms blocking translation after stress situations is mediated by phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2), performed in Arabidopsis by the protein kinase GCN2 which interacts and is activated by ILITHYIA(ILA). ILA is involved in plant immunity and its mutant lines present phenotypes not shared by the gcn2 mutants. The functional link between these two genes remains elusive in plants. In this study, we show that, although both ILA and GCN2 genes are necessary to mediate eIF2α phosphorylation upon treatments with the aromatic amino acid biosynthesis inhibitor glyphosate, their mutants develop distinct root and chloroplast phenotypes. Electron microscopy experiments reveal that ila mutants, but not gcn2, are affected in chloroplast biogenesis, explaining the macroscopic phenotype previously observed for these mutants. ila3 mutants present a complex transcriptional reprogramming affecting defense responses, photosynthesis and protein folding, among others. Double mutant analyses suggest that ILA has a distinct function which is independent of GCN2 and eIF2α phosphorylation. These results suggest that these two genes may have common but also distinct functions in Arabidopsis. Copyright © 2018 Elsevier GmbH. All rights reserved.

The molecular genetics of von Willebrand disease.

PubMed

Berber, Ergül

2012-12-01

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype.

PubMed

Fernandez, Bridget A; Green, Jane S; Bursey, Ford; Barrett, Brendan; MacMillan, Andrée; McColl, Sarah; Fernandez, Sara; Rahman, Proton; Mahoney, Krista; Pereira, Sergio L; Scherer, Stephen W; Boycott, Kym M; Woods, Michael O

2012-11-21

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with "partial OCA" in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury.

PubMed

Patsalos, Andreas; Pap, Attila; Varga, Tamas; Trencsenyi, Gyorgy; Contreras, Gerardo Alvarado; Garai, Ildiko; Papp, Zoltan; Dezso, Balazs; Pintye, Eva; Nagy, Laszlo

2017-09-01

The in situ phenotypic switch of macrophages is delayed in acute injury following irradiation. The combination of bone marrow transplantation and local muscle radiation protection allows for the identification of a myeloid cell contribution to tissue repair. PET-MRI allows monitoring of myeloid cell invasion and metabolism. Altered cellular composition prior to acute sterile injury affects the in situ phenotypic transition of invading myeloid cells to repair macrophages. There is reciprocal intercellular communication between local muscle cell compartments, such as PAX7 positive cells, and recruited macrophages during skeletal muscle regeneration. Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for clearance of necrotic debris and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6C high ) to a repair (Ly6C low ) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging, we show that preserved muscle integrity and cell composition prior to the injury is necessary for the repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions shape the macrophage in situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Analysis of epidemiological studies: facts and artifacts.

PubMed

Wright, Anne L

2002-09-01

Cohort studies have provided the foundation for much of our knowledge of childhood asthma. Four important lessons have been learned from these longitudinal studies: that asthma is a complex disease, encompassing many phenotypes; that it is linked to the development of the immune system and respiratory tract in the first years of life; that early life events strongly affect the development of asthma risk and that relationships between certain exposures and asthma risk are age dependent. The Tucson Children's Respiratory Study is used to exemplify these lessons and to illustrate the advantages of cohort studies in investigating a complex disease. Copyright 2002 Elsevier Science Ltd.

The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes.

PubMed

Karaa, Amel; Goldstein, Amy

2015-02-01

Primary mitochondrial diseases refer to a group of heterogeneous and complex genetic disorders affecting 1:5000 people. The true prevalence is anticipated to be even higher because of the complexity of achieving a diagnosis in many patients who present with multisystemic complaints ranging from infancy to adulthood. Diabetes is a prominent feature of several of these disorders which might be overlooked by the endocrinologist. We here review mitochondrial disorders and describe the phenotypic and pathogenetic differences between mitochondrial diabetes mellitus (mDM) and other more common forms of diabetes mellitus. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A cadmium-sensitive, glutathione-deficient mutant of Arabidopsis thaliana.

PubMed Central

Howden, R; Andersen, C R; Goldsbrough, P B; Cobbett, C S

1995-01-01

The roots of the cadmium-sensitive mutant of Arabidopsis thaliana, cad1-1, become brown in the presence of cadmium. A new cadmium-sensitive mutant affected at a second locus, cad2, has been identified using this phenotype. Genetic analysis has grown that the sensitive phenotype is recessive to the wild type and segregates as a single Mendelian locus. Assays of cadmium accumulation by intact plants indicated that the mutant is deficient in its ability to sequester cadmium. Undifferentiated callus tissue was also cadmium sensitive, suggesting that the mutant phenotype is expressed at the cellular level. The level of cadmium-binding complexes formed in vivo was decreased compared with the wild type and accumulation of phytochelatins was about 10% of that in the wild type. The level of glutathione, the substrate for phytochelatin biosynthesis, in tissues of the mutant was decreased to about 15 to 30% of that in the wild type. Thus, the deficiency in phytochelatin biosynthesis can be explained by a deficiency in glutathione. PMID:7770518

TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies.

PubMed

Powell, Christopher A; Kopajtich, Robert; D'Souza, Aaron R; Rorbach, Joanna; Kremer, Laura S; Husain, Ralf A; Dallabona, Cristina; Donnini, Claudia; Alston, Charlotte L; Griffin, Helen; Pyle, Angela; Chinnery, Patrick F; Strom, Tim M; Meitinger, Thomas; Rodenburg, Richard J; Schottmann, Gudrun; Schuelke, Markus; Romain, Nadine; Haller, Ronald G; Ferrero, Ileana; Haack, Tobias B; Taylor, Robert W; Prokisch, Holger; Minczuk, Michal

2015-08-06

Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history of exercise intolerance. Mutations in TRMT5 were associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA; this hypomodification was particularly prominent in skeletal muscle. Deficiency of the G37 modification was also detected in human cells subjected to TRMT5 RNAi. The pathogenicity of the detected variants was further confirmed in a heterologous yeast model and by the rescue of the molecular phenotype after re-expression of wild-type TRMT5 cDNA in cells derived from the affected individuals. Our study highlights the importance of post-transcriptional modification of mitochondrial tRNAs for faithful mitochondrial function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Ploidy-Regulated Variation in Biofilm-Related Phenotypes in Natural Isolates of Saccharomyces cerevisiae

PubMed Central

Hope, Elyse A.; Dunham, Maitreya J.

2014-01-01

The ability of yeast to form biofilms contributes to better survival under stressful conditions. We see the impact of yeast biofilms and “flocs” (clumps) in human health and industry, where forming clumps enables yeast to act as a natural filter in brewing and forming biofilms enables yeast to remain virulent in cases of fungal infection. Despite the importance of biofilms in yeast natural isolates, the majority of our knowledge about yeast biofilm genetics comes from work with a few tractable laboratory strains. A new collection of sequenced natural isolates from the Saccharomyces Genome Resequencing Project enabled us to examine the breadth of biofilm-related phenotypes in geographically, ecologically, and genetically diverse strains of Saccharomyces cerevisiae. We present a panel of 31 haploid and 24 diploid strains for which we have characterized six biofilm-related phenotypes: complex colony morphology, complex mat formation, flocculation, agar invasion, polystyrene adhesion, and psuedohyphal growth. Our results show that there is extensive phenotypic variation between and within strains, and that these six phenotypes are primarily uncorrelated or weakly correlated, with the notable exception of complex colony and complex mat formation. We also show that the phenotypic strength of these strains varies significantly depending on ploidy, and the diploid strains demonstrate both decreased and increased phenotypic strength with respect to their haploid counterparts. This is a more complex view of the impact of ploidy on biofilm-related phenotypes than previous work with laboratory strains has suggested, demonstrating the importance and enormous potential of working with natural isolates of yeast. PMID:25060625

Ploidy-regulated variation in biofilm-related phenotypes in natural isolates of Saccharomyces cerevisiae.

PubMed

Hope, Elyse A; Dunham, Maitreya J

2014-07-24

The ability of yeast to form biofilms contributes to better survival under stressful conditions. We see the impact of yeast biofilms and "flocs" (clumps) in human health and industry, where forming clumps enables yeast to act as a natural filter in brewing and forming biofilms enables yeast to remain virulent in cases of fungal infection. Despite the importance of biofilms in yeast natural isolates, the majority of our knowledge about yeast biofilm genetics comes from work with a few tractable laboratory strains. A new collection of sequenced natural isolates from the Saccharomyces Genome Resequencing Project enabled us to examine the breadth of biofilm-related phenotypes in geographically, ecologically, and genetically diverse strains of Saccharomyces cerevisiae. We present a panel of 31 haploid and 24 diploid strains for which we have characterized six biofilm-related phenotypes: complex colony morphology, complex mat formation, flocculation, agar invasion, polystyrene adhesion, and psuedohyphal growth. Our results show that there is extensive phenotypic variation between and within strains, and that these six phenotypes are primarily uncorrelated or weakly correlated, with the notable exception of complex colony and complex mat formation. We also show that the phenotypic strength of these strains varies significantly depending on ploidy, and the diploid strains demonstrate both decreased and increased phenotypic strength with respect to their haploid counterparts. This is a more complex view of the impact of ploidy on biofilm-related phenotypes than previous work with laboratory strains has suggested, demonstrating the importance and enormous potential of working with natural isolates of yeast. Copyright © 2014 Hope and Dunham.

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.

PubMed

Wesdorp, Mieke; de Koning Gans, Pia A M; Schraders, Margit; Oostrik, Jaap; Huynen, Martijn A; Venselaar, Hanka; Beynon, Andy J; van Gaalen, Judith; Piai, Vitória; Voermans, Nicol; van Rossum, Michelle M; Hartel, Bas P; Lelieveld, Stefan H; Wiel, Laurens; Verbist, Berit; Rotteveel, Liselotte J; van Dooren, Marieke F; Lichtner, Peter; Kunst, Henricus P M; Feenstra, Ilse; Admiraal, Ronald J C; Yntema, Helger G; Hoefsloot, Lies H; Pennings, Ronald J E; Kremer, Hannie

2018-05-12

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

Relationship between endophenotype and phenotype in ADHD

PubMed Central

Rommelse, Nanda NJ; Altink, Marieke E; Martin, Neilson C; Buschgens, Cathelijne JM; Faraone, Stephen V; Buitelaar, Jan K; Sergeant, Joseph A; Oosterlaan, Jaap

2008-01-01

Background It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype. Methods Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 – 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning. Results The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype. Conclusion Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and aggravate the ADHD symptoms in affected children. PMID:18234079

Cryptic breakpoint identified by whole-genome mate-pair sequencing in a rare paternally inherited complex chromosomal rearrangement.

PubMed

Aristidou, Constantia; Theodosiou, Athina; Ketoni, Andria; Bak, Mads; Mehrjouy, Mana M; Tommerup, Niels; Sismani, Carolina

2018-01-01

Precise characterization of apparently balanced complex chromosomal rearrangements in non-affected individuals is crucial as they may result in reproductive failure, recurrent miscarriages or affected offspring. We present a family, where the non-affected father and daughter were found, using FISH and karyotyping, to be carriers of a three-way complex chromosomal rearrangement [t(6;7;10)(q16.2;q34;q26.1), de novo in the father]. The family suffered from two stillbirths, one miscarriage, and has a son with severe intellectual disability. In the present study, the family was revisited using whole-genome mate-pair sequencing. Interestingly, whole-genome mate-pair sequencing revealed a cryptic breakpoint on derivative (der) chromosome 6 rendering the rearrangement even more complex. FISH using a chromosome (chr) 6 custom-designed probe and a chr10 control probe confirmed that the interstitial chr6 segment, created by the two chr6 breakpoints, was translocated onto der(10). Breakpoints were successfully validated with Sanger sequencing, and small imbalances as well as microhomology were identified. Finally, the complex chromosomal rearrangement breakpoints disrupted the SIM1 , GRIK2 , CNTNAP2 , and PTPRE genes without causing any phenotype development. In contrast to the majority of maternally transmitted complex chromosomal rearrangement cases, our study investigated a rare case where a complex chromosomal rearrangement, which most probably resulted from a Type IV hexavalent during the pachytene stage of meiosis I, was stably transmitted from a fertile father to his non-affected daughter. Whole-genome mate-pair sequencing proved highly successful in identifying cryptic complexity, which consequently provided further insight into the meiotic segregation of chromosomes and the increased reproductive risk in individuals carrying the specific complex chromosomal rearrangement. We propose that such complex rearrangements should be characterized in detail using a combination of conventional cytogenetic and NGS-based approaches to aid in better prenatal preimplantation genetic diagnosis and counseling in couples with reproductive problems.

Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

PubMed

Symonds, Joseph D; Joss, Shelagh; Metcalfe, Kay A; Somarathi, Suresh; Cruden, Jamie; Devlin, Anita M; Donaldson, Alan; DiDonato, Nataliya; Fitzpatrick, David; Kaiser, Frank J; Lampe, Anne K; Lees, Melissa M; McLellan, Ailsa; Montgomery, Tara; Mundada, Vivek; Nairn, Lesley; Sarkar, Ajoy; Schallner, Jens; Pozojevic, Jelena; Parenti, Ilaria; Tan, Jeen; Turnpenny, Peter; Whitehouse, William P; Zuberi, Sameer M

2017-04-01

The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Report from the Maryland epidemiology schizophrenia linkage study: No evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karayiorgou, M.; Hwang, J.; Elango, R.

Our collaborative group has undertaken a linkage study of schizophrenia, using a systematic sample of patients admitted to Maryland hospitals. An initial sample of 39 families, each having two or more affecteds, was available for genotyping candidate genes, candidate regions, and highly polymorphic markers randomly distributed throughout the genome. We used a single complex dominant model (with a disease gene frequency of 0.005 and age-dependent penetrance for affected phenotype: for under 35, penetrance = .45; for 35 and older, penetrance = .85). We report here 130 markers which met the exclusion criteria of LOD score < -2.00 at theta >more » 0.01 in at least 10 informative families, and no evidence for heterogeneity. We also report here markers that were tested as candidates for linkage to the schizophrenic phenotype. They were selected based on the following criteria: (a) proximity to reported chromosomal rearrangements (both 5q and 11q), (b) suggestions of linkage from other families (5q), or (c) presence of a candidate gene (5q, 11q, 3q: dopamine receptors 1, 2, and 3, respectively). We also tested for mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene and were unable to detect the C to T substitution in our schizophrenic group. 48 refs., 2 tabs.« less

Inferring fitness landscapes and selection on phenotypic states from single-cell genealogical data

PubMed Central

Kussell, Edo

2017-01-01

Recent advances in single-cell time-lapse microscopy have revealed non-genetic heterogeneity and temporal fluctuations of cellular phenotypes. While different phenotypic traits such as abundance of growth-related proteins in single cells may have differential effects on the reproductive success of cells, rigorous experimental quantification of this process has remained elusive due to the complexity of single cell physiology within the context of a proliferating population. We introduce and apply a practical empirical method to quantify the fitness landscapes of arbitrary phenotypic traits, using genealogical data in the form of population lineage trees which can include phenotypic data of various kinds. Our inference methodology for fitness landscapes determines how reproductivity is correlated to cellular phenotypes, and provides a natural generalization of bulk growth rate measures for single-cell histories. Using this technique, we quantify the strength of selection acting on different cellular phenotypic traits within populations, which allows us to determine whether a change in population growth is caused by individual cells’ response, selection within a population, or by a mixture of these two processes. By applying these methods to single-cell time-lapse data of growing bacterial populations that express a resistance-conferring protein under antibiotic stress, we show how the distributions, fitness landscapes, and selection strength of single-cell phenotypes are affected by the drug. Our work provides a unified and practical framework for quantitative measurements of fitness landscapes and selection strength for any statistical quantities definable on lineages, and thus elucidates the adaptive significance of phenotypic states in time series data. The method is applicable in diverse fields, from single cell biology to stem cell differentiation and viral evolution. PMID:28267748

Cyclin C influences the timing of mitosis in fission yeast

PubMed Central

Banyai, Gabor; Szilagyi, Zsolt; Baraznenok, Vera; Khorosjutina, Olga; Gustafsson, Claes M.

2017-01-01

The multiprotein Mediator complex is required for the regulated transcription of nearly all RNA polymerase II–dependent genes. Mediator contains the Cdk8 regulatory subcomplex, which directs periodic transcription and influences cell cycle progression in fission yeast. Here we investigate the role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control. Previous reports suggested that CycC interacts with other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle phenotypes. We find that Cdk8 and CycC interactions are stabilized within the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components. Analysis of a mutant yeast strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into S phase. PMID:28515143

Phenotyping the quality of complex medium components by simple online-monitored shake flask experiments.

PubMed

Diederichs, Sylvia; Korona, Anna; Staaden, Antje; Kroutil, Wolfgang; Honda, Kohsuke; Ohtake, Hisao; Büchs, Jochen

2014-11-07

Media containing yeast extracts and other complex raw materials are widely used for the cultivation of microorganisms. However, variations in the specific nutrient composition can occur, due to differences in the complex raw material ingredients and in the production of these components. These lot-to-lot variations can affect growth rate, product yield and product quality in laboratory investigations and biopharmaceutical production processes. In the FDA's Process Analytical Technology (PAT) initiative, the control and assessment of the quality of critical raw materials is one key aspect to maintain product quality and consistency. In this study, the Respiration Activity Monitoring System (RAMOS) was used to evaluate the impact of different yeast extracts and commercial complex auto-induction medium lots on metabolic activity and product yield of four recombinant Escherichia coli variants encoding different enzymes. Under non-induced conditions, the oxygen transfer rate (OTR) of E. coli was not affected by a variation of the supplemented yeast extract lot. The comparison of E. coli cultivations under induced conditions exhibited tremendous differences in OTR profiles and volumetric activity for all investigated yeast extract lots of different suppliers as well as lots of the same supplier independent of the E. coli variant. Cultivation in the commercial auto-induction medium lots revealed the same reproducible variations. In cultivations with parallel offline analysis, the highest volumetric activity was found at different cultivation times. Only by online monitoring of the cultures, a distinct cultivation phase (e.g. glycerol depletion) could be detected and chosen for comparable and reproducible offline analysis of the yield of functional product. This work proves that cultivations conducted in complex media may be prone to significant variation in final product quality and quantity if the quality of the raw material for medium preparation is not thoroughly checked. In this study, the RAMOS technique enabled a reliable and reproducible screening and phenotyping of complex raw material lots by online measurement of the respiration activity. Consequently, complex raw material lots can efficiently be assessed if the distinct effects on culture behavior and final product quality and quantity are visualized.

Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

PubMed Central

Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura

2009-01-01

In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) – originally identified and investigated in rats - can be measured in C57Bl/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioral phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. PMID:18771687

Phenotypic approaches to gene mapping in platelet function disorders - identification of new variant of P2Y12, TxA2 and GPVI receptors.

PubMed

Watson, S; Daly, M; Dawood, B; Gissen, P; Makris, M; Mundell, S; Wilde, J; Mumford, A

2010-01-01

Platelet number or function disorders cause a range of bleeding symptoms from mild to severe. Patients with platelet dysfunction but normal platelet number are the most prevalent and typically have mild bleeding symptoms. The study of this group of patients is particularly difficult because of the lack of a gold-standard test of platelet function and the variable penetrance of the bleeding phenotype among affected individuals. The purpose of this short review is to discuss the way in which this group of patients can be investigated through platelet phenotyping in combination with targeted gene sequencing. This approach has been used recently to identify patients with mutations in key platelet activation receptors, namely those for ADP, collagen and thromboxane A2 (TxA2). One interesting finding from this work is that for some patients, mild bleeding is associated with heterozygous mutations in platelet proteins that are co-inherited with other genetic disorders of haemostasis such as type 1 von Willebrand's disease. Thus, the phenotype of mild bleeding may be multifactorial in some patients and may be considered to be a complex trait.

The genetics of alcoholism: identifying specific genes through family studies.

PubMed

Edenberg, Howard J; Foroud, Tatiana

2006-09-01

Alcoholism is a complex disorder with both genetic and environmental risk factors. Studies in humans have begun to elucidate the genetic underpinnings of the risk for alcoholism. Here we briefly review strategies for identifying individual genes in which variations affect the risk for alcoholism and related phenotypes, in the context of one large study that has successfully identified such genes. The Collaborative Study on the Genetics of Alcoholism (COGA) is a family-based study that has collected detailed phenotypic data on individuals in families with multiple alcoholic members. A genome-wide linkage approach led to the identification of chromosomal regions containing genes that influenced alcoholism risk and related phenotypes. Subsequently, single nucleotide polymorphisms (SNPs) were genotyped in positional candidate genes located within the linked chromosomal regions, and analyzed for association with these phenotypes. Using this sequential approach, COGA has detected association with GABRA2, CHRM2 and ADH4; these associations have all been replicated by other researchers. COGA has detected association to additional genes including GABRG3, TAS2R16, SNCA, OPRK1 and PDYN, results that are awaiting confirmation. These successes demonstrate that genes contributing to the risk for alcoholism can be reliably identified using human subjects.

Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

PubMed

Chen, Xue; Sheng, Xunlun; Liu, Xiaoxing; Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also demonstrated that a targeted NGS approach is a valuable tool for the genetic diagnosis of USH2 and RP.

Targeted Next-Generation Sequencing Reveals Novel USH2A Mutations Associated with Diverse Disease Phenotypes: Implications for Clinical and Molecular Diagnosis

PubMed Central

Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also demonstrated that a targeted NGS approach is a valuable tool for the genetic diagnosis of USH2 and RP. PMID:25133613

Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease

PubMed Central

Hartman, John L.; Stisher, Chandler; Outlaw, Darryl A.; Guo, Jingyu; Shah, Najaf A.; Tian, Dehua; Santos, Sean M.; Rodgers, John W.; White, Richard A.

2015-01-01

The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on many genes. Genetic interaction, defined as contributions to a phenotype that are dependent upon particular digenic allele combinations, could improve prediction of phenotype from complex genotype, but it is difficult to study in human populations. High throughput, systematic analysis of S. cerevisiae gene knockouts or knockdowns in the context of disease-relevant phenotypic perturbations provides a tractable experimental approach to derive gene interaction networks, in order to deduce by cross-species gene homology how phenotype is buffered against disease-risk genotypes. Yeast gene interaction network analysis to date has revealed biology more complex than previously imagined. This has motivated the development of more powerful yeast cell array phenotyping methods to globally model the role of gene interaction networks in modulating phenotypes (which we call yeast phenomic analysis). The article illustrates yeast phenomic technology, which is applied here to quantify gene X media interaction at higher resolution and supports use of a human-like media for future applications of yeast phenomics for modeling human disease. PMID:25668739

Brain evolution and development: adaptation, allometry and constraint

PubMed Central

Barton, Robert A.

2016-01-01

Phenotypic traits are products of two processes: evolution and development. But how do these processes combine to produce integrated phenotypes? Comparative studies identify consistent patterns of covariation, or allometries, between brain and body size, and between brain components, indicating the presence of significant constraints limiting independent evolution of separate parts. These constraints are poorly understood, but in principle could be either developmental or functional. The developmental constraints hypothesis suggests that individual components (brain and body size, or individual brain components) tend to evolve together because natural selection operates on relatively simple developmental mechanisms that affect the growth of all parts in a concerted manner. The functional constraints hypothesis suggests that correlated change reflects the action of selection on distributed functional systems connecting the different sub-components, predicting more complex patterns of mosaic change at the level of the functional systems and more complex genetic and developmental mechanisms. These hypotheses are not mutually exclusive but make different predictions. We review recent genetic and neurodevelopmental evidence, concluding that functional rather than developmental constraints are the main cause of the observed patterns. PMID:27629025

Diet and Energy-Sensing Inputs Affect TorC1-Mediated Axon Misrouting but Not TorC2-Directed Synapse Growth in a Drosophila Model of Tuberous Sclerosis

PubMed Central

Dimitroff, Brian; Lee, Hyun-Gwan; Zhao, Na; O'Connor, Michael B.; Neufeld, Thomas P.; Selleck, Scott B.

2012-01-01

The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system. PMID:22319582

The Sex and Gender Intersection in Chronic Periodontitis

PubMed Central

Ioannidou, Effie

2017-01-01

Periodontitis, a complex polymicrobial inflammatory disease, is a public health burden affecting more than 100 million people and being partially responsible for tooth loss. Interestingly, periodontitis has a documented higher prevalence in men as compared to women signifying a possible sex/gender entanglement in the disease pathogenesis. Although relevant evidence has treated sex/gender in a simplistic dichotomous manner, periodontitis may represent a complex inflammatory disease model, in which sex biology may interfere with gender social and behavioral constructs affecting disease clinical phenotype. Even when it became clear that experimental oral health research needed to incorporate gender (and/or sex) framework in the hypothesis, researchers overwhelmingly ignored it unless the research question was directly related to reproductive system or sex-specific cancer. With the recognition of gender medicine as an independent field of research, this study challenged the current notion regarding sex/gender roles in periodontal disease. We aimed to develop the methodological and analytical framework with the recognition of sex/gender as important determinants of disease pathogenesis that require special attention. First, we aim to present relevant sex biologic evidence to understand the plausibility of the epidemiologic data. In periodontitis pathogenesis, sex dimorphism has been implicated in the disease etiology possibly affecting the bacterial component and the host immune response both in the innate and adaptive levels. With the clear distinction between sex and gender, gender oral health disparities have been explained by socioeconomic factors, cultural attitudes as well as access to preventive and regular care. Economic inequality and hardship for women have resulted in limited access to oral care. As a result, gender emerged as a complex socioeconomic and behavioral factor influencing oral health outcomes. Taken together, as disease phenotypic presentation is a multifactorial product of biology, behavior and the environment, sex dimorphism in immunity as well as gender socio-behavioral construct might play a role in the above model. Therefore, this paper will provide the conceptual framework and principles intergrading sex and gender within periodontal research in a complex biologic and socio-behavioral dimension. PMID:28824898

A Quantitative Systems Pharmacology Approach to Infer Pathways Involved in Complex Disease Phenotypes.

PubMed

Schurdak, Mark E; Pei, Fen; Lezon, Timothy R; Carlisle, Diane; Friedlander, Robert; Taylor, D Lansing; Stern, Andrew M

2018-01-01

Designing effective therapeutic strategies for complex diseases such as cancer and neurodegeneration that involve tissue context-specific interactions among multiple gene products presents a major challenge for precision medicine. Safe and selective pharmacological modulation of individual molecular entities associated with a disease often fails to provide efficacy in the clinic. Thus, development of optimized therapeutic strategies for individual patients with complex diseases requires a more comprehensive, systems-level understanding of disease progression. Quantitative systems pharmacology (QSP) is an approach to drug discovery that integrates computational and experimental methods to understand the molecular pathogenesis of a disease at the systems level more completely. Described here is the chemogenomic component of QSP for the inference of biological pathways involved in the modulation of the disease phenotype. The approach involves testing sets of compounds of diverse mechanisms of action in a disease-relevant phenotypic assay, and using the mechanistic information known for the active compounds, to infer pathways and networks associated with the phenotype. The example used here is for monogenic Huntington's disease (HD), which due to the pleiotropic nature of the mutant phenotype has a complex pathogenesis. The overall approach, however, is applicable to any complex disease.

RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.

PubMed

Shamseldin, Hanan; Alazami, Anas M; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A Micheil; Parboosingh, Jillian S; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P; Alkuraya, Fowzan S

2015-12-03

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Percolation on fitness landscapes: effects of correlation, phenotype, and incompatibilities

PubMed Central

Gravner, Janko; Pitman, Damien; Gavrilets, Sergey

2009-01-01

We study how correlations in the random fitness assignment may affect the structure of fitness landscapes, in three classes of fitness models. The first is a phenotype space in which individuals are characterized by a large number n of continuously varying traits. In a simple model of random fitness assignment, viable phenotypes are likely to form a giant connected cluster percolating throughout the phenotype space provided the viability probability is larger than 1/2n. The second model explicitly describes genotype-to-phenotype and phenotype-to-fitness maps, allows for neutrality at both phenotype and fitness levels, and results in a fitness landscape with tunable correlation length. Here, phenotypic neutrality and correlation between fitnesses can reduce the percolation threshold, and correlations at the point of phase transition between local and global are most conducive to the formation of the giant cluster. In the third class of models, particular combinations of alleles or values of phenotypic characters are “incompatible” in the sense that the resulting genotypes or phenotypes have zero fitness. This setting can be viewed as a generalization of the canonical Bateson-Dobzhansky-Muller model of speciation and is related to K- SAT problems, prominent in computer science. We analyze the conditions for the existence of viable genotypes, their number, as well as the structure and the number of connected clusters of viable genotypes. We show that analysis based on expected values can easily lead to wrong conclusions, especially when fitness correlations are strong. We focus on pairwise incompatibilities between diallelic loci, but we also address multiple alleles, complex incompatibilities, and continuous phenotype spaces. In the case of diallelic loci, the number of clusters is stochastically bounded and each cluster contains a very large sub-cube. Finally, we demonstrate that the discrete NK model shares some signature properties of models with high correlations. PMID:17692873

Neurobehavioral phenotype in Prader-Willi syndrome.

PubMed

Whittington, Joyce; Holland, Anthony

2010-11-15

The focus of this article is on the lifetime development of people with Prader-Willi syndrome (PWS) and specifically on the neurobehavioral phenotype. We consider studies of this aspect of the phenotype (the "behavioral phenotype" of the syndrome) that have confirmed that there are specific behaviors and psychiatric disorders, the propensities to which are increased in those with PWS, and cannot be accounted for by other variables such as IQ or adaptive behavior. Beginning with a description of what is observed in people with PWS, we review the evolving PWS phenotype and consider how some aspects of the phenotype might be best explained, and how this complex phenotype may relate to the equally complex genotype. We then consider in more detail some of the neurobehavioral aspects of the phenotype listed above that raise the greatest management problems for parents and carers. © 2010 Wiley-Liss, Inc.

MicroRNA-200c: A Novel Way to Attack Breast Cancer Metastases by Restoring the Epithelial Phenotype

DTIC Science & Technology

2012-02-01

complex relationships and reveal the extent to whichmiRNAs are involved with SHRs in normal physiology and the pathobiology of steroid hormoneene regulation...proges- terone counteracts estrogen-mediated proliferation. To determine whethermiRNAs play a physiological role inmodulating hormonal control of gene...effect on uterine physiology to ate is the finding that P4/PGR affects uterine contractility during abor via regulation of ZEB1 and the miR-200 family

Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders.

PubMed

Jobling, Rebekah; Stavropoulos, Dimitri James; Marshall, Christian R; Cytrynbaum, Cheryl; Axford, Michelle M; Londero, Vanessa; Moalem, Sharon; Orr, Jennifer; Rossignol, Francis; Lopes, Fatima Daniela; Gauthier, Julie; Alos, Nathalie; Rupps, Rosemarie; McKinnon, Margaret; Adam, Shelin; Nowaczyk, Malgorzata J M; Walker, Susan; Scherer, Stephen W; Nassif, Christina; Hamdan, Fadi F; Deal, Cheri L; Soucy, Jean-François; Weksberg, Rosanna; Macleod, Patrick; Michaud, Jacques L; Chitayat, David

2018-05-01

Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2 -related disorders is expanded to include growth hormone deficiency as an important and treatable complication. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

From genotype to phenotype: genetics and medical practice in the new millennium.

PubMed Central

Weatherall, D

1999-01-01

The completion of the human genome project will provide a vast amount of information about human genetic diversity. One of the major challenges for the medical sciences will be to relate genotype to phenotype. Over recent years considerable progress has been made in relating the molecular pathology of monogenic diseases to the associated clinical phenotypes. Studies of the inherited disorders of haemoglobin, notably the thalassaemias, have shown how even in these, the simplest of monogenic diseases, there is remarkable complexity with respect to their phenotypic expression. Although studies of other monogenic diseases are less far advanced, it is clear that the same level of complexity will exist. This information provides some indication of the difficulties that will be met when trying to define the genes that are involved in common multigenic disorders and, in particular, in trying to relate disease phenotypes to the complex interactions between many genes and multiple environmental factors. PMID:10670020

X chromosome regulation: diverse patterns in development, tissues and disease

PubMed Central

Deng, Xinxian; Berletch, Joel B.; Nguyen, Di K.; Disteche, Christine M.

2014-01-01

Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations. PMID:24733023

A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype.

PubMed

Waluk, Dominik P; Zur, Gila; Kaufmann, Ronnie; Welle, Monika M; Jagannathan, Vidhya; Drögemüller, Cord; Müller, Eliane J; Leeb, Tosso; Galichet, Arnaud

2016-09-08

X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns. Copyright © 2016 Waluk et al.

The effect of phenotypic traits and external cues on natal dispersal movements.

PubMed

Delgado, María del Mar; Penteriani, Vincenzo; Revilla, Eloy; Nams, Vilis O

2010-05-01

1. Natal dispersal has the potential to affect most ecological and evolutionary processes. However, despite its importance, this complex ecological process still represents a significant gap in our understanding of animal ecology due to both the lack of empirical data and the intrinsic complexity of dispersal dynamics. 2. By studying natal dispersal of 74 radiotagged juvenile eagle owls Bubo bubo (Linnaeus), in both the wandering and the settlement phases, we empirically addressed the complex interactions by which individual phenotypic traits and external cues jointly shape individual heterogeneity through the different phases of dispersal, both at nightly and weekly temporal scales. 3. Owls in poorer physical conditions travelled shorter total distances during the wandering phase, describing straighter paths and moving slower, especially when crossing heterogeneous habitats. In general, the owls in worse condition started dispersal later and took longer times to find further settlement areas. Net distances were also sex biased, with females settling at further distances. Dispersing individuals did not seem to explore wandering and settlement areas by using a search image of their natal surroundings. Eagle owls showed a heterogeneous pattern of patch occupancy, where few patches were highly visited by different owls whereas the majority were visited by just one individual. During dispersal, the routes followed by owls were an intermediate solution between optimized and randomized ones. Finally, dispersal direction had a marked directionality, largely influenced by dominant winds. These results suggest an asymmetric and anisotropic dispersal pattern, where not only the number of patches but also their functions can affect population viability. 4. The combination of the information coming from the relationships among a large set of factors acting and integrating at different spatial and temporal scales, under the perspective of heterogeneous life histories, are a fruitful ground for future understanding of natal dispersal.

Expressivity of hearing loss in cases with Usher syndrome type IIA.

PubMed

Sadeghi, André M; Cohn, Edward S; Kimberling, William J; Halvarsson, Glenn; Möller, Claes

2013-12-01

The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype-phenotype correlations. Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome.

Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum.

PubMed

Bertola, D R; Hsia, G; Alvizi, L; Gardham, A; Wakeling, E L; Yamamoto, G L; Honjo, R S; Oliveira, L A N; Di Francesco, R C; Perez, B A; Kim, C A; Passos-Bueno, M R

2018-04-01

Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Novel throughput phenotyping platforms in plant genetic studies.

PubMed

Montes, Juan M; Melchinger, Albrecht E; Reif, Jochen C

2007-10-01

Unraveling the genetic basis of complex traits in plants is limited by the lack of appropriate phenotyping platforms that enable high-throughput screening of many genotypes in multilocation field trials. Near-infrared spectroscopy on agricultural harvesters and spectral reflectance of plant canopies have recently been reported as promising components of novel phenotyping platforms. Understanding the genetic basis of complex traits is now within reach with the use of these new techniques.

Mitochondrial disease associated with complex I (NADH-CoQ oxidoreductase) deficiency.

PubMed

Scheffler, Immo E

2015-05-01

Mitochondrial diseases due to a reduced capacity for oxidative phosphorylation were first identified more than 20 years ago, and their incidence is now recognized to be quite significant. In a large proportion of cases the problem can be traced to a complex I (NADH-CoQ oxidoreductase) deficiency (Phenotype MIM #252010). Because the complex consists of 44 subunits, there are many potential targets for pathogenic mutations, both on the nuclear and mitochondrial genomes. Surprisingly, however, almost half of the complex I deficiencies are due to defects in as yet unidentified genes that encode proteins other than the structural proteins of the complex. This review attempts to summarize what we know about the molecular basis of complex I deficiencies: mutations in the known structural genes, and mutations in an increasing number of genes encoding "assembly factors", that is, proteins required for the biogenesis of a functional complex I that are not found in the final complex I. More such genes must be identified before definitive genetic counselling can be applied in all cases of affected families.

Directed evolution and synthetic biology applications to microbial systems.

PubMed

Bassalo, Marcelo C; Liu, Rongming; Gill, Ryan T

2016-06-01

Biotechnology applications require engineering complex multi-genic traits. The lack of knowledge on the genetic basis of complex phenotypes restricts our ability to rationally engineer them. However, complex phenotypes can be engineered at the systems level, utilizing directed evolution strategies that drive whole biological systems toward desired phenotypes without requiring prior knowledge of the genetic basis of the targeted trait. Recent developments in the synthetic biology field accelerates the directed evolution cycle, facilitating engineering of increasingly complex traits in biological systems. In this review, we summarize some of the most recent advances in directed evolution and synthetic biology that allows engineering of complex traits in microbial systems. Then, we discuss applications that can be achieved through engineering at the systems level. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multilevel biological characterization of exomic variants at the protein level significantly improves the identification of their deleterious effects.

PubMed

Raimondi, Daniele; Gazzo, Andrea M; Rooman, Marianne; Lenaerts, Tom; Vranken, Wim F

2016-06-15

There are now many predictors capable of identifying the likely phenotypic effects of single nucleotide variants (SNVs) or short in-frame Insertions or Deletions (INDELs) on the increasing amount of genome sequence data. Most of these predictors focus on SNVs and use a combination of features related to sequence conservation, biophysical, and/or structural properties to link the observed variant to either neutral or disease phenotype. Despite notable successes, the mapping between genetic variants and their phenotypic effects is riddled with levels of complexity that are not yet fully understood and that are often not taken into account in the predictions, despite their promise of significantly improving the prediction of deleterious mutants. We present DEOGEN, a novel variant effect predictor that can handle both missense SNVs and in-frame INDELs. By integrating information from different biological scales and mimicking the complex mixture of effects that lead from the variant to the phenotype, we obtain significant improvements in the variant-effect prediction results. Next to the typical variant-oriented features based on the evolutionary conservation of the mutated positions, we added a collection of protein-oriented features that are based on functional aspects of the gene affected. We cross-validated DEOGEN on 36 825 polymorphisms, 20 821 deleterious SNVs, and 1038 INDELs from SwissProt. The multilevel contextualization of each (variant, protein) pair in DEOGEN provides a 10% improvement of MCC with respect to current state-of-the-art tools. The software and the data presented here is publicly available at http://ibsquare.be/deogen : wvranken@vub.ac.be Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Identification of clinical target areas in the brainstem of prion‐infected mice

PubMed Central

Mirabile, Ilaria; Jat, Parmjit S.; Brandner, Sebastian

2015-01-01

Aims While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. Method We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). Results We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre‐Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. Conclusions Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre‐Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt–Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID:25311251

Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments

PubMed Central

Eicher, John D.; Gruen, Jeffrey R.

2013-01-01

Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in-depth look at the recent imaging-genetics investigations of dyslexia. PMID:23916419

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

PubMed Central

Ried, Janina S.; Jeff M., Janina; Chu, Audrey Y.; Bragg-Gresham, Jennifer L.; van Dongen, Jenny; Huffman, Jennifer E.; Ahluwalia, Tarunveer S.; Cadby, Gemma; Eklund, Niina; Eriksson, Joel; Esko, Tõnu; Feitosa, Mary F.; Goel, Anuj; Gorski, Mathias; Hayward, Caroline; Heard-Costa, Nancy L.; Jackson, Anne U.; Jokinen, Eero; Kanoni, Stavroula; Kristiansson, Kati; Kutalik, Zoltán; Lahti, Jari; Luan, Jian'an; Mägi, Reedik; Mahajan, Anubha; Mangino, Massimo; Medina-Gomez, Carolina; Monda, Keri L.; Nolte, Ilja M.; Pérusse, Louis; Prokopenko, Inga; Qi, Lu; Rose, Lynda M.; Salvi, Erika; Smith, Megan T.; Snieder, Harold; Stančáková, Alena; Ju Sung, Yun; Tachmazidou, Ioanna; Teumer, Alexander; Thorleifsson, Gudmar; van der Harst, Pim; Walker, Ryan W.; Wang, Sophie R.; Wild, Sarah H.; Willems, Sara M.; Wong, Andrew; Zhang, Weihua; Albrecht, Eva; Couto Alves, Alexessander; Bakker, Stephan J. L.; Barlassina, Cristina; Bartz, Traci M.; Beilby, John; Bellis, Claire; Bergman, Richard N.; Bergmann, Sven; Blangero, John; Blüher, Matthias; Boerwinkle, Eric; Bonnycastle, Lori L.; Bornstein, Stefan R.; Bruinenberg, Marcel; Campbell, Harry; Chen, Yii-Der Ida; Chiang, Charleston W. K.; Chines, Peter S.; Collins, Francis S; Cucca, Fracensco; Cupples, L Adrienne; D'Avila, Francesca; de Geus, Eco J .C.; Dedoussis, George; Dimitriou, Maria; Döring, Angela; Eriksson, Johan G.; Farmaki, Aliki-Eleni; Farrall, Martin; Ferreira, Teresa; Fischer, Krista; Forouhi, Nita G.; Friedrich, Nele; Gjesing, Anette Prior; Glorioso, Nicola; Graff, Mariaelisa; Grallert, Harald; Grarup, Niels; Gräßler, Jürgen; Grewal, Jagvir; Hamsten, Anders; Harder, Marie Neergaard; Hartman, Catharina A.; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew Tym; Havulinna, Aki S.; Heliövaara, Markku; Hillege, Hans; Hofman, Albert; Holmen, Oddgeir; Homuth, Georg; Hottenga, Jouke-Jan; Hui, Jennie; Husemoen, Lise Lotte; Hysi, Pirro G.; Isaacs, Aaron; Ittermann, Till; Jalilzadeh, Shapour; James, Alan L.; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Marie Justesen, Johanne; Justice, Anne E.; Kähönen, Mika; Karaleftheri, Maria; Tee Khaw, Kay; Keinanen-Kiukaanniemi, Sirkka M.; Kinnunen, Leena; Knekt, Paul B.; Koistinen, Heikki A.; Kolcic, Ivana; Kooner, Ishminder K.; Koskinen, Seppo; Kovacs, Peter; Kyriakou, Theodosios; Laitinen, Tomi; Langenberg, Claudia; Lewin, Alexandra M.; Lichtner, Peter; Lindgren, Cecilia M.; Lindström, Jaana; Linneberg, Allan; Lorbeer, Roberto; Lorentzon, Mattias; Luben, Robert; Lyssenko, Valeriya; Männistö, Satu; Manunta, Paolo; Leach, Irene Mateo; McArdle, Wendy L.; Mcknight, Barbara; Mohlke, Karen L.; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Montasser, May E.; Morris, Andrew P.; Müller, Gabriele; Musk, Arthur W.; Narisu, Narisu; Ong, Ken K.; Oostra, Ben A.; Osmond, Clive; Palotie, Aarno; Pankow, James S.; Paternoster, Lavinia; Penninx, Brenda W.; Pichler, Irene; Pilia, Maria G.; Polašek, Ozren; Pramstaller, Peter P.; Raitakari, Olli T; Rankinen, Tuomo; Rao, D. C.; Rayner, Nigel W.; Ribel-Madsen, Rasmus; Rice, Treva K.; Richards, Marcus; Ridker, Paul M.; Rivadeneira, Fernando; Ryan, Kathy A.; Sanna, Serena; Sarzynski, Mark A.; Scholtens, Salome; Scott, Robert A.; Sebert, Sylvain; Southam, Lorraine; Sparsø, Thomas Hempel; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Stolk, Ronald P.; Strauch, Konstantin; Stringham, Heather M.; Swertz, Morris A.; Swift, Amy J.; Tönjes, Anke; Tsafantakis, Emmanouil; van der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Vartiainen, Erkki; Venturini, Cristina; Verweij, Niek; Viikari, Jorma S.; Vitart, Veronique; Vohl, Marie-Claude; Vonk, Judith M.; Waeber, Gérard; Widén, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Winkler, Thomas W.; Wright, Alan F.; Yerges-Armstrong, Laura M.; Hua Zhao, Jing; Carola Zillikens, M.; Boomsma, Dorret I.; Bouchard, Claude; Chambers, John C.; Chasman, Daniel I.; Cusi, Daniele; Gansevoort, Ron T.; Gieger, Christian; Hansen, Torben; Hicks, Andrew A.; Hu, Frank; Hveem, Kristian; Jarvelin, Marjo-Riitta; Kajantie, Eero; Kooner, Jaspal S.; Kuh, Diana; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A.; Lehtimäki, Terho; Metspalu, Andres; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Palmer, Lyle J.; Pedersen, Oluf; Perola, Markus; Peters, Annette; Psaty, Bruce M.; Puolijoki, Hannu; Rauramaa, Rainer; Rudan, Igor; Salomaa, Veikko; Schwarz, Peter E. H.; Shudiner, Alan R.; Smit, Jan H.; Sørensen, Thorkild I. A.; Spector, Timothy D.; Stefansson, Kari; Stumvoll, Michael; Tremblay, Angelo; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; Völker, Uwe; Vollenweider, Peter; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Zeggini, Eleftheria; Abecasis, Goncalo R.; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; van Duijn, Cornelia M.; Fox, Caroline; Groop, Leif C.; Heid, Iris M.; Hunter, David J.; Kaplan, Robert C.; McCarthy, Mark I.; North, Kari E.; O'Connell, Jeffrey R.; Schlessinger, David; Thorsteinsdottir, Unnur; Strachan, David P.; Frayling, Timothy; Hirschhorn, Joel N.; Müller-Nurasyid, Martina; Loos, Ruth J. F.

2016-01-01

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways. PMID:27876822

Mitochondrial threshold effects.

PubMed Central

Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry

2003-01-01

The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the 'phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the 'biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a 'translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases. PMID:12467494

Constitutional mechanisms of vulnerability and resilience to nicotine dependence

PubMed Central

Hiroi, N; Scott, D

2017-01-01

The core nature of nicotine dependence is evident in wide variations in how individuals become and remain smokers. Individuals with pre-existing behavioral traits are more likely to develop nicotine dependence and experience difficulty when attempting to quit. Many molecular factors likely contribute to individual variations in the development of nicotine dependence and behavioral traits in complex manners. However, the identification of such molecules has been hampered by the phenotypic complexity of nicotine dependence and the complex ways molecules affect elements of nicotine dependence. We hypothesize that nicotine dependence is, in part, a result of interactions between nicotine and pre-existing behavioral traits. This perspective suggests that the identification of the molecular bases of such pre-existing behavioral traits will contribute to the development of effective methods for reducing smoking dependence and for helping smokers to quit. PMID:19238150

A systems-genetics approach and data mining tool to assist in the discovery of genes underlying complex traits in Oryza sativa.

PubMed

Ficklin, Stephen P; Feltus, Frank Alex

2013-01-01

Many traits of biological and agronomic significance in plants are controlled in a complex manner where multiple genes and environmental signals affect the expression of the phenotype. In Oryza sativa (rice), thousands of quantitative genetic signals have been mapped to the rice genome. In parallel, thousands of gene expression profiles have been generated across many experimental conditions. Through the discovery of networks with real gene co-expression relationships, it is possible to identify co-localized genetic and gene expression signals that implicate complex genotype-phenotype relationships. In this work, we used a knowledge-independent, systems genetics approach, to discover a high-quality set of co-expression networks, termed Gene Interaction Layers (GILs). Twenty-two GILs were constructed from 1,306 Affymetrix microarray rice expression profiles that were pre-clustered to allow for improved capture of gene co-expression relationships. Functional genomic and genetic data, including over 8,000 QTLs and 766 phenotype-tagged SNPs (p-value < = 0.001) from genome-wide association studies, both covering over 230 different rice traits were integrated with the GILs. An online systems genetics data-mining resource, the GeneNet Engine, was constructed to enable dynamic discovery of gene sets (i.e. network modules) that overlap with genetic traits. GeneNet Engine does not provide the exact set of genes underlying a given complex trait, but through the evidence of gene-marker correspondence, co-expression, and functional enrichment, site visitors can identify genes with potential shared causality for a trait which could then be used for experimental validation. A set of 2 million SNPs was incorporated into the database and serve as a potential set of testable biomarkers for genes in modules that overlap with genetic traits. Herein, we describe two modules found using GeneNet Engine, one with significant overlap with the trait amylose content and another with significant overlap with blast disease resistance.

A Systems-Genetics Approach and Data Mining Tool to Assist in the Discovery of Genes Underlying Complex Traits in Oryza sativa

PubMed Central

Ficklin, Stephen P.; Feltus, Frank Alex

2013-01-01

Many traits of biological and agronomic significance in plants are controlled in a complex manner where multiple genes and environmental signals affect the expression of the phenotype. In Oryza sativa (rice), thousands of quantitative genetic signals have been mapped to the rice genome. In parallel, thousands of gene expression profiles have been generated across many experimental conditions. Through the discovery of networks with real gene co-expression relationships, it is possible to identify co-localized genetic and gene expression signals that implicate complex genotype-phenotype relationships. In this work, we used a knowledge-independent, systems genetics approach, to discover a high-quality set of co-expression networks, termed Gene Interaction Layers (GILs). Twenty-two GILs were constructed from 1,306 Affymetrix microarray rice expression profiles that were pre-clustered to allow for improved capture of gene co-expression relationships. Functional genomic and genetic data, including over 8,000 QTLs and 766 phenotype-tagged SNPs (p-value < = 0.001) from genome-wide association studies, both covering over 230 different rice traits were integrated with the GILs. An online systems genetics data-mining resource, the GeneNet Engine, was constructed to enable dynamic discovery of gene sets (i.e. network modules) that overlap with genetic traits. GeneNet Engine does not provide the exact set of genes underlying a given complex trait, but through the evidence of gene-marker correspondence, co-expression, and functional enrichment, site visitors can identify genes with potential shared causality for a trait which could then be used for experimental validation. A set of 2 million SNPs was incorporated into the database and serve as a potential set of testable biomarkers for genes in modules that overlap with genetic traits. Herein, we describe two modules found using GeneNet Engine, one with significant overlap with the trait amylose content and another with significant overlap with blast disease resistance. PMID:23874666

Localization of canine brachycephaly using an across breed mapping approach.

PubMed

Bannasch, Danika; Young, Amy; Myers, Jeffrey; Truvé, Katarina; Dickinson, Peter; Gregg, Jeffrey; Davis, Ryan; Bongcam-Rudloff, Eric; Webster, Matthew T; Lindblad-Toh, Kerstin; Pedersen, Niels

2010-03-10

The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing.

PubMed

Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor; Beaty, Terri H; Murray, Jeffrey C; Marazita, Mary L; Leslie, Elizabeth J

2017-07-17

Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups. We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side. We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10 -4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10 -4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10 -4 ; p = 6.00 × 10 -4 ), and sex differences in VAX1 (p < 1.00 × 10 -4 ) among others. Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

On the holistic approach in cellular and cancer biology: nonlinearity, complexity, and quasi-determinism of the dynamic cellular network.

PubMed

Waliszewski, P; Molski, M; Konarski, J

1998-06-01

A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype-two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross-interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controlled in dispersed rather than centralized manner), and quasi-determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self-organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context.

A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics.

PubMed

Blackburn, Patrick R; Zimmermann, Michael T; Gass, Jennifer M; Harris, Kimberly G; Cousin, Margot A; Boczek, Nicole J; Ross, Owen A; Klee, Eric W; Brazis, Paul W; Van Gerpen, Jay A; Atwal, Paldeep S

2016-12-05

Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison. In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. ANO3 encodes anoctamin-3, a Ca +2 -dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.

Phylogeny-based comparative methods question the adaptive nature of sporophytic specializations in mosses.

PubMed

Huttunen, Sanna; Olsson, Sanna; Buchbender, Volker; Enroth, Johannes; Hedenäs, Lars; Quandt, Dietmar

2012-01-01

Adaptive evolution has often been proposed to explain correlations between habitats and certain phenotypes. In mosses, a high frequency of species with specialized sporophytic traits in exposed or epiphytic habitats was, already 100 years ago, suggested as due to adaptation. We tested this hypothesis by contrasting phylogenetic and morphological data from two moss families, Neckeraceae and Lembophyllaceae, both of which show parallel shifts to a specialized morphology and to exposed epiphytic or epilithic habitats. Phylogeny-based tests for correlated evolution revealed that evolution of four sporophytic traits is correlated with a habitat shift. For three of them, evolutionary rates of dual character-state changes suggest that habitat shifts appear prior to changes in morphology. This suggests that they could have evolved as adaptations to new habitats. Regarding the fourth correlated trait the specialized morphology had already evolved before the habitat shift. In addition, several other specialized "epiphytic" traits show no correlation with a habitat shift. Besides adaptive diversification, other processes thus also affect the match between phenotype and environment. Several potential factors such as complex genetic and developmental pathways yielding the same phenotypes, differences in strength of selection, or constraints in phenotypic evolution may lead to an inability of phylogeny-based comparative methods to detect potential adaptations.

Detection of SHOX gene aberrations in routine diagnostic practice and evaluation of phenotype scoring form effectiveness.

PubMed

Hirschfeldova, Katerina; Florianova, Martina; Kebrdlova, Vera; Urbanova, Marketa; Stekrova, Jitka

2017-02-01

Heterozygous aberrations of SHOX gene have been reported to be responsible for Léri-Weill dyschondrosteosis (LWD) and small portion of idiopathic short stature. The study was established to assess effectiveness of using phenotype 'scoring form' in patients indicated for SHOX gene defect analysis. The submitted study is based on a retrospective group of 352 unrelated patients enrolled as a part of the routine diagnostic practice and analyzed for aberrations affecting the SHOX gene. All participants were scanned for deletion/duplication within the main pseudoautosomal region (PAR1) using the multiplex ligation-dependent probe amplification (MLPA) method. The phenotype 'scoring form' is used in our laboratory practice to preselect patients for subsequent mutation analysis of SHOX gene-coding sequences. The overall detection rate was 11.1% but there was a significant increase in frequency of SHOX gene defect positive with increasing achieved score (P<0.0001). The most frequent aberration was a causal deletion within PAR1. In three probands, MLPA analysis indicated a more complex rearrangement. Madelung deformity or co-occurrence of disproportionate short stature, short forearm and muscular hypertrophy had represented the most potent markers to determine the likelihood of SHOX gene defect detection. We conclude that appliance of phenotype 'scoring form' had saved excessive sample analysis and enabled effective routine diagnostic testing.

Effect of Genetics, Environment, and Phenotype on the Metabolome of Maize Hybrids Using GC/MS and LC/MS.

PubMed

Tang, Weijuan; Hazebroek, Jan; Zhong, Cathy; Harp, Teresa; Vlahakis, Chris; Baumhover, Brian; Asiago, Vincent

2017-06-28

We evaluated the variability of metabolites in various maize hybrids due to the effect of environment, genotype, phenotype as well as the interaction of the first two factors. We analyzed 480 forage and the same number of grain samples from 21 genetically diverse non-GM Pioneer brand maize hybrids, including some with drought tolerance and viral resistance phenotypes, grown at eight North American locations. As complementary platforms, both GC/MS and LC/MS were utilized to detect a wide diversity of metabolites. GC/MS revealed 166 and 137 metabolites in forage and grain samples, respectively, while LC/MS captured 1341 and 635 metabolites in forage and grain samples, respectively. Univariate and multivariate analyses were utilized to investigate the response of the maize metabolome to the environment, genotype, phenotype, and their interaction. Based on combined percentages from GC/MS and LC/MS datasets, the environment affected 36% to 84% of forage metabolites, while less than 7% were affected by genotype. The environment affected 12% to 90% of grain metabolites, whereas less than 27% were affected by genotype. Less than 10% and 11% of the metabolites were affected by phenotype in forage and grain, respectively. Unsupervised PCA and HCA analyses revealed similar trends, i.e., environmental effect was much stronger than genotype or phenotype effects. On the basis of comparisons of disease tolerant and disease susceptible hybrids, neither forage nor grain samples originating from different locations showed obvious phenotype effects. Our findings demonstrate that the combination of GC/MS and LC/MS based metabolite profiling followed by broad statistical analysis is an effective approach to identify the relative impact of environmental, genetic and phenotypic effects on the forage and grain composition of maize hybrids.

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

PubMed Central

Tsuda, Takeshi; Fitzgerald, Kristi K.

2017-01-01

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. PMID:29367543

AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome).

PubMed

Cacciagli, Pierre; Desvignes, Jean-Pierre; Girard, Nadine; Delepine, Marc; Zelenika, Diana; Lathrop, Mark; Lévy, Nicolas; Ledbetter, David H; Dobyns, William B; Villard, Laurent

2014-03-01

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.

CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism.

PubMed

Turan, Ihsan; Hutchins, B Ian; Hacihamdioglu, Bulent; Kotan, L Damla; Gurbuz, Fatih; Ulubay, Ayca; Mengen, Eda; Yuksel, Bilgin; Wray, Susan; Topaloglu, A Kemal

2017-06-01

Gonadotropin-releasing hormone neurons originate outside the central nervous system in the olfactory placode and migrate into the central nervous system, becoming integral components of the hypothalamic-pituitary-gonadal axis. Failure of this migration can lead to idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). We have previously shown that CCDC141 knockdown leads to impaired migration of GnRH neurons but not of olfactory receptor neurons. The aim of this study was to further describe the phenotype and prevalence of CCDC141 mutations in IHH/KS. Using autozygosity mapping, candidate gene screening, whole-exome sequencing, and Sanger sequencing, those individuals carrying deleterious CDCD141 variants and their phenotypes were determined in a cohort of 120 IHH/KS families. No interventions were made. Our studies revealed nine affected individuals from four independent families in which IHH/KS is associated with inactivating CCDC141 variants, revealing a prevalence of 3.3%. Affected individuals (with the exception of those from family 1 who concomitantly have FEZF1 mutations) have normal olfactory function and anatomically normal olfactory bulbs. Four affected individuals show evidence of clinical reversibility. In three of the families, there was at least one more potentially deleterious variant in other known puberty genes with evidence of allelic heterogeneity within respective pedigrees. These studies confirm that inactivating CCDC141 variants cause normosmic IHH but not KS. This is consistent with our previous in vitro experiments showing exclusively impaired embryonic migration of GnRH neurons upon CCDC141 knockdown. These studies expand the clinical and genetic spectrum of IHH and also attest to the complexity of phenotype and genotype in IHH. Copyright © 2017 by the Endocrine Society

AP1S2 is mutated in X-linked Dandy–Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome)

PubMed Central

Cacciagli, Pierre; Desvignes, Jean-Pierre; Girard, Nadine; Delepine, Marc; Zelenika, Diana; Lathrop, Mark; Lévy, Nicolas; Ledbetter, David H; Dobyns, William B; Villard, Laurent

2014-01-01

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy–Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity. PMID:23756445

How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research.

PubMed

Wacker, Jan; Mueller, Erik M; Hennig, Jürgen; Stemmler, Gerhard

2012-02-01

The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

Comparison of the Virulence-Associated Phenotypes of Five Species of Acinetobacter baumannii Complex.

PubMed

Na, In Young; Chung, Eun Seon; Jung, Chang-Yun; Kim, Dae Hun; Shin, Juyoun; Kang, KyeongJin; Kim, Seong-Tae; Ko, Kwan Soo

2016-01-01

In this study, we compared the virulence-associated factors of Acinetobacter baumannii complex species. Sixty-three isolates of five A. baumannii complex species, including 19 A. baumannii, 15 A. nosocomialis, 13 A. seifertii, 13 A. pittii, and 3 A. calcoaceticus isolates, were included in this study. For all isolates, biofilm formation, A549 cell adherence, resistance to normal human serum, and motility were evaluated. A. baumannii complex isolates showed diversity in biofilm formation, A549 cell adherence, and serum resistance, and no strong positive relationships among these virulence characteristics. However, A. seifertii showed relatively consistent virulence-associated phenotypes. In addition, A. baumannii clone ST110 exhibited consistently high virulence-associated phenotypes. Motility was observed in seven isolates, and all four A. baumannii ST110 isolates showed twitching motility. Although some inconsistencies in virulence-associated phenotypes were seen, high virulence characteristics were observed in A. seifertii, which has been mainly reported in Korea and shows high rates of colistin resistance.

Chimeric Protein Complexes in Hybrid Species Generate Novel Phenotypes

PubMed Central

Piatkowska, Elzbieta M.; Naseeb, Samina; Knight, David; Delneri, Daniela

2013-01-01

Hybridization between species is an important mechanism for the origin of novel lineages and adaptation to new environments. Increased allelic variation and modification of the transcriptional network are the two recognized forces currently deemed to be responsible for the phenotypic properties seen in hybrids. However, since the majority of the biological functions in a cell are carried out by protein complexes, inter-specific protein assemblies therefore represent another important source of natural variation upon which evolutionary forces can act. Here we studied the composition of six protein complexes in two different Saccharomyces “sensu stricto” hybrids, to understand whether chimeric interactions can be freely formed in the cell in spite of species-specific co-evolutionary forces, and whether the different types of complexes cause a change in hybrid fitness. The protein assemblies were isolated from the hybrids via affinity chromatography and identified via mass spectrometry. We found evidence of spontaneous chimericity for four of the six protein assemblies tested and we showed that different types of complexes can cause a variety of phenotypes in selected environments. In the case of TRP2/TRP3 complex, the effect of such chimeric formation resulted in the fitness advantage of the hybrid in an environment lacking tryptophan, while only one type of parental combination of the MBF complex allowed the hybrid to grow under respiratory conditions. These phenotypes were dependent on both genetic and environmental backgrounds. This study provides empirical evidence that chimeric protein complexes can freely assemble in cells and reveals a new mechanism to generate phenotypic novelty and plasticity in hybrids to complement the genomic innovation resulting from gene duplication. The ability to exchange orthologous members has also important implications for the adaptation and subsequent genome evolution of the hybrids in terms of pattern of gene loss. PMID:24137105

Structure and composition of the courtship phenotype in the bird of paradise Parotia lawesii (Aves: Paradisaeidae).

PubMed

Scholes, Edwin

2008-01-01

Ethology is rooted in the idea that behavior is composed of discrete units and sub-units that can be compared among taxa in a phylogenetic framework. This means that behavior, like morphology and genes, is inherently modular. Yet, the concept of modularity is not well integrated into how we envision the behavioral components of phenotype. Understanding ethological modularity, and its implications for animal phenotype organization and evolution, requires that we construct interpretive schemes that permit us to examine it. In this study, I describe the structure and composition of a complex part of the behavioral phenotype of Parotia lawesii Ramsay, 1885--a bird of paradise (Aves: Paradisaeidae) from the forests of eastern New Guinea. I use archived voucher video clips, photographic ethograms, and phenotype ontology diagrams to describe the modular units comprising courtship at various levels of integration. Results show P. lawesii to have 15 courtship and mating behaviors (11 males, 4 females) hierarchically arranged within a complex seven-level structure. At the finest level examined, male displays are comprised of 49 modular sub-units (elements) differentially employed to form more complex modular units (phases and versions) at higher-levels of integration. With its emphasis on hierarchical modularity, this study provides an important conceptual framework for understanding courtship-related phenotypic complexity and provides a solid basis for comparative study of the genus Parotia.

Yap1 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin*

PubMed Central

Xie, Changqing; Guo, Yanhong; Zhu, Tianqing; Zhang, Jifeng; Ma, Peter X.; Chen, Y. Eugene

2012-01-01

The Hippo-Yap (Yes-associated protein) signaling pathway has emerged as one of the critical pathways regulating cell proliferation, differentiation, and apoptosis in response to environmental and developmental cues. However, Yap1 roles in vascular smooth muscle cell (VSMC) biology have not been investigated. VSMCs undergo phenotypic switch, a process characterized by decreased gene expression of VSMC contractile markers and increased proliferation, migration, and matrix synthesis. The goals of the present studies were to investigate the relationship between Yap1 and VSMC phenotypic switch and to determine the molecular mechanisms by which Yap1 affects this essential process in VSMC biology. Results demonstrated that the expression of Yap1 was rapidly up-regulated by stimulation with PDGF-BB (a known inducer of phenotypic switch in VSMCs) and in the injured vessel wall. Knockdown of Yap1 impaired VSMC proliferation in vitro and enhanced the expression of VSMC contractile genes as well by increasing serum response factor binding to CArG-containing regions of VSMC-specific contractile genes within intact chromatin. Conversely, the interaction between serum response factor and its co-activator myocardin was reduced by overexpression of Yap1 in a dose-dependent manner. Taken together, these results indicate that down-regulation of Yap1 promotes VSMC contractile phenotype by both up-regulating myocardin expression and promoting the association of the serum response factor-myocardin complex with VSMC contractile gene promoters and suggest that the Yap1 signaling pathway is a central regulator of phenotypic switch of VSMCs. PMID:22411986

Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy.

PubMed

Esposito, Teresa; Sampaolo, Simone; Limongelli, Giuseppe; Varone, Antonio; Formicola, Daniela; Diodato, Daria; Farina, Olimpia; Napolitano, Filomena; Pacileo, Giuseppe; Gianfrancesco, Fernando; Di Iorio, Giuseppe

2013-06-21

We report an Italian family in which the proband showed a severe phenotype characterized by the association of congenital fiber type disproportion (CFTD) with a left ventricular non-compaction cardiomyopathy (LVNC). This study was focused on the identification of the responsible gene/s. Using the whole-exome sequencing approach, we identified the proband homozygous missense mutations in two genes, the myosin heavy chain 7B (MYH7B) and the integrin alpha 7 (ITGA7). Both genes are expressed in heart and muscle tissues, and both mutations were predicted to be deleterious and were not found in the healthy population.The R890C mutation in the MYH7B gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy.The E882K mutation in the ITGA7 gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD. This study identifies two novel disease genes. Mutation in MYH7B causes a classical LVNC phenotype, whereas mutation in ITGA7 causes CFTD. Both phenotypes represent alterations of skeletal and cardiac muscle maturation and are usually not severe. The severe phenotype of the proband is most likely due to a synergic effect of these two mutations.This study provides new insights into the genetics underlying Mendelian traits and demonstrates a role for digenic inheritance in complex phenotypes.

Susceptibility of bone marrow-derived macrophages to influenza virus infection is dependent on macrophage phenotype.

PubMed

Campbell, Gillian M; Nicol, Marlynne Q; Dransfield, Ian; Shaw, Darren J; Nash, Anthony A; Dutia, Bernadette M

2015-10-01

The role of the macrophage in influenza virus infection is complex. Macrophages are critical for resolution of influenza virus infections but implicated in morbidity and mortality in severe infections. They can be infected with influenza virus and consequently macrophage infection is likely to have an impact on the host immune response. Macrophages display a range of functional phenotypes, from the prototypical pro-inflammatory classically activated cell to alternatively activated anti-inflammatory macrophages involved in immune regulation and wound healing. We were interested in how macrophages of different phenotype respond to influenza virus infection and therefore studied the infection of bone marrow-derived macrophages (BMDMs) of classical and alternative phenotype in vitro. Our results show that alternatively activated macrophages are more readily infected and killed by the virus than classically activated. Classically activated BMDMs express the pro-inflammatory markers inducible nitric oxide synthase (iNOS) and TNF-α, and TNF-α expression was further upregulated following infection. Alternatively activated macrophages express Arginase-1 and CD206; however, following infection, expression of these markers was downregulated whilst expression of iNOS and TNF-α was upregulated. Thus, infection can override the anti-inflammatory state of alternatively activated macrophages. Importantly, however, this results in lower levels of pro-inflammatory markers than those produced by classically activated cells. Our results showed that macrophage phenotype affects the inflammatory macrophage response following infection, and indicated that modulating the macrophage phenotype may provide a route to develop novel strategies to prevent and treat influenza virus infection.

An analysis of polygenes affecting wing shape on chromosome 2 in Drosophila melanogaster.

PubMed Central

Weber, K; Eisman, R; Higgins, S; Morey, L; Patty, A; Tausek, M; Zeng, Z B

2001-01-01

Genetic effects on an index of wing shape on chromosome 2 of Drosophila melanogaster were mapped using isogenic recombinants with transposable element markers. At least 10 genes with small additive effects are dispersed evenly along the chromosome. Many interactions exist, with only small net effects in homozygous recombinants and little effect on phenotypic variance. Heterozygous chromosome segments show almost no dominance. Pleiotropic effects on leg shape are only minor. At first view, wing shape genes form a rather homogeneous class, but certain complexities remain unresolved. PMID:11729152

Culture and biology in the origins of linguistic structure.

PubMed

Kirby, Simon

2017-02-01

Language is systematically structured at all levels of description, arguably setting it apart from all other instances of communication in nature. In this article, I survey work over the last 20 years that emphasises the contributions of individual learning, cultural transmission, and biological evolution to explaining the structural design features of language. These 3 complex adaptive systems exist in a network of interactions: individual learning biases shape the dynamics of cultural evolution; universal features of linguistic structure arise from this cultural process and form the ultimate linguistic phenotype; the nature of this phenotype affects the fitness landscape for the biological evolution of the language faculty; and in turn this determines individuals' learning bias. Using a combination of computational simulation, laboratory experiments, and comparison with real-world cases of language emergence, I show that linguistic structure emerges as a natural outcome of cultural evolution once certain minimal biological requirements are in place.

No Interactive Effects of Sex and Persistent Cytomegalovirus on Immune Phenotypes in Young Children: The Generation R Study.

PubMed

Jansen, Michelle A E; van den Heuvel, Diana; Jaddoe, Vincent W V; Moll, Henriette A; van Zelm, Menno C

2017-03-15

Persistent infections with cytomegalovirus (CMV) differentially affect the host immune phenotype in middle-aged males and females. Because CMV already impacts on T-cell memory at a young age, we studied whether these effects were modified by sex in 1,079 children with an average age of 6 years. Sex and CMV independently impacted on multiple B-cell and T-cell subsets. However, there was no significant effect of their interaction. Importantly, the effects of sex and CMV were in part explained by age and infection with other herpesviruses. Thus, immune aging is likely to be more complex, with involvement of hormonal changes with age, socioeconomic status, birth characteristics, and pathogen exposure. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Genome-Wide Association Study for Muscle Fat Content and Abdominal Fat Traits in Common Carp (Cyprinus carpio)

PubMed Central

Zheng, Xianhu; Kuang, Youyi; Lv, Weihua; Cao, Dingchen; Sun, Zhipeng; Sun, Xiaowen

2016-01-01

Muscle fat content is an important phenotypic trait in fish, as it affects the nutritional, technical and sensory qualities of flesh. To identify loci and candidate genes associated with muscle fat content and abdominal fat traits, we performed a genome-wide association study (GWAS) using the common carp 250 K SNP assay in a common carp F2 resource population. A total of 18 loci surpassing the genome-wide suggestive significance level were detected for 4 traits: fat content in dorsal muscle (MFdo), fat content in abdominal muscle (MFab), abdominal fat weight (AbFW), and AbFW as a percentage of eviscerated weight (AbFP). Among them, one SNP (carp089419) affecting both AbFW and AbFP reached the genome-wide significance level. Ten of those loci were harbored in or near known genes. Furthermore, relative expressions of 5 genes related to MFdo were compared using dorsal muscle samples with high and low phenotypic values. The results showed that 4 genes were differentially expressed between the high and low phenotypic groups. These genes are, therefore, prospective candidate genes for muscle fat content: ankyrin repeat domain 10a (ankrd10a), tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (tanc2), and four jointed box 1 (fjx1) and choline kinase alpha (chka). These results offer valuable insights into the complex genetic basis of fat metabolism and deposition. PMID:28030623

Mutations in COQ8B (ADCK4) found in patients with steroid‐resistant nephrotic syndrome alter COQ8B function

PubMed Central

Vazquez Fonseca, Luis; Doimo, Mara; Calderan, Cristina; Desbats, Maria Andrea; Acosta, Manuel J.; Cerqua, Cristina; Cassina, Matteo; Ashraf, Shazia; Hildebrandt, Friedhelm; Sartori, Geppo; Navas, Placido; Trevisson, Eva

2017-01-01

Abstract Mutations in COQ8B cause steroid‐resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a ΔCOQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype–phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits. PMID:29194833

INVOLVED IN DE NOVO 2-containing complex involved in RNA-directed DNA methylation in Arabidopsis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ausin, Israel; Greenberg, Maxim V.C.; Simanshu, Dhirendra K.

2012-10-23

At least three pathways control maintenance of DNA cytosine methylation in Arabidopsis thaliana. However, the RNA-directed DNA methylation (RdDM) pathway is solely responsible for establishment of this silencing mark. We previously described INVOLVED IN DE NOVO 2 (IDN2) as being an RNA-binding RdDM component that is required for DNA methylation establishment. In this study, we describe the discovery of two partially redundant proteins that are paralogous to IDN2 and that form a stable complex with IDN2 in vivo. Null mutations in both genes, termed IDN2-LIKE 1 and IDN2-LIKE 2 (IDNL1 and IDNL2), result in a phenotype that mirrors, but doesmore » not further enhance, the idn2 mutant phenotype. Genetic analysis suggests that this complex acts in a step in the downstream portion of the RdDM pathway. We also have performed structural analysis showing that the IDN2 XS domain adopts an RNA recognition motif (RRM) fold. Finally, genome-wide DNA methylation and expression analysis confirms the placement of the IDN proteins in an RdDM pathway that affects DNA methylation and transcriptional control at many sites in the genome. Results from this study identify and describe two unique components of the RdDM machinery, adding to our understanding of DNA methylation control in the Arabidopsis genome.« less

TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast.

PubMed

Rallis, Charalampos; Codlin, Sandra; Bähler, Jürg

2013-08-01

Target of rapamycin complex 1 (TORC1) is implicated in growth control and aging from yeast to humans. Fission yeast is emerging as a popular model organism to study TOR signaling, although rapamycin has been thought to not affect cell growth in this organism. Here, we analyzed the effects of rapamycin and caffeine, singly and combined, on multiple cellular processes in fission yeast. The two drugs led to diverse and specific phenotypes that depended on TORC1 inhibition, including prolonged chronological lifespan, inhibition of global translation, inhibition of cell growth and division, and reprograming of global gene expression mimicking nitrogen starvation. Rapamycin and caffeine differentially affected these various TORC1-dependent processes. Combined drug treatment augmented most phenotypes and effectively blocked cell growth. Rapamycin showed a much more subtle effect on global translation than did caffeine, while both drugs were effective in prolonging chronological lifespan. Rapamycin and caffeine did not affect the lifespan via the pH of the growth media. Rapamycin prolonged the lifespan of nongrowing cells only when applied during the growth phase but not when applied after cells had stopped proliferation. The doses of rapamycin and caffeine strongly correlated with growth inhibition and with lifespan extension. This comprehensive analysis will inform future studies into TORC1 function and cellular aging in fission yeast and beyond. © 2013 The Authors. Aging Cell published by John Wiley & Sons Ltd and the Anatomical Society.

Novel autosomal dominant mandibulofacial dysostosis with ptosis: clinical description and exclusion of TCOF1.

PubMed

Hedera, P; Toriello, H V; Petty, E M

2002-07-01

Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these, only the Bauru type of MFD has an autosomal dominant (AD) mode of inheritance established. Here we report clinical features of a kindred with a unique AD MFD with the exclusion of linkage to the TCS locus (TCOF1) on chromosome 5q31-q32. Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype. Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal. We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype.

Imagination in human social cognition, autism, and psychotic-affective conditions.

PubMed

Crespi, Bernard; Leach, Emma; Dinsdale, Natalie; Mokkonen, Mikael; Hurd, Peter

2016-05-01

Complex human social cognition has evolved in concert with risks for psychiatric disorders. Recently, autism and psychotic-affective conditions (mainly schizophrenia, bipolar disorder, and depression) have been posited as psychological 'opposites' with regard to social-cognitive phenotypes. Imagination, considered as 'forming new ideas, mental images, or concepts', represents a central facet of human social evolution and cognition. Previous studies have documented reduced imagination in autism, and increased imagination in association with psychotic-affective conditions, yet these sets of findings have yet to be considered together, or evaluated in the context of the diametric model. We first review studies of the components, manifestations, and neural correlates of imagination in autism and psychotic-affective conditions. Next, we use data on dimensional autism in healthy populations to test the hypotheses that: (1) imagination represents the facet of autism that best accounts for its strongly male-biased sex ratio, and (2) higher genetic risk of schizophrenia is associated with higher imagination, in accordance with the predictions of the diametric model. The first hypothesis was supported by a systematic review and meta-analysis showing that Imagination exhibits the strongest male bias of all Autism Quotient (AQ) subscales, in non-clinical populations. The second hypothesis was supported, for males, by associations between schizophrenia genetic risk scores, derived from a set of single-nucleotide polymorphisms, and the AQ Imagination subscale. Considered together, these findings indicate that imagination, especially social imagination as embodied in the default mode human brain network, mediates risk and diametric dimensional phenotypes of autism and psychotic-affective conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Ab initio genotype–phenotype association reveals intrinsic modularity in genetic networks

PubMed Central

Slonim, Noam; Elemento, Olivier; Tavazoie, Saeed

2006-01-01

Microbial species express an astonishing diversity of phenotypic traits, behaviors, and metabolic capacities. However, our molecular understanding of these phenotypes is based almost entirely on studies in a handful of model organisms that together represent only a small fraction of this phenotypic diversity. Furthermore, many microbial species are not amenable to traditional laboratory analysis because of their exotic lifestyles and/or lack of suitable molecular genetic techniques. As an adjunct to experimental analysis, we have developed a computational information-theoretic framework that produces high-confidence gene–phenotype predictions using cross-species distributions of genes and phenotypes across 202 fully sequenced archaea and eubacteria. In addition to identifying the genetic basis of complex traits, our approach reveals the organization of these genes into generic preferentially co-inherited modules, many of which correspond directly to known enzymatic pathways, molecular complexes, signaling pathways, and molecular machines. PMID:16732191

A random set scoring model for prioritization of disease candidate genes using protein complexes and data-mining of GeneRIF, OMIM and PubMed records.

PubMed

Jiang, Li; Edwards, Stefan M; Thomsen, Bo; Workman, Christopher T; Guldbrandtsen, Bernt; Sørensen, Peter

2014-09-24

Prioritizing genetic variants is a challenge because disease susceptibility loci are often located in genes of unknown function or the relationship with the corresponding phenotype is unclear. A global data-mining exercise on the biomedical literature can establish the phenotypic profile of genes with respect to their connection to disease phenotypes. The importance of protein-protein interaction networks in the genetic heterogeneity of common diseases or complex traits is becoming increasingly recognized. Thus, the development of a network-based approach combined with phenotypic profiling would be useful for disease gene prioritization. We developed a random-set scoring model and implemented it to quantify phenotype relevance in a network-based disease gene-prioritization approach. We validated our approach based on different gene phenotypic profiles, which were generated from PubMed abstracts, OMIM, and GeneRIF records. We also investigated the validity of several vocabulary filters and different likelihood thresholds for predicted protein-protein interactions in terms of their effect on the network-based gene-prioritization approach, which relies on text-mining of the phenotype data. Our method demonstrated good precision and sensitivity compared with those of two alternative complex-based prioritization approaches. We then conducted a global ranking of all human genes according to their relevance to a range of human diseases. The resulting accurate ranking of known causal genes supported the reliability of our approach. Moreover, these data suggest many promising novel candidate genes for human disorders that have a complex mode of inheritance. We have implemented and validated a network-based approach to prioritize genes for human diseases based on their phenotypic profile. We have devised a powerful and transparent tool to identify and rank candidate genes. Our global gene prioritization provides a unique resource for the biological interpretation of data from genome-wide association studies, and will help in the understanding of how the associated genetic variants influence disease or quantitative phenotypes.

A comparative study of major histocompatibility complex and red blood cell antigen phenotypes as risk factors for recurrent urinary tract infections in women.

PubMed

Hopkins, W J; Heisey, D M; Lorentzen, D F; Uehling, D T

1998-05-01

Recurrent urinary tract infections (RUTI) are a significant health problem for many women, and host characteristics that increase susceptibility are not completely defined. This study evaluated data from 99 patients to examine further the question of a possible association between major histocompatibility complex (MHC) or red blood cell (RBC) antigen phenotype and predisposition to RUTIs. MHC class I and II, ABO, and Lewis RBC phenotypes were determined serologically. The MHC class II phenotypes of 55 subjects were also determined by DNA polymerase chain reaction techniques. There were no significant differences in the proportions of HLA-A or -B antigen types between patients and controls, nor in the frequencies of serologically or DNA-defined HLA-DR or -DQ phenotypes. Patient ABO and Lewis RBC phenotypes were not statistically different than those for controls. Thus, the overall risk for women to develop RUTIs does not appear to be associated with any single HLA, ABO, or Lewis phenotype.

Maneuvering in the Complex Path from Genotype to Phenotype

NASA Astrophysics Data System (ADS)

Strohman, Richard

2002-04-01

Human disease phenotypes are controlled not only by genes but by lawful self-organizing networks that display system-wide dynamics. These networks range from metabolic pathways to signaling pathways that regulate hormone action. When perturbed, networks alter their output of matter and energy which, depending on the environmental context, can produce either a pathological or a normal phenotype. Study of the dynamics of these networks by approaches such as metabolic control analysis may provide new insights into the pathogenesis and treatment of complex diseases.

Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

PubMed Central

Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

2014-01-01

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder. PMID:24522887

The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation.

PubMed

Bermeo, Sandra; Al-Saedi, Ahmed; Kassem, Moustapha; Vidal, Christopher; Duque, Gustavo

2017-12-01

Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this pro-osteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic differentiation were performed. MAN1 knockdown increased osteogenesis and mineralization. In contrast, osteogenesis remained stable upon MAN1 overexpression. Regarding a mechanism, we found that low levels of MAN1 facilitated the nuclear accumulation of regulatory smads and smads-related complexes, with a concurrently high expression of nuclear β-Catenin. In addition, we found adipogenesis to be decreased in both conditions, although predominantly affected by MAN1 overexpression. Finally, lamin A, a protein of the nuclear envelope that regulates MSC differentiation, was unaffected by changes in MAN1. In conclusion, our studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis. These effects could have an important role in the understanding of the role of the proteins of the nuclear envelope in bone formation. J. Cell. Biochem. 118: 4425-4435, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses

PubMed Central

Kringel, D; Ultsch, A; Zimmermann, M; Jansen, J-P; Ilias, W; Freynhagen, R; Griessinger, N; Kopf, A; Stein, C; Doehring, A; Resch, E; Lötsch, J

2017-01-01

Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces ‘big data’ exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics. PMID:27139154

Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses.

PubMed

Kringel, D; Ultsch, A; Zimmermann, M; Jansen, J-P; Ilias, W; Freynhagen, R; Griessinger, N; Kopf, A; Stein, C; Doehring, A; Resch, E; Lötsch, J

2017-10-01

Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics.

Membrane-targeted WAVE mediates photoreceptor axon targeting in the absence of the WAVE complex in Drosophila

PubMed Central

Stephan, Raiko; Gohl, Christina; Fleige, Astrid; Klämbt, Christian; Bogdan, Sven

2011-01-01

A tight spatial-temporal coordination of F-actin dynamics is crucial for a large variety of cellular processes that shape cells. The Abelson interactor (Abi) has a conserved role in Arp2/3-dependent actin polymerization, regulating Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE). In this paper, we report that Abi exerts nonautonomous control of photoreceptor axon targeting in the Drosophila visual system through WAVE. In abi mutants, WAVE is unstable but restored by reexpression of Abi, confirming that Abi controls the integrity of the WAVE complex in vivo. Remarkably, expression of a membrane-tethered WAVE protein rescues the axonal projection defects of abi mutants in the absence of the other subunits of the WAVE complex, whereas cytoplasmic WAVE only slightly affects the abi mutant phenotype. Thus complex formation not only stabilizes WAVE, but also provides further membrane-recruiting signals, resulting in an activation of WAVE. PMID:21900504

Phenotypic integration and the evolution of signal repertoires: A case study of treefrog acoustic communication.

PubMed

Reichert, Michael S; Höbel, Gerlinde

2018-03-01

Animal signals are inherently complex phenotypes with many interacting parts combining to elicit responses from receivers. The pattern of interrelationships between signal components reflects the extent to which each component is expressed, and responds to selection, either in concert with or independently of others. Furthermore, many species have complex repertoires consisting of multiple signal types used in different contexts, and common morphological and physiological constraints may result in interrelationships extending across the multiple signals in species' repertoires. The evolutionary significance of interrelationships between signal traits can be explored within the framework of phenotypic integration, which offers a suite of quantitative techniques to characterize complex phenotypes. In particular, these techniques allow for the assessment of modularity and integration, which describe, respectively, the extent to which sets of traits covary either independently or jointly. Although signal and repertoire complexity are thought to be major drivers of diversification and social evolution, few studies have explicitly measured the phenotypic integration of signals to investigate the evolution of diverse communication systems. We applied methods from phenotypic integration studies to quantify integration in the two primary vocalization types (advertisement and aggressive calls) in the treefrogs Hyla versicolor , Hyla cinerea, and Dendropsophus ebraccatus . We recorded male calls and calculated standardized phenotypic variance-covariance ( P ) matrices for characteristics within and across call types. We found significant integration across call types, but the strength of integration varied by species and corresponded with the acoustic similarity of the call types within each species. H. versicolor had the most modular advertisement and aggressive calls and the least acoustically similar call types. Additionally, P was robust to changing social competition levels in H. versicolor . Our findings suggest new directions in animal communication research in which the complex relationships among the traits of multiple signals are a key consideration for understanding signal evolution.

The genetic architecture of a complex ecological trait: host plant use in the specialist moth, HELIOTHIS SUBFLEXA

USDA-ARS?s Scientific Manuscript database

The study of the genetic basis of ecological adaptation remains in its infancy, and most studies have focused on phenotypically simple traits. Host plant use by herbivorous insects is phenotypically complex. While research has illuminated the evolutionary determinants of host use, knowledge of its...

Domesticated, Genetically Engineered, and Wild Plant Relatives Exhibit Unintended Phenotypic Differences: A Comparative Meta-Analysis Profiling Rice, Canola, Maize, Sunflower, and Pumpkin

PubMed Central

Hernández-Terán, Alejandra; Wegier, Ana; Benítez, Mariana; Lira, Rafael; Escalante, Ana E.

2017-01-01

Agronomic management of plants is a powerful evolutionary force acting on their populations. The management of cultivated plants is carried out by the traditional process of human selection or plant breeding and, more recently, by the technologies used in genetic engineering (GE). Even though crop modification through GE is aimed at specific traits, it is possible that other non-target traits can be affected by genetic modification due to the complex regulatory processes of plant metabolism and development. In this study, we conducted a meta-analysis profiling the phenotypic consequences of plant breeding and GE, and compared modified cultivars with wild relatives in five crops of global economic and cultural importance: rice, maize, canola, sunflower, and pumpkin. For these five species, we analyzed the literature with documentation of phenotypic traits that are potentially related to fitness for the same species in comparable conditions. The information was analyzed to evaluate whether the different processes of modification had influenced the phenotype in such a way as to cause statistical differences in the state of specific phenotypic traits or grouping of the organisms depending on their genetic origin [wild, domesticated with genetic engineering (domGE), and domesticated without genetic engineering (domNGE)]. In addition, we tested the hypothesis that, given that transgenic plants are a construct designed to impact, in many cases, a single trait of the plant (e.g., lepidopteran resistance), the phenotypic differences between domGE and domNGE would be either less (or inexistent) than between the wild and domesticated relatives (either domGE or domNGE). We conclude that (1) genetic modification (either by selective breeding or GE) can be traced phenotypically when comparing wild relatives with their domesticated relatives (domGE and domNGE) and (2) the existence and the magnitude of the phenotypic differences between domGE and domNGE of the same crop suggest consequences of genetic modification beyond the target trait(s). PMID:29259610

Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster

PubMed Central

Morozova, Tatiana V; Anholt, Robert RH; Mackay, Trudy FC

2007-01-01

Background Alcoholism is a complex disorder determined by interactions between genetic and environmental risk factors. Drosophila represents a powerful model system to dissect the genetic architecture of alcohol sensitivity, as large numbers of flies can readily be reared in defined genetic backgrounds and under controlled environmental conditions. Furthermore, flies exposed to ethanol undergo physiological and behavioral changes that resemble human alcohol intoxication, including loss of postural control, sedation, and development of tolerance. Results We performed artificial selection for alcohol sensitivity for 35 generations and created duplicate selection lines that are either highly sensitive or resistant to ethanol exposure along with unselected control lines. We used whole genome expression analysis to identify 1,678 probe sets with different expression levels between the divergent lines, pooled across replicates, at a false discovery rate of q < 0.001. We assessed to what extent genes with altered transcriptional regulation might be causally associated with ethanol sensitivity by measuring alcohol sensitivity of 37 co-isogenic P-element insertional mutations in 35 candidate genes, and found that 32 of these mutants differed in sensitivity to ethanol exposure from their co-isogenic controls. Furthermore, 23 of these novel genes have human orthologues. Conclusion Combining whole genome expression profiling with selection for genetically divergent lines is an effective approach for identifying candidate genes that affect complex traits, such as alcohol sensitivity. Because of evolutionary conservation of function, it is likely that human orthologues of genes affecting alcohol sensitivity in Drosophila may contribute to alcohol-associated phenotypes in humans. PMID:17973985

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes

PubMed Central

Rangaswamy, Madhavi; Porjesz, Bernice

2010-01-01

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders. PMID:18634760

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes.

PubMed

Rangaswamy, Madhavi; Porjesz, Bernice

2008-10-15

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders.

Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

PubMed

Monks, D A; Swift-Gallant, A

2018-02-01

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I

PubMed Central

Bonatti, Francesco; Adorni, Alessia; Matichecchia, Annalisa; Mozzoni, Paola; Uliana, Vera; Pisani, Francesco; Garavelli, Livia; Graziano, Claudio; Gnoli, Maria; Bigoni, Stefania; Boschi, Elena; Martorana, Davide; Percesepe, Antonio

2017-01-01

Neurofibromatosis type I, a genetic disorder due to mutations in the NF1 gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all NF1 gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype/phenotype correlation was found, confirming previous evidences. PMID:28961165

Sugars in peach fruit: a breeding perspective

PubMed Central

Cirilli, Marco; Bassi, Daniele; Ciacciulli, Angelo

2016-01-01

The last decade has been characterized by a decrease in peach (Prunus persica) fruit consumption in many countries, foremost due to unsatisfactory quality. The sugar content is one of the most important quality traits perceived by consumers, and the development of novel peach cultivars with sugar-enhanced content is a primary objective of breeding programs to revert the market inertia. Nevertheless, the progress reachable through classical phenotypic selection is limited by the narrow genetic bases of peach breeding material and by the complex quantitative nature of the trait, which is deeply affected by environmental conditions and agronomical management. The development of molecular markers applicable in MAS or MAB has become an essential strategy to boost the selection efficiency. Despite the enormous advances in ‘omics’ sciences, providing powerful tools for plant genotyping, the identification of the genetic bases of sugar-related traits is hindered by the lack of adequate phenotyping methods that are able to address strong within-plant variability. This review provides an overview of the current knowledge of the metabolic pathways and physiological mechanisms regulating sugar accumulation in peach fruit, the main advances in phenotyping approaches and genetic background, and finally addressing new research priorities and prospective for breeders. PMID:26816618

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

PubMed

Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

2002-06-01

To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

Genome-wide association studies dissect the genetic networks underlying agronomical traits in soybean.

PubMed

Fang, Chao; Ma, Yanming; Wu, Shiwen; Liu, Zhi; Wang, Zheng; Yang, Rui; Hu, Guanghui; Zhou, Zhengkui; Yu, Hong; Zhang, Min; Pan, Yi; Zhou, Guoan; Ren, Haixiang; Du, Weiguang; Yan, Hongrui; Wang, Yanping; Han, Dezhi; Shen, Yanting; Liu, Shulin; Liu, Tengfei; Zhang, Jixiang; Qin, Hao; Yuan, Jia; Yuan, Xiaohui; Kong, Fanjiang; Liu, Baohui; Li, Jiayang; Zhang, Zhiwu; Wang, Guodong; Zhu, Baoge; Tian, Zhixi

2017-08-24

Soybean (Glycine max [L.] Merr.) is one of the most important oil and protein crops. Ever-increasing soybean consumption necessitates the improvement of varieties for more efficient production. However, both correlations among different traits and genetic interactions among genes that affect a single trait pose a challenge to soybean breeding. To understand the genetic networks underlying phenotypic correlations, we collected 809 soybean accessions worldwide and phenotyped them for two years at three locations for 84 agronomic traits. Genome-wide association studies identified 245 significant genetic loci, among which 95 genetically interacted with other loci. We determined that 14 oil synthesis-related genes are responsible for fatty acid accumulation in soybean and function in line with an additive model. Network analyses demonstrated that 51 traits could be linked through the linkage disequilibrium of 115 associated loci and these links reflect phenotypic correlations. We revealed that 23 loci, including the known Dt1, E2, E1, Ln, Dt2, Fan, and Fap loci, as well as 16 undefined associated loci, have pleiotropic effects on different traits. This study provides insights into the genetic correlation among complex traits and will facilitate future soybean functional studies and breeding through molecular design.

Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.

PubMed

Burrage, Lindsay C; Tang, Sha; Wang, Jing; Donti, Taraka R; Walkiewicz, Magdalena; Luchak, J Michael; Chen, Li-Chieh; Schmitt, Eric S; Niu, Zhiyv; Erana, Rodrigo; Hunter, Jill V; Graham, Brett H; Wong, Lee-Jun; Scaglia, Fernando

2014-11-01

Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) is a rare mitochondrial disorder that has previously been associated with mutations in PUS1 and YARS2. In the present report, we describe a 6-year old male with an MLASA plus phenotype. This patient had features of MLASA in the setting of developmental delay, sensorineural hearing loss, epilepsy, agenesis of the corpus callosum, failure to thrive, and stroke-like episodes. Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N). Whole exome sequencing did not identify mutations or variants in PUS1 or YARS2 or any known nuclear genes that could affect mitochondrial function and explain this phenotype. Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect. Thus, this mutation in MT-ATP6 may represent the first mtDNA point mutation associated with the MLASA phenotype. Copyright © 2014 Elsevier Inc. All rights reserved.

De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females

PubMed Central

Popp, Bernt; Støve, Svein I; Endele, Sabine; Myklebust, Line M; Hoyer, Juliane; Sticht, Heinrich; Azzarello-Burri, Silvia; Rauch, Anita; Arnesen, Thomas; Reis, André

2015-01-01

Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity. PMID:25099252

Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation

PubMed Central

2013-01-01

Background Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as “activation”, is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress. Methods Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) or conditioned medium from lipopolysaccharide-activated microglia to promote activation and then exposed to a protocol of iron overload. Results We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance. Conclusions We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state. PMID:24160637

SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant

PubMed Central

Dauber, Andrew; Golzio, Christelle; Guenot, Cécile; Jodelka, Francine M.; Kibaek, Maria; Kjaergaard, Susanne; Leheup, Bruno; Martinet, Danielle; Nowaczyk, Malgorzata J.M.; Rosenfeld, Jill A.; Zeesman, Susan; Zunich, Janice; Beckmann, Jacques S.; Hirschhorn, Joel N.; Hastings, Michelle L.; Jacquemont, Sebastien; Katsanis, Nicholas

2013-01-01

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions. PMID:24140112

TATES: Efficient Multivariate Genotype-Phenotype Analysis for Genome-Wide Association Studies

PubMed Central

van der Sluis, Sophie; Posthuma, Danielle; Dolan, Conor V.

2013-01-01

To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype–phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype–phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5–9 times higher than the power of univariate tests based on composite scores and 1.5–2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype–phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor. PMID:23359524

Network Analysis Reveals Putative Genes Affecting Meat Quality in Angus Cattle.

PubMed

Mateescu, Raluca G; Garrick, Dorian J; Reecy, James M

2017-01-01

Improvements in eating satisfaction will benefit consumers and should increase beef demand which is of interest to the beef industry. Tenderness, juiciness, and flavor are major determinants of the palatability of beef and are often used to reflect eating satisfaction. Carcass qualities are used as indicator traits for meat quality, with higher quality grade carcasses expected to relate to more tender and palatable meat. However, meat quality is a complex concept determined by many component traits making interpretation of genome-wide association studies (GWAS) on any one component challenging to interpret. Recent approaches combining traditional GWAS with gene network interactions theory could be more efficient in dissecting the genetic architecture of complex traits. Phenotypic measures of 23 traits reflecting carcass characteristics, components of meat quality, along with mineral and peptide concentrations were used along with Illumina 54k bovine SNP genotypes to derive an annotated gene network associated with meat quality in 2,110 Angus beef cattle. The efficient mixed model association (EMMAX) approach in combination with a genomic relationship matrix was used to directly estimate the associations between 54k SNP genotypes and each of the 23 component traits. Genomic correlated regions were identified by partial correlations which were further used along with an information theory algorithm to derive gene network clusters. Correlated SNP across 23 component traits were subjected to network scoring and visualization software to identify significant SNP. Significant pathways implicated in the meat quality complex through GO term enrichment analysis included angiogenesis, inflammation, transmembrane transporter activity, and receptor activity. These results suggest that network analysis using partial correlations and annotation of significant SNP can reveal the genetic architecture of complex traits and provide novel information regarding biological mechanisms and genes that lead to complex phenotypes, like meat quality, and the nutritional and healthfulness value of beef. Improvements in genome annotation and knowledge of gene function will contribute to more comprehensive analyses that will advance our ability to dissect the complex architecture of complex traits.

Effects of structural complexity on within-canopy light environments and leaf traits in a northern mixed deciduous forest.

PubMed

Fotis, Alexander T; Curtis, Peter S

2017-10-01

Canopy structure influences forest productivity through its effects on the distribution of radiation and the light-induced changes in leaf physiological traits. Due to the difficulty of accessing and measuring forest canopies, few field-based studies have quantitatively linked these divergent scales of canopy functioning. The objective of our study was to investigate how canopy structure affects light profiles within a forest canopy and whether leaves of mature trees adjust morphologically and biochemically to the light environments characteristic of canopies with different structural complexity. We used a combination of light detection and ranging (LiDAR) data and hemispherical photographs to quantify canopy structure and light environments, respectively, and a telescoping pole to sample leaves. Leaf mass per area (LMA), nitrogen on an area basis (Narea) and chlorophyll on a mass basis (Chlmass) were measured in red maple (Acer rubrum), american beech (Fagus grandifolia), white pine (Pinus strobus), and northern red oak (Quercus rubra) at different heights in plots with similar leaf area index but contrasting canopy complexity (rugosity). We found that more complex canopies had greater porosity and reduced light variability in the midcanopy while total light interception was unchanged relative to less complex canopies. Leaf phenotypes of F. grandifolia, Q. rubra and P. strobus were more sun-acclimated in the midstory of structurally complex canopies while leaf phenotypes of A. rubrum were more shade-acclimated (lower LMA) in the upper canopy of more complex stands, despite no differences in total light interception. Broadleaf species showed further differences in acclimation with increased Narea and reduced Chlmass in leaves with higher LMA, while P. strobus showed no change in Narea and Chlmass with higher LMA. Our results provide new insight on how light distribution and leaf acclimation in mature trees might be altered when natural and anthropogenic disturbances cause structural changes in the canopy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Nuclear Pore-Associated TREX-2 Complex Employs Mediator to Regulate Gene Expression

PubMed Central

Schneider, Maren; Hellerschmied, Doris; Schubert, Tobias; Amlacher, Stefan; Vinayachandran, Vinesh; Reja, Rohit; Pugh, B. Franklin; Clausen, Tim; Köhler, Alwin

2015-01-01

Summary Nuclear pore complexes (NPCs) influence gene expression besides their established function in nuclear transport. The TREX-2 complex localizes to the NPC basket and affects gene-NPC interactions, transcription, and mRNA export. How TREX-2 regulates the gene expression machinery is unknown. Here, we show that TREX-2 interacts with the Mediator complex, an essential regulator of RNA Polymerase (Pol) II. Structural and biochemical studies identify a conserved region on TREX-2, which directly binds the Mediator Med31/Med7N submodule. TREX-2 regulates assembly of Mediator with the Cdk8 kinase and is required for recruitment and site-specific phosphorylation of Pol II. Transcriptome and phenotypic profiling confirm that TREX-2 and Med31 are functionally interdependent at specific genes. TREX-2 additionally uses its Mediator-interacting surface to regulate mRNA export suggesting a mechanism for coupling transcription initiation and early steps of mRNA processing. Our data provide mechanistic insight into how an NPC-associated adaptor complex accesses the core transcription machinery. PMID:26317468

Vitamin K epoxide reductase complex subunit 1 (Vkorc1) haplotype diversity in mouse priority strains

PubMed Central

Song, Ying; Vera, Nicole; Kohn, Michael H

2008-01-01

Background Polymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc1, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP). Here we sequenced the Vkorc1 gene in 40 mouse priority strains. We analyzed Vkorc1 haplotypes with respect to prothrombin time (PT) and bone mineral density and composition (BMD and BMC); phenotypes expected to be vitamin K-dependent and represented by data in the Mouse Phenome Database (MPD). Findings In the commonly used laboratory strains of Mus musculus domesticus we identified only four haplotypes differing in the intron or 5' region sequence of the Vkorc1. Six haplotypes differing by coding and non-coding polymorphisms were identified in the other subspecies of Mus. We detected no significant association of Vkorc1 haplotypes with PT, BMD and BMC within each subspecies of Mus. Vkorc1 haplotype sequences divergence between subspecies was associated with PT, BMD and BMC. Conclusion Phenotypic variation in PT, BMD and BMC within subspecies of Mus, while substantial, appears to be dominated by genetic variation in genes other than the Vkorc1. This was particularly evident for M. m. domesticus, where a single haplotype was observed in conjunction with virtually the entire range of PT, BMD and BMC values of all 5 subspecies of Mus included in this study. Differences in these phenotypes between subspecies also should not be attributed to Vkorc1 variants, but should be viewed as a result of genome wide genetic divergence. PMID:19046458

Genotypic and Phenotypic Correlations of Multidrug-Resistant Acinetobacter baumannii-A. calcoaceticus Complex Strains Isolated from Patients at the National Naval Medical Center

USDA-ARS?s Scientific Manuscript database

Acinetobacter baumannii-calcoaceticus complex (ABC) infections have complicated the care of U.S. combat casualties. In this study, 102 ABC isolates from wounded soldiers treated at National Naval Medical Center (NNMC) were characterized by phenotype and genotype to identify clones in this population...

GiNA, an efficient and high-throughput software for horticultural phenotyping

USDA-ARS?s Scientific Manuscript database

Traditional methods for trait phenotyping have been a bottleneck for research in many crop species due to their intensive labor, high cost, complex implementation, lack of reproducibility and propensity to subjective bias. Recently, multiple high-throughput phenotyping platforms have been developed,...

A Multidisciplinary, Open Access Platform for Research on Biomolecules.

PubMed

Bähler, Jürg

2011-08-22

I am pleased to introduce Biomolecules, a new journal to report on all aspects of science that focuses on biologically derived substances, from small molecules to complex polymers. Some examples are lipids, carbohydrates, vitamins, hormones, amino acids, nucleotides, peptides, RNA and polysaccharides, but this list is far from exhaustive. Research on biomolecules encompasses multiple fascinating questions. How are biomolecules synthesized and modified? What are their structures and interactions with other biomolecules? How do biomolecules function in biological processes, at the level of organelles, cells, organs, organisms, or even ecosystems? How do biomolecules affect either the organism that produces them or other organisms of the same or different species? How are biomolecules shaped by evolution, and how in turn do they affect cellular phenotypes? What is the systems-level contribution of biomolecules to biological function? [...].

Tissue Factor-Factor VII Complex As a Key Regulator of Ovarian Cancer Phenotypes.

PubMed

Koizume, Shiro; Miyagi, Yohei

2015-01-01

Tissue factor (TF) is an integral membrane protein widely expressed in normal human cells. Blood coagulation factor VII (fVII) is a key enzyme in the extrinsic coagulation cascade that is predominantly secreted by hepatocytes and released into the bloodstream. The TF-fVII complex is aberrantly expressed on the surface of cancer cells, including ovarian cancer cells. This procoagulant complex can initiate intracellular signaling mechanisms, resulting in malignant phenotypes. Cancer tissues are chronically exposed to hypoxia. TF and fVII can be induced in response to hypoxia in ovarian cancer cells at the gene expression level, leading to the autonomous production of the TF-fVII complex. Here, we discuss the roles of the TF-fVII complex in the induction of malignant phenotypes in ovarian cancer cells. The hypoxic nature of ovarian cancer tissues and the roles of TF expression in endometriosis are discussed. Arguments will be extended to potential strategies to treat ovarian cancers based on our current knowledge of TF-fVII function.

Carrier screening for cystic fibrosis.

PubMed

Dungan, Jeffrey S

2010-03-01

Cystic fibrosis is the first genetic disorder for which universal screening of preconceptional or prenatal patients became a component of standard prenatal care. The molecular genetics and mutation profile of the CFTR gene are complex, with a wide range of phenotypic consequences. Carrier screening can facilitate risk assessment for prospective parents to have an affected offspring, although there remains a small residual risk for carrying a mutation even with a negative screening result. There are ethnic differences with respect to disease incidence and effectiveness of carrier testing, which may complicate counseling. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function.

PubMed

Vazquez Fonseca, Luis; Doimo, Mara; Calderan, Cristina; Desbats, Maria Andrea; Acosta, Manuel J; Cerqua, Cristina; Cassina, Matteo; Ashraf, Shazia; Hildebrandt, Friedhelm; Sartori, Geppo; Navas, Placido; Trevisson, Eva; Salviati, Leonardo

2018-03-01

Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a ΔCOQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits. © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.

Genetic variation of growth dynamics in maize (Zea mays L.) revealed through automated non-invasive phenotyping.

PubMed

Muraya, Moses M; Chu, Jianting; Zhao, Yusheng; Junker, Astrid; Klukas, Christian; Reif, Jochen C; Altmann, Thomas

2017-01-01

Hitherto, most quantitative trait loci of maize growth and biomass yield have been identified for a single time point, usually the final harvest stage. Through this approach cumulative effects are detected, without considering genetic factors causing phase-specific differences in growth rates. To assess the genetics of growth dynamics, we employed automated non-invasive phenotyping to monitor the plant sizes of 252 diverse maize inbred lines at 11 different developmental time points; 50 k SNP array genotype data were used for genome-wide association mapping and genomic selection. The heritability of biomass was estimated to be over 71%, and the average prediction accuracy amounted to 0.39. Using the individual time point data, 12 main effect marker-trait associations (MTAs) and six pairs of epistatic interactions were detected that displayed different patterns of expression at various developmental time points. A subset of them also showed significant effects on relative growth rates in different intervals. The detected MTAs jointly explained up to 12% of the total phenotypic variation, decreasing with developmental progression. Using non-parametric functional mapping and multivariate mapping approaches, four additional marker loci affecting growth dynamics were detected. Our results demonstrate that plant biomass accumulation is a complex trait governed by many small effect loci, most of which act at certain restricted developmental phases. This highlights the need for investigation of stage-specific growth affecting genes to elucidate important processes operating at different developmental phases. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Enhancement of plant metabolite fingerprinting by machine learning.

PubMed

Scott, Ian M; Vermeer, Cornelia P; Liakata, Maria; Corol, Delia I; Ward, Jane L; Lin, Wanchang; Johnson, Helen E; Whitehead, Lynne; Kular, Baldeep; Baker, John M; Walsh, Sean; Dave, Anuja; Larson, Tony R; Graham, Ian A; Wang, Trevor L; King, Ross D; Draper, John; Beale, Michael H

2010-08-01

Metabolite fingerprinting of Arabidopsis (Arabidopsis thaliana) mutants with known or predicted metabolic lesions was performed by (1)H-nuclear magnetic resonance, Fourier transform infrared, and flow injection electrospray-mass spectrometry. Fingerprinting enabled processing of five times more plants than conventional chromatographic profiling and was competitive for discriminating mutants, other than those affected in only low-abundance metabolites. Despite their rapidity and complexity, fingerprints yielded metabolomic insights (e.g. that effects of single lesions were usually not confined to individual pathways). Among fingerprint techniques, (1)H-nuclear magnetic resonance discriminated the most mutant phenotypes from the wild type and Fourier transform infrared discriminated the fewest. To maximize information from fingerprints, data analysis was crucial. One-third of distinctive phenotypes might have been overlooked had data models been confined to principal component analysis score plots. Among several methods tested, machine learning (ML) algorithms, namely support vector machine or random forest (RF) classifiers, were unsurpassed for phenotype discrimination. Support vector machines were often the best performing classifiers, but RFs yielded some particularly informative measures. First, RFs estimated margins between mutant phenotypes, whose relations could then be visualized by Sammon mapping or hierarchical clustering. Second, RFs provided importance scores for the features within fingerprints that discriminated mutants. These scores correlated with analysis of variance F values (as did Kruskal-Wallis tests, true- and false-positive measures, mutual information, and the Relief feature selection algorithm). ML classifiers, as models trained on one data set to predict another, were ideal for focused metabolomic queries, such as the distinctiveness and consistency of mutant phenotypes. Accessible software for use of ML in plant physiology is highlighted.

Neurodevelopmental Hypothesis about the Etiology of Autism Spectrum Disorders

PubMed Central

Inui, Toshio; Kumagaya, Shinichiro; Myowa-Yamakoshi, Masako

2017-01-01

Previous models or hypotheses of autism spectral disorder (ASD) failed to take into full consideration the chronological and causal developmental trajectory, leading to the emergence of diverse phenotypes through a complex interaction between individual etiologies and environmental factors. Those phenotypes include persistent deficits in social communication and social interaction (criteria A in DSM-5), and restricted, repetitive patterns of behavior, interests, or activities (criteria B in DSM-5). In this article, we proposed a domain-general model that can explain criteria in DSM-5 based on the assumption that the same etiological mechanism would trigger the various phenotypes observed in different individuals with ASD. In the model, we assumed the following joint causes as the etiology of autism: (1) Hypoplasia of the pons in the brainstem, occurring immediately following neural tube closure; and (2) Deficiency in the GABA (γ-aminobutyric acid) developmental switch during the perinatal period. Microstructural abnormalities of the pons directly affect both the structural and functional development of the brain areas strongly connected to it, especially amygdala. The impairment of GABA switch could not only lead to the deterioration of inhibitory processing in the neural network, but could also cause abnormal cytoarchitecture. We introduced a perspective that atypical development in both brain structure and function can give full explanation of diverse phenotypes and pathogenetic mechanism of ASD. Finally, we discussed about neural mechanisms underlying the phenotypic characteristics of ASD that are not described in DSM-5 but should be considered as important foundation: sleep, global precedence, categorical perception, intelligence, interoception and motor control. PMID:28744208

Genetic and environmental pathways to complex diseases.

PubMed

Gohlke, Julia M; Thomas, Reuben; Zhang, Yonqing; Rosenstein, Michael C; Davis, Allan P; Murphy, Cynthia; Becker, Kevin G; Mattingly, Carolyn J; Portier, Christopher J

2009-05-05

Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches. Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes. Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.

Analytic Complexity and Challenges in Identifying Mixtures of Exposures Associated with Phenotypes in the Exposome Era.

PubMed

Patel, Chirag J

2017-01-01

Mixtures, or combinations and interactions between multiple environmental exposures, are hypothesized to be causally linked with disease and health-related phenotypes. Established and emerging molecular measurement technologies to assay the exposome , the comprehensive battery of exposures encountered from birth to death, promise a new way of identifying mixtures in disease in the epidemiological setting. In this opinion, we describe the analytic complexity and challenges in identifying mixtures associated with phenotype and disease. Existing and emerging machine-learning methods and data analytic approaches (e.g., "environment-wide association studies" [EWASs]), as well as large cohorts may enhance possibilities to identify mixtures of correlated exposures associated with phenotypes; however, the analytic complexity of identifying mixtures is immense. If the exposome concept is realized, new analytical methods and large sample sizes will be required to ascertain how mixtures are associated with disease. The author recommends documenting prevalent correlated exposures and replicated main effects prior to identifying mixtures.

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.

PubMed

Higuchi, Yujiro; Okunushi, Ryuta; Hara, Taichi; Hashiguchi, Akihiro; Yuan, Junhui; Yoshimura, Akiko; Murayama, Kei; Ohtake, Akira; Ando, Masahiro; Hiramatsu, Yu; Ishihara, Satoshi; Tanabe, Hajime; Okamoto, Yuji; Matsuura, Eiji; Ueda, Takehiro; Toda, Tatsushi; Yamashita, Sumimasa; Yamada, Kenichiro; Koide, Takashi; Yaguchi, Hiroaki; Mitsui, Jun; Ishiura, Hiroyuki; Yoshimura, Jun; Doi, Koichiro; Morishita, Shinichi; Sato, Ken; Nakagawa, Masanori; Yamaguchi, Masamitsu; Tsuji, Shoji; Takashima, Hiroshi

2018-06-01

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

Novel mutations in the CDKL5 gene in complex genotypes associated with West syndrome with variable phenotype: First description of somatic mosaic state.

PubMed

Jdila, Marwa Ben; Issa, Abir Ben; Khabou, Boudour; Rhouma, Bochra Ben; Kamoun, Fatma; Ammar-Keskes, Leila; Triki, Chahnez; Fakhfakh, Faiza

2017-10-01

West syndrome is a rare epileptic encephalopathy of early infancy, characterized by epileptic spasms, hypsarrhythmia, and psychomotor retardation beginning in the first year of life. The present study reports the clinical, molecular and bioinformatic investigation in the three studied West patients. The results revealed a complex genotype with more than one mutation in each patient including the known mutations c.1910C>G (P2, P3); c.2372A>C in P3 and c.2395C>G in P1 and novel variants including c.616G>A, shared by the three patients P1, P2 and P3; c.1403G>C shared by P2 and P3 and c.2288A>G in patient P1. All the mutations were at somatic mosaic state and were de novo in the patients except ones (c.2372A>C). To our knowledge; the somatic mosaic state is described for the first time in patients with West syndrome. Five identified mutations were located in the C-terminal domain of the protein, while the novel mutation (c.616G>A) was in the catalytic domain. Bioinformatic tools predicted that this latter is the most pathogenic substitution affecting 3D protein structure and the secondary mRNA structure. Complex genotype composed of different combinations of mutations in each patient seems to be related to the phenotype variability. Copyright © 2017. Published by Elsevier B.V.

Why nature prevails over nurture in the making of the elite athlete.

PubMed

Georgiades, Evelina; Klissouras, Vassilis; Baulch, Jamie; Wang, Guan; Pitsiladis, Yannis

2017-11-14

While the influence of nature (genes) and nurture (environment) on elite sporting performance remains difficult to precisely determine, the dismissal of either as a contributing factor to performance is unwarranted. It is accepted that a complex interaction of a combination of innumerable factors may mold a talented athlete into a champion. The prevailing view today is that understanding elite human performance will require the deciphering of two major sources of individual differences, genes and the environment. It is widely accepted that superior performers are endowed with a high genetic potential actualised through hard and prodigious effort. Heritability studies using the twin model have provided the basis to disentangle genetic and environmental factors that contribute to complex human traits and have paved the way to the detection of specific genes for elite sport performance. Yet, the heritability for most phenotypes essential to elite human performance is above 50% but below 100%, meaning that the environment is also important. Furthermore, individual differences can potentially also be explained not only by the impact of DNA sequence variation on biology and behaviour, but also by the effects of epigenetic changes which affect phenotype by modifying gene expression. Despite this complexity, the overwhelming and accumulating evidence, amounted through experimental research spanning almost two centuries, tips the balance in favour of nature in the "nature" and "nurture" debate. In other words, truly elite-level athletes are built - but only from those born with innate ability.

Accessing the Phenotype Gap: Enabling Systematic Investigation of Paralog Functional Complexity with CRISPR.

PubMed

Ewen-Campen, Ben; Mohr, Stephanie E; Hu, Yanhui; Perrimon, Norbert

2017-10-09

Single-gene knockout experiments can fail to reveal function in the context of redundancy, which is frequently observed among duplicated genes (paralogs) with overlapping functions. We discuss the complexity associated with studying paralogs and outline how recent advances in CRISPR will help address the "phenotype gap" and impact biomedical research. Copyright © 2017 Elsevier Inc. All rights reserved.

Genomic networks of hybrid sterility.

PubMed

Turner, Leslie M; White, Michael A; Tautz, Diethard; Payseur, Bret A

2014-02-01

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci ("Dobzhansky-Muller incompatibilities"). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven 'hotspots,' seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL-but not cis eQTL-were substantially lower when mapping was restricted to a 'fertile' subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics.

Genomic Networks of Hybrid Sterility

PubMed Central

Turner, Leslie M.; White, Michael A.; Tautz, Diethard; Payseur, Bret A.

2014-01-01

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci (“Dobzhansky-Muller incompatibilities”). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL—but not cis eQTL—were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics. PMID:24586194

XERODERMA PIGMENTOSUM, TRICHOTHIODYSTROPHY AND COCKAYNE SYNDROME: A COMPLEX GENOTYPE-PHENOTYPE RELATIONSHIP

PubMed Central

Kraemer, Kenneth H.; Patronas, Nicholas J.; Schiffmann, Raphael; Brooks, Brian P.; Tamura, Deborah; DiGiovanna, John J.

2008-01-01

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least 8 overlapping phenotypes. The clinical features of these patients have some similarities and but also have marked differences. NER is involved in protection against sunlight induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes. PMID:17276014

Potential responses to climate change in organisms with complex life histories: evolution and plasticity in Pacific salmon.

PubMed

Crozier, L G; Hendry, A P; Lawson, P W; Quinn, T P; Mantua, N J; Battin, J; Shaw, R G; Huey, R B

2008-05-01

Salmon life histories are finely tuned to local environmental conditions, which are intimately linked to climate. We summarize the likely impacts of climate change on the physical environment of salmon in the Pacific Northwest and discuss the potential evolutionary consequences of these changes, with particular reference to Columbia River Basin spring/summer Chinook (Oncorhynchus tshawytscha) and sockeye (Oncorhynchus nerka) salmon. We discuss the possible evolutionary responses in migration and spawning date egg and juvenile growth and development rates, thermal tolerance, and disease resistance. We know little about ocean migration pathways, so cannot confidently suggest the potential changes in this life stage. Climate change might produce conflicting selection pressures in different life stages, which will interact with plastic (i.e. nongenetic) changes in various ways. To clarify these interactions, we present a conceptual model of how changing environmental conditions shift phenotypic optima and, through plastic responses, phenotype distributions, affecting the force of selection. Our predictions are tentative because we lack data on the strength of selection, heritability, and ecological and genetic linkages among many of the traits discussed here. Despite the challenges involved in experimental manipulation of species with complex life histories, such research is essential for full appreciation of the biological effects of climate change.

Potential responses to climate change in organisms with complex life histories: evolution and plasticity in Pacific salmon

PubMed Central

Crozier, L G; Hendry, A P; Lawson, P W; Quinn, T P; Mantua, N J; Battin, J; Shaw, R G; Huey, R B

2008-01-01

Salmon life histories are finely tuned to local environmental conditions, which are intimately linked to climate. We summarize the likely impacts of climate change on the physical environment of salmon in the Pacific Northwest and discuss the potential evolutionary consequences of these changes, with particular reference to Columbia River Basin spring/summer Chinook (Oncorhynchus tshawytscha) and sockeye (Oncorhynchus nerka) salmon. We discuss the possible evolutionary responses in migration and spawning date egg and juvenile growth and development rates, thermal tolerance, and disease resistance. We know little about ocean migration pathways, so cannot confidently suggest the potential changes in this life stage. Climate change might produce conflicting selection pressures in different life stages, which will interact with plastic (i.e. nongenetic) changes in various ways. To clarify these interactions, we present a conceptual model of how changing environmental conditions shift phenotypic optima and, through plastic responses, phenotype distributions, affecting the force of selection. Our predictions are tentative because we lack data on the strength of selection, heritability, and ecological and genetic linkages among many of the traits discussed here. Despite the challenges involved in experimental manipulation of species with complex life histories, such research is essential for full appreciation of the biological effects of climate change. PMID:25567630

A knowledge based approach to matching human neurodegenerative disease and animal models

PubMed Central

Maynard, Sarah M.; Mungall, Christopher J.; Lewis, Suzanna E.; Imam, Fahim T.; Martone, Maryann E.

2013-01-01

Neurodegenerative diseases present a wide and complex range of biological and clinical features. Animal models are key to translational research, yet typically only exhibit a subset of disease features rather than being precise replicas of the disease. Consequently, connecting animal to human conditions using direct data-mining strategies has proven challenging, particularly for diseases of the nervous system, with its complicated anatomy and physiology. To address this challenge we have explored the use of ontologies to create formal descriptions of structural phenotypes across scales that are machine processable and amenable to logical inference. As proof of concept, we built a Neurodegenerative Disease Phenotype Ontology (NDPO) and an associated Phenotype Knowledge Base (PKB) using an entity-quality model that incorporates descriptions for both human disease phenotypes and those of animal models. Entities are drawn from community ontologies made available through the Neuroscience Information Framework (NIF) and qualities are drawn from the Phenotype and Trait Ontology (PATO). We generated ~1200 structured phenotype statements describing structural alterations at the subcellular, cellular and gross anatomical levels observed in 11 human neurodegenerative conditions and associated animal models. PhenoSim, an open source tool for comparing phenotypes, was used to issue a series of competency questions to compare individual phenotypes among organisms and to determine which animal models recapitulate phenotypic aspects of the human disease in aggregate. Overall, the system was able to use relationships within the ontology to bridge phenotypes across scales, returning non-trivial matches based on common subsumers that were meaningful to a neuroscientist with an advanced knowledge of neuroanatomy. The system can be used both to compare individual phenotypes and also phenotypes in aggregate. This proof of concept suggests that expressing complex phenotypes using formal ontologies provides considerable benefit for comparing phenotypes across scales and species. PMID:23717278

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

PubMed

Koczkowska, Magdalena; Chen, Yunjia; Callens, Tom; Gomes, Alicia; Sharp, Angela; Johnson, Sherrell; Hsiao, Meng-Chang; Chen, Zhenbin; Balasubramanian, Meena; Barnett, Christopher P; Becker, Troy A; Ben-Shachar, Shay; Bertola, Debora R; Blakeley, Jaishri O; Burkitt-Wright, Emma M M; Callaway, Alison; Crenshaw, Melissa; Cunha, Karin S; Cunningham, Mitch; D'Agostino, Maria D; Dahan, Karin; De Luca, Alessandro; Destrée, Anne; Dhamija, Radhika; Eoli, Marica; Evans, D Gareth R; Galvin-Parton, Patricia; George-Abraham, Jaya K; Gripp, Karen W; Guevara-Campos, Jose; Hanchard, Neil A; Hernández-Chico, Concepcion; Immken, LaDonna; Janssens, Sandra; Jones, Kristi J; Keena, Beth A; Kochhar, Aaina; Liebelt, Jan; Martir-Negron, Arelis; Mahoney, Maurice J; Maystadt, Isabelle; McDougall, Carey; McEntagart, Meriel; Mendelsohn, Nancy; Miller, David T; Mortier, Geert; Morton, Jenny; Pappas, John; Plotkin, Scott R; Pond, Dinel; Rosenbaum, Kenneth; Rubin, Karol; Russell, Laura; Rutledge, Lane S; Saletti, Veronica; Schonberg, Rhonda; Schreiber, Allison; Seidel, Meredith; Siqveland, Elizabeth; Stockton, David W; Trevisson, Eva; Ullrich, Nicole J; Upadhyaya, Meena; van Minkelen, Rick; Verhelst, Helene; Wallace, Margaret R; Yap, Yoon-Sim; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen; Martin, Yolanda; Korf, Bruce R; Legius, Eric; Messiaen, Ludwine M

2018-01-04

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Experience affects the outcome of agonistic contests without affecting the selective advantage of size.

PubMed

Kasumovic, Michael M; Elias, Damian O; Punzalan, David; Mason, Andrew C; Andrade, Maydianne C B

2009-06-01

In the field, phenotypic determinants of competitive success are not always absolute. For example, contest experience may alter future competitive performance. As future contests are not determined solely on phenotypic attributes, prior experience could also potentially alter phenotype-fitness associations. In this study, we examined the influence of single and multiple experiences on contest outcomes in the jumping spider Phidippus clarus. We also examined whether phenotype-fitness associations altered as individuals gained more experience. Using both size-matched contests and a tournament design, we found that both winning and losing experience affected future contest success; males with prior winning experience were more likely to win subsequent contests. Although experience was a significant determinant of success in future contests, male weight was approximately 1.3 times more important than experience in predicting contest outcomes. Despite the importance of experience in determining contest outcomes, patterns of selection did not change between rounds. Overall, our results show that experience can be an important determinant in contest outcomes, even in short-lived invertebrates, and that experience alone is unlikely to alter phenotype-fitness associations.

An efficient genome-wide association test for multivariate phenotypes based on the Fisher combination function.

PubMed

Yang, James J; Li, Jia; Williams, L Keoki; Buu, Anne

2016-01-05

In genome-wide association studies (GWAS) for complex diseases, the association between a SNP and each phenotype is usually weak. Combining multiple related phenotypic traits can increase the power of gene search and thus is a practically important area that requires methodology work. This study provides a comprehensive review of existing methods for conducting GWAS on complex diseases with multiple phenotypes including the multivariate analysis of variance (MANOVA), the principal component analysis (PCA), the generalizing estimating equations (GEE), the trait-based association test involving the extended Simes procedure (TATES), and the classical Fisher combination test. We propose a new method that relaxes the unrealistic independence assumption of the classical Fisher combination test and is computationally efficient. To demonstrate applications of the proposed method, we also present the results of statistical analysis on the Study of Addiction: Genetics and Environment (SAGE) data. Our simulation study shows that the proposed method has higher power than existing methods while controlling for the type I error rate. The GEE and the classical Fisher combination test, on the other hand, do not control the type I error rate and thus are not recommended. In general, the power of the competing methods decreases as the correlation between phenotypes increases. All the methods tend to have lower power when the multivariate phenotypes come from long tailed distributions. The real data analysis also demonstrates that the proposed method allows us to compare the marginal results with the multivariate results and specify which SNPs are specific to a particular phenotype or contribute to the common construct. The proposed method outperforms existing methods in most settings and also has great applications in GWAS on complex diseases with multiple phenotypes such as the substance abuse disorders.

FSHD myotubes with different phenotypes exhibit distinct proteomes.

PubMed

Tassin, Alexandra; Leroy, Baptiste; Laoudj-Chenivesse, Dalila; Wauters, Armelle; Vanderplanck, Céline; Le Bihan, Marie-Catherine; Coppée, Frédérique; Wattiez, Ruddy; Belayew, Alexandra

2012-01-01

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder linked to a contraction of the D4Z4 repeat array in the 4q35 subtelomeric region. This deletion induces epigenetic modifications that affect the expression of several genes located in the vicinity. In each D4Z4 element, we identified the double homeobox 4 (DUX4) gene. DUX4 expresses a transcription factor that plays a major role in the development of FSHD through the initiation of a large gene dysregulation cascade that causes myogenic differentiation defects, atrophy and reduced response to oxidative stress. Because miRNAs variably affect mRNA expression, proteomic approaches are required to define the dysregulated pathways in FSHD. In this study, we optimized a differential isotope protein labeling (ICPL) method combined with shotgun proteomic analysis using a gel-free system (2DLC-MS/MS) to study FSHD myotubes. Primary CD56(+) FSHD myoblasts were found to fuse into myotubes presenting various proportions of an atrophic or a disorganized phenotype. To better understand the FSHD myogenic defect, our improved proteomic procedure was used to compare predominantly atrophic or disorganized myotubes to the same matching healthy control. FSHD atrophic myotubes presented decreased structural and contractile muscle components. This phenotype suggests the occurrence of atrophy-associated proteolysis that likely results from the DUX4-mediated gene dysregulation cascade. The skeletal muscle myosin isoforms were decreased while non-muscle myosin complexes were more abundant. In FSHD disorganized myotubes, myosin isoforms were not reduced, and increased proteins were mostly involved in microtubule network organization and myofibrillar remodeling. A common feature of both FSHD myotube phenotypes was the disturbance of several caveolar proteins, such as PTRF and MURC. Taken together, our data suggest changes in trafficking and in the membrane microdomains of FSHD myotubes. Finally, the adjustment of a nuclear fractionation compatible with mass spectrometry allowed us to highlight alterations of proteins involved in mRNA processing and stability.

FSHD Myotubes with Different Phenotypes Exhibit Distinct Proteomes

PubMed Central

Laoudj-Chenivesse, Dalila; Wauters, Armelle; Vanderplanck, Céline; Le Bihan, Marie-Catherine; Coppée, Frédérique; Wattiez, Ruddy; Belayew, Alexandra

2012-01-01

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder linked to a contraction of the D4Z4 repeat array in the 4q35 subtelomeric region. This deletion induces epigenetic modifications that affect the expression of several genes located in the vicinity. In each D4Z4 element, we identified the double homeobox 4 (DUX4) gene. DUX4 expresses a transcription factor that plays a major role in the development of FSHD through the initiation of a large gene dysregulation cascade that causes myogenic differentiation defects, atrophy and reduced response to oxidative stress. Because miRNAs variably affect mRNA expression, proteomic approaches are required to define the dysregulated pathways in FSHD. In this study, we optimized a differential isotope protein labeling (ICPL) method combined with shotgun proteomic analysis using a gel-free system (2DLC-MS/MS) to study FSHD myotubes. Primary CD56+ FSHD myoblasts were found to fuse into myotubes presenting various proportions of an atrophic or a disorganized phenotype. To better understand the FSHD myogenic defect, our improved proteomic procedure was used to compare predominantly atrophic or disorganized myotubes to the same matching healthy control. FSHD atrophic myotubes presented decreased structural and contractile muscle components. This phenotype suggests the occurrence of atrophy-associated proteolysis that likely results from the DUX4-mediated gene dysregulation cascade. The skeletal muscle myosin isoforms were decreased while non-muscle myosin complexes were more abundant. In FSHD disorganized myotubes, myosin isoforms were not reduced, and increased proteins were mostly involved in microtubule network organization and myofibrillar remodeling. A common feature of both FSHD myotube phenotypes was the disturbance of several caveolar proteins, such as PTRF and MURC. Taken together, our data suggest changes in trafficking and in the membrane microdomains of FSHD myotubes. Finally, the adjustment of a nuclear fractionation compatible with mass spectrometry allowed us to highlight alterations of proteins involved in mRNA processing and stability. PMID:23272181

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.

PubMed

Zerbi, Valerio; Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

2018-07-01

Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

Complexity and diversity.

PubMed

Doebeli, Michael; Ispolatov, Iaroslav

2010-04-23

The mechanisms for the origin and maintenance of biological diversity are not fully understood. It is known that frequency-dependent selection, generating advantages for rare types, can maintain genetic variation and lead to speciation, but in models with simple phenotypes (that is, low-dimensional phenotype spaces), frequency dependence needs to be strong to generate diversity. However, we show that if the ecological properties of an organism are determined by multiple traits with complex interactions, the conditions needed for frequency-dependent selection to generate diversity are relaxed to the point where they are easily satisfied in high-dimensional phenotype spaces. Mathematically, this phenomenon is reflected in properties of eigenvalues of quadratic forms. Because all living organisms have at least hundreds of phenotypes, this casts the potential importance of frequency dependence for the origin and maintenance of diversity in a new light.

Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells.

PubMed

Tabata, Yoshikuni; Murai, Norio; Sasaki, Takeo; Taniguchi, Sachie; Suzuki, Shuichi; Yamazaki, Kazuto; Ito, Masashi

2015-10-01

Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009's cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells' multipotency, leading to understanding of stem cell biology. © 2015 Society for Laboratory Automation and Screening.

Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

PubMed

McElyea, Samantha D; Starbuck, John M; Tumbleson-Brink, Danika M; Harrington, Emily; Blazek, Joshua D; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J

2016-11-15

Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene–phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

Informatics and machine learning to define the phenotype.

PubMed

Basile, Anna Okula; Ritchie, Marylyn DeRiggi

2018-03-01

For the past decade, the focus of complex disease research has been the genotype. From technological advancements to the development of analysis methods, great progress has been made. However, advances in our definition of the phenotype have remained stagnant. Phenotype characterization has recently emerged as an exciting area of informatics and machine learning. The copious amounts of diverse biomedical data that have been collected may be leveraged with data-driven approaches to elucidate trait-related features and patterns. Areas covered: In this review, the authors discuss the phenotype in traditional genetic associations and the challenges this has imposed.Approaches for phenotype refinement that can aid in more accurate characterization of traits are also discussed. Further, the authors highlight promising machine learning approaches for establishing a phenotype and the challenges of electronic health record (EHR)-derived data. Expert commentary: The authors hypothesize that through unsupervised machine learning, data-driven approaches can be used to define phenotypes rather than relying on expert clinician knowledge. Through the use of machine learning and an unbiased set of features extracted from clinical repositories, researchers will have the potential to further understand complex traits and identify patient subgroups. This knowledge may lead to more preventative and precise clinical care.

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

PubMed Central

Dumesic, Daniel A.; Oberfield, Sharon E.; Stener-Victorin, Elisabet; Marshall, John C.; Laven, Joop S.

2015-01-01

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. PMID:26426951

Phenotypic and genomic characterization of the antimicrobial producer Rheinheimera sp. EpRS3 isolated from the medicinal plant Echinacea purpurea: insights into its biotechnological relevance.

PubMed

Presta, Luana; Bosi, Emanuele; Fondi, Marco; Maida, Isabel; Perrin, Elena; Miceli, Elisangela; Maggini, Valentina; Bogani, Patrizia; Firenzuoli, Fabio; Di Pilato, Vincenzo; Rossolini, Gian Maria; Mengoni, Alessio; Fani, Renato

2017-04-01

In recent years, there has been increasing interest in plant microbiota; however, despite medicinal plant relevance, very little is known about their highly complex endophytic communities. In this work, we report on the genomic and phenotypic characterization of the antimicrobial compound producer Rheinheimera sp. EpRS3, a bacterial strain isolated from the rhizospheric soil of the medicinal plant Echinacea purpurea. In particular, EpRS3 is able to inhibit growth of different bacterial pathogens (Bcc, Acinetobacter baumannii, and Klebsiella pneumoniae) which might be related to the presence of gene clusters involved in the biosynthesis of different types of secondary metabolites. The outcomes presented in this work highlight the fact that the strain possesses huge biotechnological potential; indeed, it also shows antimicrobial effects upon well-described multidrug-resistant (MDR) human pathogens, and it affects plant root elongation and morphology, mimicking indole acetic acid (IAA) action. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Plasticity first: molecular signatures of a complex morphological trait in filamentous cyanobacteria.

PubMed

Koch, Robin; Kupczok, Anne; Stucken, Karina; Ilhan, Judith; Hammerschmidt, Katrin; Dagan, Tal

2017-08-31

Filamentous cyanobacteria that differentiate multiple cell types are considered the peak of prokaryotic complexity and their evolution has been studied in the context of multicellularity origins. Species that form true-branching filaments exemplify the most complex cyanobacteria. However, the mechanisms underlying the true-branching morphology remain poorly understood despite of several investigations that focused on the identification of novel genes or pathways. An alternative route for the evolution of novel traits is based on existing phenotypic plasticity. According to that scenario - termed genetic assimilation - the fixation of a novel phenotype precedes the fixation of the genotype. Here we show that the evolution of transcriptional regulatory elements constitutes a major mechanism for the evolution of new traits. We found that supplementation with sucrose reconstitutes the ancestral branchless phenotype of two true-branching Fischerella species and compared the transcription start sites (TSSs) between the two phenotypic states. Our analysis uncovers several orthologous TSSs whose transcription level is correlated with the true-branching phenotype. These TSSs are found in genes that encode components of the septosome and elongasome (e.g., fraC and mreB). The concept of genetic assimilation supplies a tenable explanation for the evolution of novel traits but testing its feasibility is hindered by the inability to recreate and study the evolution of present-day traits. We present a novel approach to examine transcription data for the plasticity first route and provide evidence for its occurrence during the evolution of complex colony morphology in true-branching cyanobacteria. Our results reveal a route for evolution of the true-branching phenotype in cyanobacteria via modification of the transcription level of pre-existing genes. Our study supplies evidence for the 'plasticity-first' hypothesis and highlights the importance of transcriptional regulation in the evolution of novel traits.

Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes.

PubMed

Correa, Fernanda A; Jorge, Alexander Al; Nakaguma, Marilena; Canton, Ana Pm; Costa, Silvia S; Funari, Mariana F; Lerario, Antonio M; Franca, Marcela M; Carvalho, Luciani R; Krepischi, Ana Cv; Arnhold, Ivo Jp; Rosenberg, Carla; Mendonca, Berenice B

2018-03-01

The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes. We selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing. Twenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7 Mb and a 4-Mb deletion at 4q35.1q35.2. Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism. © 2017 John Wiley & Sons Ltd.

Clinical phenotype-based gene prioritization: an initial study using semantic similarity and the human phenotype ontology.

PubMed

Masino, Aaron J; Dechene, Elizabeth T; Dulik, Matthew C; Wilkens, Alisha; Spinner, Nancy B; Krantz, Ian D; Pennington, Jeffrey W; Robinson, Peter N; White, Peter S

2014-07-21

Exome sequencing is a promising method for diagnosing patients with a complex phenotype. However, variant interpretation relative to patient phenotype can be challenging in some scenarios, particularly clinical assessment of rare complex phenotypes. Each patient's sequence reveals many possibly damaging variants that must be individually assessed to establish clear association with patient phenotype. To assist interpretation, we implemented an algorithm that ranks a given set of genes relative to patient phenotype. The algorithm orders genes by the semantic similarity computed between phenotypic descriptors associated with each gene and those describing the patient. Phenotypic descriptor terms are taken from the Human Phenotype Ontology (HPO) and semantic similarity is derived from each term's information content. Model validation was performed via simulation and with clinical data. We simulated 33 Mendelian diseases with 100 patients per disease. We modeled clinical conditions by adding noise and imprecision, i.e. phenotypic terms unrelated to the disease and terms less specific than the actual disease terms. We ranked the causative gene against all 2488 HPO annotated genes. The median causative gene rank was 1 for the optimal and noise cases, 12 for the imprecision case, and 60 for the imprecision with noise case. Additionally, we examined a clinical cohort of subjects with hearing impairment. The disease gene median rank was 22. However, when also considering the patient's exome data and filtering non-exomic and common variants, the median rank improved to 3. Semantic similarity can rank a causative gene highly within a gene list relative to patient phenotype characteristics, provided that imprecision is mitigated. The clinical case results suggest that phenotype rank combined with variant analysis provides significant improvement over the individual approaches. We expect that this combined prioritization approach may increase accuracy and decrease effort for clinical genetic diagnosis.

Nonlinear effects in evolution - an ab initio study: A model in which the classical theory of evolution occurs as a special case.

PubMed

Clerc, Daryl G

2016-07-21

An ab initio approach was used to study the molecular-level interactions that connect gene-mutation to changes in an organism׳s phenotype. The study provides new insights into the evolutionary process and presents a simplification whereby changes in phenotypic properties may be studied in terms of the binding affinities of the chemical interactions affected by mutation, rather than by correlation to the genes. The study also reports the role that nonlinear effects play in the progression of organs, and how those effects relate to the classical theory of evolution. Results indicate that the classical theory of evolution occurs as a special case within the ab initio model - a case having two attributes. The first attribute: proteins and promoter regions are not shared among organs. The second attribute: continuous limiting behavior exists in the physical properties of organs as well as in the binding affinity of the associated chemical interactions, with respect to displacements in the chemical properties of proteins and promoter regions induced by mutation. Outside of the special case, second-order coupling contributions are significant and nonlinear effects play an important role, a result corroborated by analyses of published activity levels in binding and transactivation assays. Further, gradations in the state of perfection of an organ may be small or large depending on the type of mutation, and not necessarily closely-separated as maintained by the classical theory. Results also indicate that organs progress with varying degrees of interdependence, the likelihood of successful mutation decreases with increasing complexity of the affected chemical system, and differences between the ab initio model and the classical theory increase with increasing complexity of the organism. Copyright © 2016 The Author. Published by Elsevier Ltd.. All rights reserved.

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

PubMed Central

Schott, B H; Assmann, A; Schmierer, P; Soch, J; Erk, S; Garbusow, M; Mohnke, S; Pöhland, L; Romanczuk-Seiferth, N; Barman, A; Wüstenberg, T; Haddad, L; Grimm, O; Witt, S; Richter, S; Klein, M; Schütze, H; Mühleisen, T W; Cichon, S; Rietschel, M; Noethen, M M; Tost, H; Gundelfinger, E D; Düzel, E; Heinz, A; Meyer-Lindenberg, A; Seidenbecher, C I; Walter, H

2014-01-01

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability' of complex phenotypes. PMID:24643163

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

PubMed

Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

2015-11-01

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Phenotype/genotype correlation in a case series of Stargardt's patients identifies novel mutations in the ABCA4 gene.

PubMed

Gemenetzi, M; Lotery, A J

2013-11-01

To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and confirmed ABCA4 mutations. Entire coding region analysis of the ABCA4 gene by direct sequencing of seven patients with clinical findings of STGD seen in the Retina Clinics of Southampton Eye Unit between 2002 and 2011.Phenotypic variables recorded were BCVA, fluorescein angiographic appearance, electrophysiology, and visual fields. All patients had heterozygous amino acid-changing variants (missense mutations) in the ABCA4 gene. A splice sequence change was found in a 30-year-old patient with severly affected vision. Two novel sequence changes were identified: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient. The identified ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA. Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype. This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information may prove useful in selection of candidates for clinical trials in ABCA4 disease.

Evolutionary characters, phenotypes and ontologies: curating data from the systematic biology literature.

PubMed

Dahdul, Wasila M; Balhoff, James P; Engeman, Jeffrey; Grande, Terry; Hilton, Eric J; Kothari, Cartik; Lapp, Hilmar; Lundberg, John G; Midford, Peter E; Vision, Todd J; Westerfield, Monte; Mabee, Paula M

2010-05-20

The wealth of phenotypic descriptions documented in the published articles, monographs, and dissertations of phylogenetic systematics is traditionally reported in a free-text format, and it is therefore largely inaccessible for linkage to biological databases for genetics, development, and phenotypes, and difficult to manage for large-scale integrative work. The Phenoscape project aims to represent these complex and detailed descriptions with rich and formal semantics that are amenable to computation and integration with phenotype data from other fields of biology. This entails reconceptualizing the traditional free-text characters into the computable Entity-Quality (EQ) formalism using ontologies. We used ontologies and the EQ formalism to curate a collection of 47 phylogenetic studies on ostariophysan fishes (including catfishes, characins, minnows, knifefishes) and their relatives with the goal of integrating these complex phenotype descriptions with information from an existing model organism database (zebrafish, http://zfin.org). We developed a curation workflow for the collection of character, taxonomic and specimen data from these publications. A total of 4,617 phenotypic characters (10,512 states) for 3,449 taxa, primarily species, were curated into EQ formalism (for a total of 12,861 EQ statements) using anatomical and taxonomic terms from teleost-specific ontologies (Teleost Anatomy Ontology and Teleost Taxonomy Ontology) in combination with terms from a quality ontology (Phenotype and Trait Ontology). Standards and guidelines for consistently and accurately representing phenotypes were developed in response to the challenges that were evident from two annotation experiments and from feedback from curators. The challenges we encountered and many of the curation standards and methods for improving consistency that we developed are generally applicable to any effort to represent phenotypes using ontologies. This is because an ontological representation of the detailed variations in phenotype, whether between mutant or wildtype, among individual humans, or across the diversity of species, requires a process by which a precise combination of terms from domain ontologies are selected and organized according to logical relations. The efficiencies that we have developed in this process will be useful for any attempt to annotate complex phenotypic descriptions using ontologies. We also discuss some ramifications of EQ representation for the domain of systematics.

Breeding and Genetics Symposium: networks and pathways to guide genomic selection.

PubMed

Snelling, W M; Cushman, R A; Keele, J W; Maltecca, C; Thomas, M G; Fortes, M R S; Reverter, A

2013-02-01

Many traits affecting profitability and sustainability of meat, milk, and fiber production are polygenic, with no single gene having an overwhelming influence on observed variation. No knowledge of the specific genes controlling these traits has been needed to make substantial improvement through selection. Significant gains have been made through phenotypic selection enhanced by pedigree relationships and continually improving statistical methodology. Genomic selection, recently enabled by assays for dense SNP located throughout the genome, promises to increase selection accuracy and accelerate genetic improvement by emphasizing the SNP most strongly correlated to phenotype although the genes and sequence variants affecting phenotype remain largely unknown. These genomic predictions theoretically rely on linkage disequilibrium (LD) between genotyped SNP and unknown functional variants, but familial linkage may increase effectiveness when predicting individuals related to those in the training data. Genomic selection with functional SNP genotypes should be less reliant on LD patterns shared by training and target populations, possibly allowing robust prediction across unrelated populations. Although the specific variants causing polygenic variation may never be known with certainty, a number of tools and resources can be used to identify those most likely to affect phenotype. Associations of dense SNP genotypes with phenotype provide a 1-dimensional approach for identifying genes affecting specific traits; in contrast, associations with multiple traits allow defining networks of genes interacting to affect correlated traits. Such networks are especially compelling when corroborated by existing functional annotation and established molecular pathways. The SNP occurring within network genes, obtained from public databases or derived from genome and transcriptome sequences, may be classified according to expected effects on gene products. As illustrated by functionally informed genomic predictions being more accurate than naive whole-genome predictions of beef tenderness, coupling evidence from livestock genotypes, phenotypes, gene expression, and genomic variants with existing knowledge of gene functions and interactions may provide greater insight into the genes and genomic mechanisms affecting polygenic traits and facilitate functional genomic selection for economically important traits.

Assessing the complex architecture of polygenic traits in diverged yeast populations.

PubMed

Cubillos, Francisco A; Billi, Eleonora; Zörgö, Enikö; Parts, Leopold; Fargier, Patrick; Omholt, Stig; Blomberg, Anders; Warringer, Jonas; Louis, Edward J; Liti, Gianni

2011-04-01

Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits. © 2011 Blackwell Publishing Ltd.

Spine malformation complex in 3 diverse syndromic entities: Case reports.

PubMed

Kaissi, Ali Al; van Egmond-Fröhlich, Andreas; Ryabykh, Sergey; Ochirov, Polina; Kenis, Vladimir; Hofstaetter, Jochen G; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

2016-12-01

Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and (c) the diagnosis.

Contrasting the effects of proton irradiation on dendritic complexity of subiculum neurons in wild type and MCAT mice.

PubMed

Chmielewski, Nicole N; Caressi, Chongshan; Giedzinski, Erich; Parihar, Vipan K; Limoli, Charles L

2016-06-01

Growing evidence suggests that radiation-induced oxidative stress directly affects a wide range of biological changes with an overall negative impact on CNS function. In the past we have demonstrated that transgenic mice over-expressing human catalase targeted to the mitochondria (MCAT) exhibit a range of neuroprotective phenotypes following irradiation that include improved neurogenesis, dendritic complexity, and cognition. To determine the extent of the neuroprotective phenotype afforded by MCAT expression in different hippocampal regions, we analyzed subiculum neurons for changes in neuronal structure and synaptic integrity after exposure to low dose (0.5 Gy) 150 MeV proton irradiation. One month following irradiation of WT and MCAT mice, a range of morphometric parameters were quantified along Golgi-Cox impregnated neurons. Compared with WT mice, subiculum neurons from MCAT mice exhibited increased trends (albeit not statistically significant) toward increased dendritic complexity in both control and irradiated cohorts. However, Sholl analysis of MCAT mice revealed significantly increased arborization of the distal dendritic tree, indicating a protective effect on secondary and tertiary branching. Interestingly, radiation-induced increases in postsynaptic density protein (PSD-95) puncta were not as pronounced in MCAT compared with WT mice, and were significantly lower after the 0.5 Gy dose. As past data has linked radiation exposure to reduced dendritic complexity, elevated PSD-95 and impaired cognition, reductions in mitochondrial oxidative stress have proven useful in ameliorating many of these radiation-induced sequelae. Data presented here shows similar trends, and again points to the potential benefits of reducing oxidative stress in the brain to attenuate radiation injury. Environ. Mol. Mutagen. 57:364-371, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice.

PubMed

Holloway, Terrell; Moreno, Jose L; González-Maeso, Javier

2016-07-09

The heteromeric receptor complex between 5-HT2A and mGlu2 has been implicated in some of the behavioral phenotypes in mouse models of psychosis(1,2). Consequently, investigation of structural details of the interaction between 5-HT2A and mGlu2 affecting schizophrenia-related behaviors represents a powerful translational tool. As previously shown, the head-twitch response (HTR) in mice is elicited by hallucinogenic drugs and this behavioral response is absent in 5-HT2A knockout (KO) mice(3,4). Additionally, by conditionally expressing the 5-HT2A receptor only in cortex, it was demonstrated that 5-HT2A receptor-dependent signaling pathways on cortical pyramidal neurons are sufficient to elicit head-twitch behavior in response to hallucinogenic drugs(3). Finally, it has been shown that the head-twitch behavioral response induced by the hallucinogens DOI and lysergic acid diethylamide (LSD) is significantly decreased in mGlu2-KO mice(5). These findings suggest that mGlu2 is at least in part necessary for the 5-HT2A receptor-dependent psychosis-like behavioral effects induced by LSD-like drugs. However, this does not provide evidence as to whether the 5-HT2A-mGlu2 receptor complex is necessary for this behavioral phenotype. To address this question, herpes simplex virus (HSV) constructs to express either mGlu2 or mGlu2ΔTM4N (mGlu2/mGlu3 chimeric construct that does not form the 5-HT2A-mGlu2 receptor complex) in the frontal cortex of mGlu2-KO mice were used to examine whether this GPCR heteromeric complex is needed for the behavioral effects induced by LSD-like drugs(6).

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome.

PubMed

Millar-Büchner, Pamela; Philp, Amber R; Gutierrez, Noemí; Villanueva, Sandra; Kerr, Bredford; Flores, Carlos A

2016-12-01

Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.

β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology

PubMed Central

Liu, Xiaosong; Zhao, Xiaohui; Zeng, Xianglu; Bossers, Koen; Swaab, Dick F; Zhao, Jian; Pei, Gang

2013-01-01

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretase-mediated amyloid-β (Aβ) pathology plays an important role. We found that a multifunctional protein, β-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1. Deficiency of β-arrestin1 or inhibition of binding of β-arrestin1 with APH-1 by small peptides reduced Aβ production without affecting Notch processing. Genetic ablation of β-arrestin1 diminished Aβ pathology and behavioral deficits in transgenic AD mice. Moreover, in brains of sporadic AD patients and transgenic AD mice, the expression of β-arrestin1 was upregulated and correlated well with neuropathological severity and senile Aβ plaques. Thus, our study identifies a regulatory mechanism underlying both γ-secretase assembly and AD pathogenesis, and indicates that specific reduction of Aβ pathology can be achieved by regulation of the γ-secretase assembly. PMID:23208420

Interdependence of the rad50 hook and globular domain functions.

PubMed

Hohl, Marcel; Kochańczyk, Tomasz; Tous, Cristina; Aguilera, Andrés; Krężel, Artur; Petrini, John H J

2015-02-05

Rad50 contains a conserved Zn(2+) coordination domain (the Rad50 hook) that functions as a homodimerization interface. Hook ablation phenocopies Rad50 deficiency in all respects. Here, we focused on rad50 mutations flanking the Zn(2+)-coordinating hook cysteines. These mutants impaired hook-mediated dimerization, but recombination between sister chromatids was largely unaffected. This may reflect that cohesin-mediated sister chromatid interactions are sufficient for double-strand break repair. However, Mre11 complex functions specified by the globular domain, including Tel1 (ATM) activation, nonhomologous end joining, and DNA double-strand break end resection were affected, suggesting that dimerization exerts a broad influence on Mre11 complex function. These phenotypes were suppressed by mutations within the coiled-coil and globular ATPase domains, suggesting a model in which conformational changes in the hook and globular domains are transmitted via the extended coils of Rad50. We propose that transmission of spatial information in this manner underlies the regulation of Mre11 complex functions. Copyright © 2015 Elsevier Inc. All rights reserved.

A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

PubMed

Vilain, C; Rens, C; Aeby, A; Balériaux, D; Van Bogaert, P; Remiche, G; Smet, J; Van Coster, R; Abramowicz, M; Pirson, I

2012-09-01

Although deficiency of complex I of the mitochondrial respiratory chain is a frequent cause of encephalopathy in children, only a few mutations have been reported in each of its subunits. In the absence of families large enough for conclusive segregation analysis and of robust functional testing, it is difficult to unequivocally show the causality of the observed mutations and to delineate genotype-phenotype correlations, making additional observations necessary. We observed two consanguineous siblings with an early-onset encephalopathy, medulla, brainstem and mesencephalon lesions on brain magnetic resonance imaging and death before 8 months of age, caused by a complex I deficiency. We used a homozygosity mapping approach and identified a missense mutation in the NDUFV1 gene. The mutation, p.Arg386His, affects a highly conserved residue, contiguous to a cysteine residue known to coordinate an Fe ion. This observation adds to our understanding of complex I deficiency disease. It validates the important role of Arg386 and therefore supports the current molecular model of iron-sulfur clusters in NDUFV1. © 2011 John Wiley & Sons A/S.

Use of Multivariate Linkage Analysis for Dissection of a Complex Cognitive Trait

PubMed Central

Marlow, Angela J.; Fisher, Simon E.; Francks, Clyde; MacPhie, I. Laurence; Cherny, Stacey S.; Richardson, Alex J.; Talcott, Joel B.; Stein, John F.; Monaco, Anthony P.; Cardon, Lon R.

2003-01-01

Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits. PMID:12587094

High-fat diets exaggerate endocrine and metabolic phenotypes in a rat model of DHEA-induced PCOS.

PubMed

Zhang, Haolin; Yi, Ming; Zhang, Yan; Jin, Hongyan; Zhang, Wenxin; Yang, Jingjing; Yan, Liying; Li, Rong; Zhao, Yue; Qiao, Jie

2016-04-01

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder with unclear etiology and unsatisfactory management. Effects of diets on the phenotype of PCOS were not fully understood. In the present study, we applied 45 and 60% high-fat diets (HFDs) on a rat model of PCOS induced by postnatal DHEA injection. We found that both DHEA and DHEA+HFDs rats exhibited reproductive abnormalities, including hyperandrogenism, irregular cycles and polycystic ovaries. The addition of HFDs, especially 60% HFDs, exaggerated morphological changes of ovaries and a number of metabolic changes, including increased body weight and body fat content, impaired glucose tolerance and increased serum insulin levels. Results from qPCR showed that DHEA-induced increased expression of hypothalamic androgen receptor and LH receptor were reversed by the addition of 60% HFDs. In contrast, the ovarian expression of LH receptor and insulin receptor mRNA was upregulated only with the addition of 60% HFDs. These findings indicated that DHEA and DHEA+HFDs might influence PCOS phenotypes through distinct mechanisms: DHEA affects the normal function of hypothalamus-pituitary-ovarian axis through LH, whereas the addition of HFDs exaggerated endocrine and metabolic dysfunction through ovarian responses to insulin-related mechanisms. We concluded that the addition of HFDs yielded distinct phenotypes of DHEA-induced PCOS and could be used for studies on both reproductive and metabolic features of the syndrome. © 2016 Society for Reproduction and Fertility.

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

PubMed Central

Slavotinek, Anne M; Baranzini, Sergio E; Schanze, Denny; Labelle-Dumais, Cassandre; Short, Kieran M; Chao, Ryan; Yahyavi, Mani; Bijlsma, Emilia K; Chu, Catherine; Musone, Stacey; Wheatley, Ashleigh; Kwok, Pui-Yan; Marles, Sandra; Fryns, Jean-Pierre; Maga, A Murat; Hassan, Mohamed G; Gould, Douglas B; Madireddy, Lohith; Li, Chumei; Cox, Timothy C; Smyth, Ian; Chudley, Albert E; Zenker, Martin

2014-01-01

Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/ microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. Methods and results This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1bat/bat mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. Conclusions The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS–FREM complex diseases. PMID:21507892

Global change and the evolution of phenotypic plasticity in plants.

PubMed

Matesanz, Silvia; Gianoli, Ernesto; Valladares, Fernando

2010-09-01

Global change drivers create new environmental scenarios and selective pressures, affecting plant species in various interacting ways. Plants respond with changes in phenology, physiology, and reproduction, with consequences for biotic interactions and community composition. We review information on phenotypic plasticity, a primary means by which plants cope with global change scenarios, recommending promising approaches for investigating the evolution of plasticity and describing constraints to its evolution. We discuss the important but largely ignored role of phenotypic plasticity in range shifts and review the extensive literature on invasive species as models of evolutionary change in novel environments. Plasticity can play a role both in the short-term response of plant populations to global change as well as in their long-term fate through the maintenance of genetic variation. In new environmental conditions, plasticity of certain functional traits may be beneficial (i.e., the plastic response is accompanied by a fitness advantage) and thus selected for. Plasticity can also be relevant in the establishment and persistence of plants in novel environments that are crucial for populations at the colonizing edge in range shifts induced by climate change. Experimental studies show taxonomically widespread plastic responses to global change drivers in many functional traits, though there is a lack of empirical support for many theoretical models on the evolution of phenotypic plasticity. Future studies should assess the adaptive value and evolutionary potential of plasticity under complex, realistic global change scenarios. Promising tools include resurrection protocols and artificial selection experiments. © 2010 New York Academy of Sciences.

Optimizing complex phenotypes through model-guided multiplex genome engineering

DOE PAGES

Kuznetsov, Gleb; Goodman, Daniel B.; Filsinger, Gabriel T.; ...

2017-05-25

Here, we present a method for identifying genomic modifications that optimize a complex phenotype through multiplex genome engineering and predictive modeling. We apply our method to identify six single nucleotide mutations that recover 59% of the fitness defect exhibited by the 63-codon E. coli strain C321.ΔA. By introducing targeted combinations of changes in multiplex we generate rich genotypic and phenotypic diversity and characterize clones using whole-genome sequencing and doubling time measurements. Regularized multivariate linear regression accurately quantifies individual allelic effects and overcomes bias from hitchhiking mutations and context-dependence of genome editing efficiency that would confound other strategies.

Optimizing complex phenotypes through model-guided multiplex genome engineering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuznetsov, Gleb; Goodman, Daniel B.; Filsinger, Gabriel T.

Here, we present a method for identifying genomic modifications that optimize a complex phenotype through multiplex genome engineering and predictive modeling. We apply our method to identify six single nucleotide mutations that recover 59% of the fitness defect exhibited by the 63-codon E. coli strain C321.ΔA. By introducing targeted combinations of changes in multiplex we generate rich genotypic and phenotypic diversity and characterize clones using whole-genome sequencing and doubling time measurements. Regularized multivariate linear regression accurately quantifies individual allelic effects and overcomes bias from hitchhiking mutations and context-dependence of genome editing efficiency that would confound other strategies.

Adaptive processes drive ecomorphological convergent evolution in antwrens (Thamnophilidae).

PubMed

Bravo, Gustavo A; Remsen, J V; Brumfield, Robb T

2014-10-01

Phylogenetic niche conservatism (PNC) and convergence are contrasting evolutionary patterns that describe phenotypic similarity across independent lineages. Assessing whether and how adaptive processes give origin to these patterns represent a fundamental step toward understanding phenotypic evolution. Phylogenetic model-based approaches offer the opportunity not only to distinguish between PNC and convergence, but also to determine the extent that adaptive processes explain phenotypic similarity. The Myrmotherula complex in the Neotropical family Thamnophilidae is a polyphyletic group of sexually dimorphic small insectivorous forest birds that are relatively homogeneous in size and shape. Here, we integrate a comprehensive species-level molecular phylogeny of the Myrmotherula complex with morphometric and ecological data within a comparative framework to test whether phenotypic similarity is described by a pattern of PNC or convergence, and to identify evolutionary mechanisms underlying body size and shape evolution. We show that antwrens in the Myrmotherula complex represent distantly related clades that exhibit adaptive convergent evolution in body size and divergent evolution in body shape. Phenotypic similarity in the group is primarily driven by their tendency to converge toward smaller body sizes. Differences in body size and shape across lineages are associated to ecological and behavioral factors. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens.

PubMed

Asarnow, Daniel; Rojo-Arreola, Liliana; Suzuki, Brian M; Caffrey, Conor R; Singh, Rahul

2015-05-01

Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose-response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites. QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html. rahul@sfsu.edu. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cancer cell: using inflammation to invade the host

PubMed Central

Arias, José-Ignacio; Aller, María-Angeles; Arias, Jaime

2007-01-01

Background Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms involved are not fully characterized. The invasive capacity of cancers is reflected in the classic metastatic cascade: tumor (T), node (N) and metastasis (M). However, this staging system for cancer would also have a tumoral biological significance. Presentation of the hypothesis To integrate the mechanisms that control the inflammatory response in the actual staging system of cancer. It is considered that in both processes of inflammation and cancer, three successive phenotypes are presented that represent the expression of trophic functional systems of increasing metabolic complexity for using oxygen. Testing the hypothesis While a malignant tumor develops it express phenotypes that also share the inflammatory response such as: an ischemic phenotype (anoxic-hypoxic), a leukocytic phenotype with anaerobic glycolysis and migration, and an angiogenic phenotype with hyperactivity of glycolytic enzymes, tumor proliferation and metastasis, and cachexia of the host. The increasing metabolic complexity of the tumor cell to use oxygen allows for it to be released, migrate and proliferate, thus creating structures of growing complexity. Implication of the hypothesis One aim of cancer gene therapy could be the induction of oxidative phosphorylation, the last metabolic step required by inflammation in order to differentiate the tissue that it produces. PMID:17437633

Long-term dynamics of adaptive evolution in a globally important phytoplankton species to ocean acidification

PubMed Central

Schlüter, Lothar; Lohbeck, Kai T.; Gröger, Joachim P.; Riebesell, Ulf; Reusch, Thorsten B. H.

2016-01-01

Marine phytoplankton may adapt to ocean change, such as acidification or warming, because of their large population sizes and short generation times. Long-term adaptation to novel environments is a dynamic process, and phenotypic change can take place thousands of generations after exposure to novel conditions. We conducted a long-term evolution experiment (4 years = 2100 generations), starting with a single clone of the abundant and widespread coccolithophore Emiliania huxleyi exposed to three different CO2 levels simulating ocean acidification (OA). Growth rates as a proxy for Darwinian fitness increased only moderately under both levels of OA [+3.4% and +4.8%, respectively, at 1100 and 2200 μatm partial pressure of CO2 (Pco2)] relative to control treatments (ambient CO2, 400 μatm). Long-term adaptation to OA was complex, and initial phenotypic responses of ecologically important traits were later reverted. The biogeochemically important trait of calcification, in particular, that had initially been restored within the first year of evolution was later reduced to levels lower than the performance of nonadapted populations under OA. Calcification was not constitutively lost but returned to control treatment levels when high CO2–adapted isolates were transferred back to present-day control CO2 conditions. Selection under elevated CO2 exacerbated a general decrease of cell sizes under long-term laboratory evolution. Our results show that phytoplankton may evolve complex phenotypic plasticity that can affect biogeochemically important traits, such as calcification. Adaptive evolution may play out over longer time scales (>1 year) in an unforeseen way under future ocean conditions that cannot be predicted from initial adaptation responses. PMID:27419227

eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling

PubMed Central

Attar-Schneider, Oshrat; Pasmanik-Chor, Metsada; Tartakover-Matalon, Shelly

2015-01-01

Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis-multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. PMID:25717031

Characterizing heterogeneous cellular responses to perturbations.

PubMed

Slack, Michael D; Martinez, Elisabeth D; Wu, Lani F; Altschuler, Steven J

2008-12-09

Cellular populations have been widely observed to respond heterogeneously to perturbation. However, interpreting the observed heterogeneity is an extremely challenging problem because of the complexity of possible cellular phenotypes, the large dimension of potential perturbations, and the lack of methods for separating meaningful biological information from noise. Here, we develop an image-based approach to characterize cellular phenotypes based on patterns of signaling marker colocalization. Heterogeneous cellular populations are characterized as mixtures of phenotypically distinct subpopulations, and responses to perturbations are summarized succinctly as probabilistic redistributions of these mixtures. We apply our method to characterize the heterogeneous responses of cancer cells to a panel of drugs. We find that cells treated with drugs of (dis-)similar mechanism exhibit (dis-)similar patterns of heterogeneity. Despite the observed phenotypic diversity of cells observed within our data, low-complexity models of heterogeneity were sufficient to distinguish most classes of drug mechanism. Our approach offers a computational framework for assessing the complexity of cellular heterogeneity, investigating the degree to which perturbations induce redistributions of a limited, but nontrivial, repertoire of underlying states and revealing functional significance contained within distinct patterns of heterogeneous responses.

Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

PubMed

Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R; Kaisaki, Pamela J; Otto, Georg W; Ma, Man Chun John; Keane, Thomas M; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J

2013-08-01

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Food allergy phenotypes: The key to personalized therapy.

PubMed

Deschildre, A; Lejeune, S; Cap, M; Flammarion, S; Jouannic, L; Amat, F; Just, J

2017-09-01

Food allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non-IgE-mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE-mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies. © 2017 John Wiley & Sons Ltd.

In Search of the Perfect Phenotype: An Analysis of Linkage and Association Studies of Reading and Reading-Related Processes

PubMed Central

Skiba, Thomas; Landi, Nicole; Wagner, Richard

2011-01-01

Reading ability and specific reading disability (SRD) are complex traits involving several cognitive processes and are shaped by a complex interplay of genetic and environmental forces. Linkage studies of these traits have identified several susceptibility loci. Association studies have gone further in detecting candidate genes that might underlie these signals. These results have been obtained in samples of mainly European ancestry, which vary in their languages, inclusion criteria, and phenotype assessments. Such phenotypic heterogeneity across samples makes understanding the relationship between reading (dis)ability and reading-related processes and the genetic factors difficult; in addition, it may negatively influence attempts at replication. In moving forward, the identification of preferable phenotypes for future sample collection may improve the replicability of findings. This review of all published linkage and association results from the past 15 years was conducted to determine if certain phenotypes produce more replicable and consistent results than others. PMID:21243420

Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

PubMed Central

Atanur, Santosh S.; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R.; Kaisaki, Pamela J.; Otto, Georg W.; Ma, Man Chun John; Keane, Thomas M.; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R.; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J.; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J.

2013-01-01

Summary Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. PaperClip PMID:23890820

Phenotypic Characteristics Associated with Virulence of Clinical Isolates from the Sporothrix Complex

PubMed Central

Almeida-Paes, Rodrigo; de Oliveira, Luã Cardoso; Oliveira, Manoel Marques Evangelista; Gutierrez-Galhardo, Maria Clara; Nosanchuk, Joshua Daniel; Zancopé-Oliveira, Rosely Maria

2015-01-01

The Sporothrix complex members cause sporotrichosis, a subcutaneous mycosis with a wide spectrum of clinical manifestations. Several specific phenotypic characteristics are associated with virulence in many fungi, but studies in this field involving the Sporothrix complex species are scarce. Melanization, thermotolerance, and production of proteases, catalase, and urease were investigated in 61 S. brasiliensis, one S. globosa, and 10 S. schenckii strains. The S. brasiliensis strains showed a higher expression of melanin and urease compared with S. schenckii. These two species, however, presented similar thermotolerances. Our S. globosa strain had low expression of all studied virulence factors. The relationship between these phenotypes and clinical aspects of sporotrichosis was also evaluated. Strains isolated from patients with spontaneous regression of infection were heavily melanized and produced high urease levels. Melanin was also related to dissemination of internal organs and protease production was associated with HIV-coinfection. A murine sporotrichosis model showed that a S. brasiliensis strain with high expression of virulence factors was able to disseminate and yield a high fungal burden in comparison with a control S. schenckii strain. Our results show that virulence-related phenotypes are variably expressed within the Sporothrix complex species and might be involved in clinical aspects of sporotrichosis. PMID:25961005

ADHD latent class clusters: DSM-IV subtypes and comorbidity

PubMed Central

Elia, Josephine; Arcos-Burgos, Mauricio; Bolton, Kelly L.; Ambrosini, Paul J.; Berrettini, Wade; Muenke, Maximilian

2014-01-01

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6–18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. PMID:19900717

Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability.

PubMed

Gal, Moran; Levanon, Erez Y; Hujeirat, Yasir; Khayat, Morad; Pe'er, Jacob; Shalev, Stavit

2014-12-01

Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway. © 2014 Wiley Periodicals, Inc.

Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation.

PubMed

Haubek, Dorte; Gjørup, Hans; Jensen, Lillian G; Juncker, Inger; Nyegaard, Mette; Børglum, Anders D; Poulsen, Sven; Hertz, Jens M

2011-11-01

BACKGROUND.  Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES.  The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS.  Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION.  We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients. © 2011 The Authors. International Journal of Paediatric Dentistry © 2011 BSPD, IAPD and Blackwell Publishing Ltd.

Developmental plasticity in reptiles: Insights into thermal and maternal effects on chameleon phenotypes.

PubMed

Andrews, Robin M

2018-04-23

Embryonic environments affect a range of phenotypic traits including sex and reproductive success. I determined (1) how the interaction between incubation temperature and egg size affects sex allocation of Chamaeleo calyptratus and (2) how incubation temperature and maternal parent (clutch) affect water uptake by eggs and body size, growth, and climbing speed of hatchlings and juveniles. Eggs from five clutches were exposed to five temperature treatments with clutches replicated within and among treatments. Temperature affected sex, but only when egg size was included as a factor in analyses. At intermediate (28°C) temperatures, daughters were more likely to be produced from large eggs and sons more likely to be produced from small eggs, while at 25 and 30°C, the pattern of sex allocation was reversed. Temperature and clutch affected water uptake and body size. Nonetheless, the direction of temperature and clutch effects on water uptake by eggs and on the size of hatchlings were not the same and the direction of temperature effects on body sizes of hatchlings and juveniles differed as well. Clutch affected hatchling size but not juvenile size and growth rate. Clutch, but not incubation temperature, affected climbing speed, but the fastest hatchlings were not from the same clutches as the fastest juveniles. The independent effects of incubation temperature and clutch indicate that hatchling phenotypes are influenced largely by conditions experienced during incubation, while juvenile phenotypes are influenced largely by conditions experienced in the rearing environment. © 2018 Wiley Periodicals, Inc.

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

PubMed Central

Hwang, Grace; Sun, Fengyun; Eppig, John J.; Handel, Mary Ann

2017-01-01

SMC complexes include three major classes: cohesin, condensin and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis have not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre-driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase IIα to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females. PMID:28302748

Using Mouse Models to Explore Genotype-Phenotype Relationship in Down Syndrome

ERIC Educational Resources Information Center

Salehi, Ahmad; Faizi, Mehrdad; Belichenko, Pavel V.; Mobley, William C.

2007-01-01

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of…

Phenological shifts in North American red squirrels: disentangling the roles of phenotypic plasticity and microevolution.

PubMed

Lane, Jeffrey E; McAdam, Andrew G; McFarlane, S Eryn; Williams, Cory T; Humphries, Murray M; Coltman, David W; Gorrell, Jamieson C; Boutin, Stan

2018-06-01

Phenological shifts are the most widely reported ecological responses to climate change, but the requirements to distinguish their causes (i.e. phenotypic plasticity vs. microevolution) are rarely met. To do so, we analysed almost two decades of parturition data from a wild population of North American red squirrels (Tamiasciurus hudsonicus). Although an observed advance in parturition date during the first decade provided putative support for climate change-driven microevolution, a closer look revealed a more complex pattern. Parturition date was heritable [h 2  = 0.14 (0.07-0.21 (HPD interval)] and under phenotypic selection [β = -0.14 ± 0.06 (SE)] across the full study duration. However, the early advance reversed in the second decade. Further, selection did not act on the genetic contribution to variation in parturition date, and observed changes in predicted breeding values did not exceed those expected due to genetic drift. Instead, individuals responded plastically to environmental variation, and high food [white spruce (Picea glauca) seed] production in the first decade appears to have produced a plastic advance. In addition, there was little evidence of climate change affecting the advance, as there was neither a significant influence of spring temperature on parturition date or evidence of a change in spring temperatures across the study duration. Heritable traits not responding to selection in accordance with quantitative genetic predictions have long presented a puzzle to evolutionary ecologists. Our results on red squirrels provide empirical support for one potential solution: phenotypic selection arising from an environmental, as opposed to genetic, covariance between the phenotypic trait and annual fitness. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.

The Chromatin Assembly Factor Complex 1 (CAF1) and 5-Azacytidine (5-AzaC) Affect Cell Motility in Src-transformed Human Epithelial Cells.

PubMed

Endo, Akinori; Ly, Tony; Pippa, Raffaella; Bensaddek, Dalila; Nicolas, Armel; Lamond, Angus I

2017-01-06

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show that Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Effects of hypo-O-GlcNAcylation on Drosophila development.

PubMed

Mariappa, Daniel; Ferenbach, Andrew T; van Aalten, Daan M F

2018-05-11

Post-translational modification of serine/threonine residues in nucleocytoplasmic proteins with GlcNAc ( O -GlcNAcylation) is an essential regulatory mechanism in many cellular processes. In Drosophila , null mutants of the Polycomb gene O -GlcNAc transferase ( OGT ; also known as super sex combs ( sxc )) display homeotic phenotypes. To dissect the requirement for O -GlcNAc signaling in Drosophila development, we used CRISPR/Cas9 gene editing to generate rationally designed sxc catalytically hypomorphic or null point mutants. Of the fertile males derived from embryos injected with the CRISPR/Cas9 reagents, 25% produced progeny carrying precise point mutations with no detectable off-target effects. One of these mutants, the catalytically inactive sxc K872M , was recessive lethal, whereas a second mutant, the hypomorphic sxc H537A , was homozygous viable. We observed that reduced total protein O -GlcNAcylation in the sxc H537A mutant is associated with a wing vein phenotype and temperature-dependent lethality. Genetic interaction between sxc H537A and a null allele of Drosophila host cell factor ( dHcf ), encoding an extensively O -GlcNAcylated transcriptional coactivator, resulted in abnormal scutellar bristle numbers. A similar phenotype was also observed in sxc H537A flies lacking a copy of skuld ( skd ), a Mediator complex gene known to affect scutellar bristle formation. Interestingly, this phenotype was independent of OGT Polycomb function or dHcf downstream targets. In conclusion, the generation of the endogenous OGT hypomorphic mutant sxc H537A enabled us to identify pleiotropic effects of globally reduced protein O -GlcNAc during Drosophila development. The mutants generated and phenotypes observed in this study provide a platform for discovery of OGT substrates that are critical for Drosophila development. © 2018 Mariappa et al.

Enhancement of Plant Metabolite Fingerprinting by Machine Learning1[W

PubMed Central

Scott, Ian M.; Vermeer, Cornelia P.; Liakata, Maria; Corol, Delia I.; Ward, Jane L.; Lin, Wanchang; Johnson, Helen E.; Whitehead, Lynne; Kular, Baldeep; Baker, John M.; Walsh, Sean; Dave, Anuja; Larson, Tony R.; Graham, Ian A.; Wang, Trevor L.; King, Ross D.; Draper, John; Beale, Michael H.

2010-01-01

Metabolite fingerprinting of Arabidopsis (Arabidopsis thaliana) mutants with known or predicted metabolic lesions was performed by 1H-nuclear magnetic resonance, Fourier transform infrared, and flow injection electrospray-mass spectrometry. Fingerprinting enabled processing of five times more plants than conventional chromatographic profiling and was competitive for discriminating mutants, other than those affected in only low-abundance metabolites. Despite their rapidity and complexity, fingerprints yielded metabolomic insights (e.g. that effects of single lesions were usually not confined to individual pathways). Among fingerprint techniques, 1H-nuclear magnetic resonance discriminated the most mutant phenotypes from the wild type and Fourier transform infrared discriminated the fewest. To maximize information from fingerprints, data analysis was crucial. One-third of distinctive phenotypes might have been overlooked had data models been confined to principal component analysis score plots. Among several methods tested, machine learning (ML) algorithms, namely support vector machine or random forest (RF) classifiers, were unsurpassed for phenotype discrimination. Support vector machines were often the best performing classifiers, but RFs yielded some particularly informative measures. First, RFs estimated margins between mutant phenotypes, whose relations could then be visualized by Sammon mapping or hierarchical clustering. Second, RFs provided importance scores for the features within fingerprints that discriminated mutants. These scores correlated with analysis of variance F values (as did Kruskal-Wallis tests, true- and false-positive measures, mutual information, and the Relief feature selection algorithm). ML classifiers, as models trained on one data set to predict another, were ideal for focused metabolomic queries, such as the distinctiveness and consistency of mutant phenotypes. Accessible software for use of ML in plant physiology is highlighted. PMID:20566707

Autism Phenotypes in Tuberous Sclerosis Complex: Diagnostic and Treatment Considerations.

PubMed

Gipson, Tanjala T; Poretti, Andrea; Thomas, Emily A; Jenkins, Kosunique T; Desai, Sonal; Johnston, Michael V

2015-12-01

Tuberous sclerosis complex is a multisystem, chronic genetic condition characterized by systemic growth of benign tumors and often accompanied by epilepsy, autism spectrum disorders, and intellectual disability. Nonetheless, the neurodevelopmental phenotype of these patients is not often detailed. The authors describe 3 individuals with tuberous sclerosis complex who share common characteristics that can help to identify a distinct profile of autism spectrum disorder. These findings include typical cognitive development, expressive and pragmatic language deficits, and anxiety. The authors also describe features specific to tuberous sclerosis complex that require consideration before diagnosing an autism spectrum disorder. Identifying distinct profiles of autism spectrum disorder in tuberous sclerosis complex can help optimize treatment across the life span. © The Author(s) 2015.

The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 2: tentative explanations for differing prevalence figures in GTS, including the possible effects of psychopathology, aetiology, cultural differences, and differing phenotypes.

PubMed

Robertson, Mary M

2008-11-01

As has been demonstrated, Gilles de la Tourette Syndrome (GTS) occurs in at least 1% of the population worldwide. However, earlier studies suggested a lower prevalence. In addition, the prevalence figures for different studies very between 0.4% and 3.8%. Moreover, the prevalence appears to vary in some parts of the world and races, with a lower rate in Afro-Americans and sub-Saharan black Africans. In this the second part of the review, possible reasons for the differences in prevalence and epidemiology are discussed. Tentative explanations for differing prevalence figures in GTS include problems with the diagnosis of GTS, the multidimensional nature of tics, as well as other tic factors including the waxing and waning of symptoms and the suppressibility of symptoms. Other factors inherent to GTS include the fact that there is no diagnostic test and indeed no definitive diagnosis other than clinical, the fact that psychosocial stresses can lead to increased tic severity, and that comorbid disorders may mask tics. The varying methods of study employed can also effect prevalence. There may be some regional differences in GTS as well, which may be due to a lack of awareness of GTS, or it may be a true reflection of low prevalence as in some populations GTS does appear rare. With regard to the sub-Saharan Africa data and possibly the African American data, matters are much more complex than meets the eye. The following reasons are all possible for the apparent rarity in these populations and include (i) other medical priorities and less propensity to seek health care, (ii) lack of awareness of GTS, (iii) chance, (iv) ethnic and epigenetic differences and reasons, (v) genetic and allelic differences in different races, and (vi) an admixture of races. The aetiology of GTS is also complex, with influences from complex genetic mechanisms, pre- and perinatal difficulties and, in a subgroup, some infections, possibly by epigenetic mechanisms. These may well affect phenotype and, thus, prevalence. There have even been suggestions that people with GTS are increasing. Recent data suggests that GTS is not a unitary condition and that there may well be different types of GTS. The prevalence of GTS in these individual subtypes is unknown. It is suggested that a new nomenclature be adopted for GTS in future, pending further genetic and phenomenological studies. To what extent the aetiology affects the phenotype and, thus, the prevalence is still unclear.

Mutations in CTC1, Encoding the CTS Telomere Maintenance Complex Component 1, Cause Cerebroretinal Microangiopathy with Calcifications and Cysts

PubMed Central

Polvi, Anne; Linnankivi, Tarja; Kivelä, Tero; Herva, Riitta; Keating, James P.; Mäkitie, Outi; Pareyson, Davide; Vainionpää, Leena; Lahtinen, Jenni; Hovatta, Iiris; Pihko, Helena; Lehesjoki, Anna-Elina

2012-01-01

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare multisystem disorder characterized by extensive intracranial calcifications and cysts, leukoencephalopathy, and retinal vascular abnormalities. Additional features include poor growth, skeletal and hematological abnormalities, and recurrent gastrointestinal bleedings. Autosomal-recessive inheritance has been postulated. The pathogenesis of CRMCC is unknown, but its phenotype has key similarities with Revesz syndrome, which is caused by mutations in TINF2, a gene encoding a member of the telomere protecting shelterin complex. After a whole-exome sequencing approach in four unrelated individuals with CRMCC, we observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. Sanger sequencing revealed seven more compound heterozygous mutations in eight more unrelated affected individuals. Two individuals who displayed late-onset cerebral findings, a normal fundus appearance, and no systemic findings did not have CTC1 mutations, implying that systemic findings are an important indication for CTC1 sequencing. Of the 11 mutations identified, four were missense, one was nonsense, two resulted in in-frame amino acid deletions, and four were short frameshift-creating deletions. All but two affected individuals were compound heterozygous for a missense mutation and a frameshift or nonsense mutation. No individuals with two frameshift or nonsense mutations were identified, which implies that severe disturbance of CTC1 function from both alleles might not be compatible with survival. Our preliminary functional experiments did not show evidence of severely affected telomere integrity in the affected individuals. Therefore, determining the underlying pathomechanisms associated with deficient CTC1 function will require further studies. PMID:22387016

Evolutionary genetics of maternal effects

PubMed Central

Wolf, Jason B.; Wade, Michael J.

2016-01-01

Maternal genetic effects (MGEs), where genes expressed by mothers affect the phenotype of their offspring, are important sources of phenotypic diversity in a myriad of organisms. We use a single‐locus model to examine how MGEs contribute patterns of heritable and nonheritable variation and influence evolutionary dynamics in randomly mating and inbreeding populations. We elucidate the influence of MGEs by examining the offspring genotype‐phenotype relationship, which determines how MGEs affect evolutionary dynamics in response to selection on offspring phenotypes. This approach reveals important results that are not apparent from classic quantitative genetic treatments of MGEs. We show that additive and dominance MGEs make different contributions to evolutionary dynamics and patterns of variation, which are differentially affected by inbreeding. Dominance MGEs make the offspring genotype‐phenotype relationship frequency dependent, resulting in the appearance of negative frequency‐dependent selection, while additive MGEs contribute a component of parent‐of‐origin dependent variation. Inbreeding amplifies the contribution of MGEs to the additive genetic variance and, therefore enhances their evolutionary response. Considering evolutionary dynamics of allele frequency change on an adaptive landscape, we show that this landscape differs from the mean fitness surface, and therefore, under some condition, fitness peaks can exist but not be “available” to the evolving population. PMID:26969266

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.

PubMed

Romero-Moya, Damià; Santos-Ocaña, Carlos; Castaño, Julio; Garrabou, Gloria; Rodríguez-Gómez, José A; Ruiz-Bonilla, Vanesa; Bueno, Clara; González-Rodríguez, Patricia; Giorgetti, Alessandra; Perdiguero, Eusebio; Prieto, Cristina; Moren-Nuñez, Constanza; Fernández-Ayala, Daniel J; Victoria Cascajo, Maria; Velasco, Iván; Canals, Josep Maria; Montero, Raquel; Yubero, Delia; Jou, Cristina; López-Barneo, José; Cardellach, Francesc; Muñoz-Cánoves, Pura; Artuch, Rafael; Navas, Plácido; Menendez, Pablo

2017-07-01

Coenzyme Q 10 (CoQ 10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ 10 biosynthesis (COQ genes) cause primary CoQ 10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ 10 ], CoQ 10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4 ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4 ed -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ 10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ 10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687-1703. © 2017 AlphaMed Press.

Variants in TTC25 affect autistic trait in patients with autism spectrum disorder and general population.

PubMed

Vojinovic, Dina; Brison, Nathalie; Ahmad, Shahzad; Noens, Ilse; Pappa, Irene; Karssen, Lennart C; Tiemeier, Henning; van Duijn, Cornelia M; Peeters, Hilde; Amin, Najaf

2017-08-01

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with a complex genetic architecture. To identify genetic variants underlying ASD, we performed single-variant and gene-based genome-wide association studies using a dense genotyping array containing over 2.3 million single-nucleotide variants in a discovery sample of 160 families with at least one child affected with non-syndromic ASD using a binary (ASD yes/no) phenotype and a quantitative autistic trait. Replication of the top findings was performed in Psychiatric Genomics Consortium and Erasmus Rucphen Family (ERF) cohort study. Significant association of quantitative autistic trait was observed with the TTC25 gene at 17q21.2 (effect size=10.2, P-value=3.4 × 10 -7 ) in the gene-based analysis. The gene also showed nominally significant association in the cohort-based ERF study (effect=1.75, P-value=0.05). Meta-analysis of discovery and replication improved the association signal (P-value meta =1.5 × 10 -8 ). No genome-wide significant signal was observed in the single-variant analysis of either the binary ASD phenotype or the quantitative autistic trait. Our study has identified a novel gene TTC25 to be associated with quantitative autistic trait in patients with ASD. The replication of association in a cohort-based study and the effect estimate suggest that variants in TTC25 may also be relevant for broader ASD phenotype in the general population. TTC25 is overexpressed in frontal cortex and testis and is known to be involved in cilium movement and thus an interesting candidate gene for autistic trait.

A Newly Described Bovine Type 2 Scurs Syndrome Segregates with a Frame-Shift Mutation in TWIST1

PubMed Central

Capitan, Aurélien; Grohs, Cécile; Weiss, Bernard; Rossignol, Marie-Noëlle; Reversé, Patrick; Eggen, André

2011-01-01

The developmental pathways involved in horn development are complex and still poorly understood. Here we report the description of a new dominant inherited syndrome in the bovine Charolais breed that we have named type 2 scurs. Clinical examination revealed that, despite a strong phenotypic variability, all affected individuals show both horn abnormalities similar to classical scurs phenotype and skull interfrontal suture synostosis. Based on a genome-wide linkage analysis using Illumina BovineSNP50 BeadChip genotyping data from 57 half-sib and full-sib progeny, this locus was mapped to a 1.7 Mb interval on bovine chromosome 4. Within this region, the TWIST1 gene encoding a transcription factor was considered as a strong candidate gene since its haploinsufficiency is responsible for the human Saethre-Chotzen syndrome, characterized by skull coronal suture synostosis. Sequencing of the TWIST1 gene identified a c.148_157dup (p.A56RfsX87) frame-shift mutation predicted to completely inactivate this gene. Genotyping 17 scurred and 20 horned founders of our pedigree as well as 48 unrelated horned controls revealed a perfect association between this mutation and the type 2 scurs phenotype. Subsequent genotyping of 32 individuals born from heterozygous parents showed that homozygous mutated progeny are completely absent, which is consistent with the embryonic lethality reported in Drosophila and mouse suffering from TWIST1 complete insufficiency. Finally, data from previous studies on model species and a fine description of type 2 scurs symptoms allowed us to propose different mechanisms to explain the features of this syndrome. In conclusion, this first report on the identification of a potential causal mutation affecting horn development in cattle offers a unique opportunity to better understand horn ontogenesis. PMID:21814570

Hyperphagia and Obesity in Prader⁻Willi Syndrome: PCSK1 Deficiency and Beyond?

PubMed

Ramos-Molina, Bruno; Molina-Vega, María; Fernández-García, José C; Creemers, John W

2018-06-07

Prader⁻Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment. Proprotein convertase subtilisin/kexin type 1 ( PCSK1 ) deficiency, a rare recessive congenital disorder, partially overlaps phenotypically with PWS, but both genetic disorders show clear dissimilarities as well. The recent observation that PCSK1 is downregulated in a model of human PWS suggests that overlapping pathways are affected. In this review we will not only discuss the mechanisms by which PWS and PCSK1 deficiency could lead to hyperphagia but also the therapeutic interventions to treat obesity in both genetic disorders.

The Val192Leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.

PubMed Central

Hou, Y.; Vavougios, G.; Hinek, A.; Wu, K. K.; Hechtman, P.; Kaplan, F.; Mahuran, D. J.

1996-01-01

Substitution mutations adversely affecting the alpha-subunit of beta-hexosaminidase A (alphabeta) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an "active-site" residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This biochemical phenotype is referred to as the "B1-variant form" of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, alpha-Val192Leu. Chinese hamster ovary cells were permanently cotransfected with an alpha-cDNA-construct encoding the substitution and a mutant beta-cDNA (beta-Arg211Lys), encoding a beta-subunit that is inactive but normal in all other respects. We were surprised to find that the Val192Leu substitution, produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val192Leu substitution does not specifically affect the alpha-active site. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8659543

The Val192Leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.

PubMed

Hou, Y; Vavougios, G; Hinek, A; Wu, K K; Hechtman, P; Kaplan, F; Mahuran, D J

1996-07-01

Substitution mutations adversely affecting the alpha-subunit of beta-hexosaminidase A (alphabeta) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an "active-site" residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This biochemical phenotype is referred to as the "B1-variant form" of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, alpha-Val192Leu. Chinese hamster ovary cells were permanently cotransfected with an alpha-cDNA-construct encoding the substitution and a mutant beta-cDNA (beta-Arg211Lys), encoding a beta-subunit that is inactive but normal in all other respects. We were surprised to find that the Val192Leu substitution, produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val192Leu substitution does not specifically affect the alpha-active site.

A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).

PubMed

Mauri, Nico; Kleiter, Miriam; Leschnik, Michael; Högler, Sandra; Dietschi, Elisabeth; Wiedmer, Michaela; Dietrich, Joëlle; Henke, Diana; Steffen, Frank; Schuller, Simone; Gurtner, Corinne; Stokar-Regenscheit, Nadine; O'Toole, Donal; Bilzer, Thomas; Herden, Christiane; Oevermann, Anna; Jagannathan, Vidhya; Leeb, Tosso

2017-02-09

Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10 :c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome. Copyright © 2017 Mauri et al.

The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks.

PubMed

Morozova, Tatiana V; Goldman, David; Mackay, Trudy F C; Anholt, Robert R H

2012-02-20

Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.

PubMed

Wang, Jie; Wan, Ke; Sun, Jiayu; Li, Weihao; Liu, Hong; Han, Yuchi; Chen, Yucheng

2018-01-17

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Spine malformation complex in 3 diverse syndromic entities

PubMed Central

Kaissi, Ali Al; van Egmond-Fröhlich, Andreas; Ryabykh, Sergey; Ochirov, Polina; Kenis, Vladimir; Hofstaetter, Jochen G.; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

2016-01-01

Abstract Rationale: Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. Patients concerns: Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. Diagnoses: We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). Interventions: Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. Outcomes: The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. Lesons: Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and (c) the diagnosis. PMID:27977582

Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome

PubMed Central

Gerards, M; Sluiter, W; van den Bosch, B J C; de Wit, L E A; Calis, C M H; Frentzen, M; Akbari, H; Schoonderwoerd, K; Scholte, H R; Jongbloed, R J; Hendrickx, A T M; de Coo, I F M

2009-01-01

Background Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. Methods and results A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30–40% of mature complex I present in patients and 70–90% in carriers. Conclusions A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations. PMID:19542079

Environmentally induced (co)variance in sperm and offspring phenotypes as a source of epigenetic effects.

PubMed

Marshall, Dustin J

2015-01-01

Traditionally, it has been assumed that sperm are a vehicle for genes and nothing more. As such, the only source of variance in offspring phenotype via the paternal line has been genetic effects. More recently, however, it has been shown that the phenotype or environment of fathers can affect the phenotype of offspring, challenging traditional theory with implications for evolution, ecology and human in vitro fertilisation. Here, I review sources of non-genetic variation in the sperm phenotype and evidence for co-variation between sperm and offspring phenotypes. I distinguish between two environmental sources of variation in sperm phenotype: the pre-release environment and the post-release environment. Pre-release, sperm phenotypes can vary within species according to male phenotype (e.g. body size) and according to local conditions such as the threat of sperm competition. Post-release, the physicochemical conditions that sperm experience, either when freely spawned or when released into the female reproductive tract, can further filter or modify sperm phenotypes. I find evidence that both pre- and post-release sperm environments can affect offspring phenotype; fertilisation is not a new beginning – rather, the experiences of sperm with the father and upon release can drive variation in the phenotype of the offspring. Interestingly, there was some evidence for co-variation between the stress resistance of sperm and the stress resistance of offspring, though more studies are needed to determine whether such effects are widespread. Overall, it appears that environmentally induced covariation between sperm and offspring phenotypes is non-negligible and further work is needed to determine their prevalence and strength. © 2015. Published by The Company of Biologists Ltd.

p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex.

PubMed

Pardossi-Piquard, Raphaëlle; Dunys, Julie; Giaime, Emilie; Guillot-Sestier, Marie-Victoire; St George-Hyslop, Peter; Checler, Frédéric; Alves da Costa, Cristine

2009-04-01

Nicastrin (NCT) is a component of the presenilin (PS)-dependent gamma-secretase complexes that liberate amyloid beta-peptides from the beta-Amyloid Precursor Protein. Several lines of evidence indicate that the members of these complexes could also contribute to the control of cell death. Here we show that over-expression of NCT increases the viability of human embryonic kidney (HEK293) cells and decreases staurosporine (STS)- and thapsigargin (TPS)-induced caspase-3 activation in various cell lines from human and neuronal origins by Akt-dependent pathway. NCT lowers p53 expression, transcriptional activity and promoter transactivation and reduces p53 phosphorylation. NCT-associated protection against STS-stimulated cell death was completely abolished by p53 deficiency. Conversely, the depletion of NCT drastically enhances STS-induced caspase-3 activation and p53 pathway and favored p53 nuclear translocation. We examined whether NCT protective function depends on PS-dependent gamma-secretase activity. First, a 29-amino acid deletion known to reduce NCT-dependent amyloid beta-peptide production did not affect NCT-associated protective phenotype. Second, NCT still reduces STS-induced caspase-3 activation in fibroblasts lacking PS1 and PS2. Third, the gamma-secretase inhibitor DFK167 did not affect NCT-mediated reduction of p53 activity. Altogether, our study indicates that NCT controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways and that this function remains independent of the activity and molecular integrity of the gamma-secretase complexes.

Stable Accumulation of Photosystem II Requires ONE-HELIX PROTEIN1 (OHP1) of the Light Harvesting-Like Family1[OPEN

PubMed Central

Takahashi, Kaori; Funk, Christiane; Nomura, Yuko

2018-01-01

The cellular functions of two Arabidopsis (Arabidopsis thaliana) one-helix proteins, OHP1 and OHP2 (also named LIGHT-HARVESTING-LIKE2 [LIL2] and LIL6, respectively, because they have sequence similarity to light-harvesting chlorophyll a/b-binding proteins), remain unclear. Tagged null mutants of OHP1 and OHP2 (ohp1 and ohp2) showed stunted growth with pale-green leaves on agar plates, and these mutants were unable to grow on soil. Leaf chlorophyll fluorescence and the composition of thylakoid membrane proteins revealed that ohp1 deletion substantially affected photosystem II (PSII) core protein function and led to reduced levels of photosystem I core proteins; however, it did not affect LHC accumulation. Transgenic ohp1 plants rescued with OHP1-HA or OHP1-Myc proteins developed a normal phenotype. Using these tagged OHP1 proteins in transgenic plants, we localized OHP1 to thylakoid membranes, where it formed protein complexes with both OHP2 and High Chlorophyll Fluorescence244 (HCF244). We also found PSII core proteins D1/D2, HCF136, and HCF173 and a few other plant-specific proteins associated with the OHP1/OHP2-HCF244 complex, suggesting that these complexes are early intermediates in PSII assembly. OHP1 interacted directly with HCF244 in the complex. Therefore, OHP1 and HCF244 play important roles in the stable accumulation of PSII. PMID:29438089

Complex Homology and the Evolution of Nervous Systems

PubMed Central

Liebeskind, Benjamin J.; Hillis, David M.; Zakon, Harold H.; Hofmann, Hans A.

2016-01-01

We examine the complex evolution of animal nervous systems and discuss the ramifications of this complexity for inferring the nature of early animals. Although reconstructing the origins of nervous systems remains a central challenge in biology, and the phenotypic complexity of early animals remains controversial, a compelling picture is emerging. We now know that the nervous system and other key animal innovations contain a large degree of homoplasy, at least on the molecular level. Conflicting hypotheses about early nervous system evolution are due primarily to differences in the interpretation of this homoplasy. We highlight the need for explicit discussion of assumptions and discuss the limitations of current approaches for inferring ancient phenotypic states. PMID:26746806

Phenotype-information-phenotype cycle for deconvolution of combinatorial antibody libraries selected against complex systems.

PubMed

Zhang, Hongkai; Torkamani, Ali; Jones, Teresa M; Ruiz, Diana I; Pons, Jaume; Lerner, Richard A

2011-08-16

Use of large combinatorial antibody libraries and next-generation sequencing of nucleic acids are two of the most powerful methods in modern molecular biology. The libraries are screened using the principles of evolutionary selection, albeit in real time, to enrich for members with a particular phenotype. This selective process necessarily results in the loss of information about less-fit molecules. On the other hand, sequencing of the library, by itself, gives information that is mostly unrelated to phenotype. If the two methods could be combined, the full potential of very large molecular libraries could be realized. Here we report the implementation of a phenotype-information-phenotype cycle that integrates information and gene recovery. After selection for phage-encoded antibodies that bind to targets expressed on the surface of Escherichia coli, the information content of the selected pool is obtained by pyrosequencing. Sequences that encode specific antibodies are identified by a bioinformatic analysis and recovered by a stringent affinity method that is uniquely suited for gene isolation from a highly degenerate collection of nucleic acids. This approach can be generalized for selection of antibodies against targets that are present as minor components of complex systems.

Characterization of a Novel MMS-Sensitive Allele of Schizosaccharomyces pombe mcm4+

PubMed Central

Ranatunga, Nimna S.; Forsburg, Susan L.

2016-01-01

The minichromosome maintenance (MCM) complex is the conserved helicase motor of the eukaryotic replication fork. Mutations in the Mcm4 subunit are associated with replication stress and double strand breaks in multiple systems. In this work, we characterize a new temperature-sensitive allele of Schizosaccharomyces pombe mcm4+. Uniquely among known mcm4 alleles, this mutation causes sensitivity to the alkylation damaging agent methyl methanesulfonate (MMS). Even in the absence of treatment or temperature shift, mcm4-c106 cells show increased repair foci of RPA and Rad52, and require the damage checkpoint for viability, indicating genome stress. The mcm4-c106 mutant is synthetically lethal with mutations disrupting fork protection complex (FPC) proteins Swi1 and Swi3. Surprisingly, we found that the deletion of rif1+ suppressed the MMS-sensitive phenotype without affecting temperature sensitivity. Together, these data suggest that mcm4-c106 destabilizes replisome structure. PMID:27473316

Significance of fibrotic bands in utero--Amniotic band sequence with limb body wall complex: A rare case of fetal autopsy.

PubMed

Devi, P Lekshmi; Cicy, P J; Thambi, Renu; Poothiode, Usha

2015-01-01

Amniotic band sequence (ABS) includes a wide spectrum of abnormalities resulting from entrapment of various fetal parts from a disrupted amnion, ranging from a mere constriction ring affecting a finger to a fatal form called limb body wall complex (LBWC). Reported cases of ABS with LBWC are very few. The spectrum of anomalies depends on which part gets entrapped and at what point of gestation. Hence, the clinical presentation can be extremely variable. Early detection of such cases using sonology is really challenging due to the small size of the fibrotic bands. Here, we present a case of amniotic band syndrome with LBWC in a fetus at 24 weeks of gestation, which was referred for an autopsy. The fetus also showed scoliosis, gastroschisis, lumbosacral meningocele, congenital talipes equinovarus, and cleft palate, thus having features of placenta cranial and placenta abdominal phenotype which is very rare.

Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons.

PubMed

Tsujikawa, Motokazu; Malicki, Jarema

2004-06-10

Cilia play diverse roles in vertebrate and invertebrate sensory neurons. We show that a mutation of the zebrafish oval (ovl) locus affects a component of the ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia are generated but not maintained, producing the absence of photoreceptor outer segments. A loss of cilia also occurs in auditory hair cells and olfactory sensory neurons. In all three sense organs, cilia defects are followed by degeneration of sensory cells. Similar phenotypes are induced by the absence of the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A protein, ift140. The degeneration of mutant photoreceptor cells is caused, at least partially, by the ectopic accumulation of opsins. These studies reveal an essential role for IFT genes in vertebrate sensory neurons and implicate the molecular components of intraflagellar transport in degenerative disorders of these cells.

The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks

PubMed Central

2012-01-01

Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms. PMID:22348705

Integrating modelling and phenotyping approaches to identify and screen complex traits - Illustration for transpiration efficiency in cereals.

PubMed

Chenu, K; van Oosterom, E J; McLean, G; Deifel, K S; Fletcher, A; Geetika, G; Tirfessa, A; Mace, E S; Jordan, D R; Sulman, R; Hammer, G L

2018-02-21

Following advances in genetics, genomics, and phenotyping, trait selection in breeding is limited by our ability to understand interactions within the plants and with their environments, and to target traits of most relevance for the target population of environments. We propose an integrated approach that combines insights from crop modelling, physiology, genetics, and breeding to identify traits valuable for yield gain in the target population of environments, develop relevant high-throughput phenotyping platforms, and identify genetic controls and their values in production environments. This paper uses transpiration efficiency (biomass produced per unit of water used) as an example of a complex trait of interest to illustrate how the approach can guide modelling, phenotyping, and selection in a breeding program. We believe that this approach, by integrating insights from diverse disciplines, can increase the resource use efficiency of breeding programs for improving yield gains in target populations of environments.

Daddy issues: paternal effects on phenotype

PubMed Central

Rando, Oliver J.

2012-01-01

The once-popular, then heretical, idea that ancestral environment can affect the phenotype of future generations is coming back into vogue, due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. PMID:23141533

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

PubMed

Reijnders, Margot R F; Miller, Kerry A; Alvi, Mohsan; Goos, Jacqueline A C; Lees, Melissa M; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B A; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A L; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W E; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M; Cremer, Kirsten; Strom, Tim M; Bird, Lynne M; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S; Edery, Patrick; Yap, Patrick; Terhal, Paulien A; van der Spek, Peter J; Lakeman, Phillis; Taylor, Rachel L; Littlejohn, Rebecca O; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P A; Kant, Sarina G; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M A; Douzgou, Sofia; Wall, Steven A; Küry, Sébastien; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J; Twigg, Stephen R F; Mathijssen, Irene M J; Nellaker, Christoffer; Brunner, Han G; Wilkie, Andrew O M

2018-06-07

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Unveiling network-based functional features through integration of gene expression into protein networks.

PubMed

Jalili, Mahdi; Gebhardt, Tom; Wolkenhauer, Olaf; Salehzadeh-Yazdi, Ali

2018-06-01

Decoding health and disease phenotypes is one of the fundamental objectives in biomedicine. Whereas high-throughput omics approaches are available, it is evident that any single omics approach might not be adequate to capture the complexity of phenotypes. Therefore, integrated multi-omics approaches have been used to unravel genotype-phenotype relationships such as global regulatory mechanisms and complex metabolic networks in different eukaryotic organisms. Some of the progress and challenges associated with integrated omics studies have been reviewed previously in comprehensive studies. In this work, we highlight and review the progress, challenges and advantages associated with emerging approaches, integrating gene expression and protein-protein interaction networks to unravel network-based functional features. This includes identifying disease related genes, gene prioritization, clustering protein interactions, developing the modules, extract active subnetworks and static protein complexes or dynamic/temporal protein complexes. We also discuss how these approaches contribute to our understanding of the biology of complex traits and diseases. This article is part of a Special Issue entitled: Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. Copyright © 2018 Elsevier B.V. All rights reserved.

Conceptual Foundations of Systems Biology Explaining Complex Cardiac Diseases.

PubMed

Louridas, George E; Lourida, Katerina G

2017-02-21

Systems biology is an important concept that connects molecular biology and genomics with computing science, mathematics and engineering. An endeavor is made in this paper to associate basic conceptual ideas of systems biology with clinical medicine. Complex cardiac diseases are clinical phenotypes generated by integration of genetic, molecular and environmental factors. Basic concepts of systems biology like network construction, modular thinking, biological constraints (downward biological direction) and emergence (upward biological direction) could be applied to clinical medicine. Especially, in the field of cardiology, these concepts can be used to explain complex clinical cardiac phenotypes like chronic heart failure and coronary artery disease. Cardiac diseases are biological complex entities which like other biological phenomena can be explained by a systems biology approach. The above powerful biological tools of systems biology can explain robustness growth and stability during disease process from modulation to phenotype. The purpose of the present review paper is to implement systems biology strategy and incorporate some conceptual issues raised by this approach into the clinical field of complex cardiac diseases. Cardiac disease process and progression can be addressed by the holistic realistic approach of systems biology in order to define in better terms earlier diagnosis and more effective therapy.

On the value of the phenotypes in the genomic era.

PubMed

Gonzalez-Recio, O; Coffey, M P; Pryce, J E

2014-12-01

Genetic improvement programs around the world rely on the collection of accurate phenotypic data. These phenotypes have an inherent value that can be estimated as the contribution of an additional record to genetic gain. Here, the contribution of phenotypes to genetic gain was calculated using traditional progeny testing (PT) and 2 genomic selection (GS) strategies that, for simplicity, included either males or females in the reference population. A procedure to estimate the theoretical economic contribution of a phenotype to a breeding program is described for both GS and PT breeding programs through the increment in genetic gain per unit of increase in estimated breeding value reliability obtained when an additional phenotypic record is added. The main factors affecting the value of a phenotype were the economic value of the trait, the number of phenotypic records already available for the trait, and its heritability. Furthermore, the value of a phenotype was affected by several other factors, including the cost of establishing the breeding program and the cost of phenotyping and genotyping. The cost of achieving a reliability of 0.60 was assessed for different reference populations for GS. Genomic reference populations of more sires with small progeny group sizes (e.g., 20 equivalent daughters) had a lower cost than those reference populations with either large progeny group sizes for fewer genotyped sires, or female reference populations, unless the heritability was large and the cost of phenotyping exceeded a few hundred dollars; then, female reference populations were preferable from an economic perspective. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

PubMed

Kalueff, A V; Fox, M A; Gallagher, P S; Murphy, D L

2007-06-01

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

Mutants of the Paf1 Complex Alter Phenotypic Expression of the Yeast Prion [PSI+

PubMed Central

Strawn, Lisa A.; Lin, Changyi A.; Tank, Elizabeth M.H.; Osman, Morwan M.; Simpson, Sarah A.

2009-01-01

The yeast [PSI+] prion is an epigenetic modifier of translation termination fidelity that causes nonsense suppression. The prion [PSI+] forms when the translation termination factor Sup35p adopts a self-propagating conformation. The presence of the [PSI+] prion modulates survivability in a variety of growth conditions. Nonsense suppression is essential for many [PSI+]-mediated phenotypes, but many do not appear to be due to read-through of a single stop codon, but instead are multigenic traits. We hypothesized that other global mechanisms act in concert with [PSI+] to influence [PSI+]-mediated phenotypes. We have identified one such global regulator, the Paf1 complex (Paf1C). Paf1C is conserved in eukaryotes and has been implicated in several aspects of transcriptional and posttranscriptional regulation. Mutations in Ctr9p and other Paf1C components reduced [PSI+]-mediated nonsense suppression. The CTR9 deletion also alters nonsense suppression afforded by other genetic mutations but not always to the same extent as the effects on [PSI+]-mediated read-through. Our data suggest that the Paf1 complex influences mRNA translatability but not solely through changes in transcript stability or abundance. Finally, we demonstrate that the CTR9 deletion alters several [PSI+]-dependent phenotypes. This provides one example of how [PSI+] and genetic modifiers can interact to uncover and regulate phenotypic variability. PMID:19225160

Thermoregulatory behaviour affects prevalence of chytrid fungal infection in a wild population of Panamanian golden frogs

PubMed Central

Richards-Zawacki, Corinne L.

2010-01-01

Predicting how climate change will affect disease dynamics requires an understanding of how the environment affects host–pathogen interactions. For amphibians, global declines and extinctions have been linked to a pathogenic chytrid fungus, Batrachochytrium dendrobatidis. Using a combination of body temperature measurements and disease assays conducted before and after the arrival of B. dendrobatidis, this study tested the hypothesis that body temperature affects the prevalence of infection in a wild population of Panamanian golden frogs (Atelopus zeteki). The timing of first detection of the fungus was consistent with that of a wave of epidemic infections spreading south and eastward through Central America. During the epidemic, many golden frogs modified their thermoregulatory behaviour, raising body temperatures above their normal set point. Odds of infection decreased with increasing body temperature, demonstrating that even slight environmental or behavioural changes have the potential to affect an individual's vulnerability to infection. The thermal dependency of the relationship between B. dendrobatidis and its amphibian hosts demonstrates how the progression of an epidemic can be influenced by complex interactions between host and pathogen phenotypes and the environments in which they are found. PMID:19864287

Protocol for Identifying Natural Agents That Selectively Affect Adhesion, Thickness, Architecture, Cellular Phenotypes, Extracellular Matrix, and Human White Blood Cell Impenetrability of Candida albicans Biofilms

PubMed Central

Park, Yang-Nim; Srikantha, Thyagarajan; Daniels, Karla J.; Jacob, Melissa R.; Agarwal, Ameeta K.; Li, Xing-Cong

2017-01-01

ABSTRACT In the screening of natural plant extracts for antifungal activity, assessment of their effects on the growth of cells in suspension or in the wells of microtiter plates is expedient. However, microorganisms, including Candida albicans, grow in nature as biofilms, which are organized cellular communities with a complex architecture capable of conditioning their microenvironment, communicating, and excluding low- and high-molecular-weight molecules and white blood cells. Here, a confocal laser scanning microscopy (CLSM) protocol for testing the effects of large numbers of agents on biofilm development is described. The protocol assessed nine parameters from a single z-stack series of CLSM scans for each individual biofilm analyzed. The parameters included adhesion, thickness, formation of a basal yeast cell polylayer, hypha formation, the vertical orientation of hyphae, the hyphal bend point, pseudohypha formation, calcofluor white staining of the extracellular matrix (ECM), and human white blood cell impenetrability. The protocol was applied first to five plant extracts and derivative compounds and then to a collection of 88 previously untested plant extracts. They were found to cause a variety of phenotypic profiles, as was the case for 64 of the 88 extracts (73%). Half of the 46 extracts that did not affect biofilm thickness affected other biofilm parameters. Correlations between specific effects were revealed. The protocol will be useful not only in the screening of chemical libraries but also in the analysis of compounds with known effects and mutations. PMID:28893778

Cortical Folding of the Primate Brain: An Interdisciplinary Examination of the Genetic Architecture, Modularity, and Evolvability of a Significant Neurological Trait in Pedigreed Baboons (Genus Papio)

PubMed Central

Atkinson, Elizabeth G.; Rogers, Jeffrey; Mahaney, Michael C.; Cox, Laura A.; Cheverud, James M.

2015-01-01

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ∼1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical–cortical connectivity, and gyrification’s potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution. PMID:25873632

Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients

PubMed Central

Borsatto, Taciane; Sperb-Ludwig, Fernanda; Lima, Samyra E.; S. Carvalho, Maria R.; S. Fonseca, Pablo A.; S. Camelo, José; M. Ribeiro, Erlane; F. V. de Medeiros, Paula; M. Lourenço, Charles; F. M. de Souza, Carolina; Boy, Raquel; Félix, Têmis M.; M. Bittar, Camila; L. C. Pinto, Louise; C. Neto, Eurico; J. Blom, Henk; D. Schwartz, Ida V.

2017-01-01

Introduction The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. Methods All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. Results Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients. Conclusions The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity. PMID:28498829

Environmental Control of Root System Biology.

PubMed

Rellán-Álvarez, Rubén; Lobet, Guillaume; Dinneny, José R

2016-04-29

The plant root system traverses one of the most complex environments on earth. Understanding how roots support plant life on land requires knowing how soil properties affect the availability of nutrients and water and how roots manipulate the soil environment to optimize acquisition of these resources. Imaging of roots in soil allows the integrated analysis and modeling of environmental interactions occurring at micro- to macroscales. Advances in phenotyping of root systems is driving innovation in cross-platform-compatible methods for data analysis. Root systems acclimate to the environment through architectural changes that act at the root-type level as well as through tissue-specific changes that affect the metabolic needs of the root and the efficiency of nutrient uptake. A molecular understanding of the signaling mechanisms that guide local and systemic signaling is providing insight into the regulatory logic of environmental responses and has identified points where crosstalk between pathways occurs.

Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities.

PubMed

Lapek, John D; Greninger, Patricia; Morris, Robert; Amzallag, Arnaud; Pruteanu-Malinici, Iulian; Benes, Cyril H; Haas, Wilhelm

2017-10-01

The formation of protein complexes and the co-regulation of the cellular concentrations of proteins are essential mechanisms for cellular signaling and for maintaining homeostasis. Here we use isobaric-labeling multiplexed proteomics to analyze protein co-regulation and show that this allows the identification of protein-protein associations with high accuracy. We apply this 'interactome mapping by high-throughput quantitative proteome analysis' (IMAHP) method to a panel of 41 breast cancer cell lines and show that deviations of the observed protein co-regulations in specific cell lines from the consensus network affects cellular fitness. Furthermore, these aberrant interactions serve as biomarkers that predict the drug sensitivity of cell lines in screens across 195 drugs. We expect that IMAHP can be broadly used to gain insight into how changing landscapes of protein-protein associations affect the phenotype of biological systems.

Of mice and men: molecular genetics of congenital heart disease.

PubMed

Andersen, Troels Askhøj; Troelsen, Karin de Linde Lind; Larsen, Lars Allan

2014-04-01

Congenital heart disease (CHD) affects nearly 1 % of the population. It is a complex disease, which may be caused by multiple genetic and environmental factors. Studies in human genetics have led to the identification of more than 50 human genes, involved in isolated CHD or genetic syndromes, where CHD is part of the phenotype. Furthermore, mapping of genomic copy number variants and exome sequencing of CHD patients have led to the identification of a large number of candidate disease genes. Experiments in animal models, particularly in mice, have been used to verify human disease genes and to gain further insight into the molecular pathology behind CHD. The picture emerging from these studies suggest that genetic lesions associated with CHD affect a broad range of cellular signaling components, from ligands and receptors, across down-stream effector molecules to transcription factors and co-factors, including chromatin modifiers.

Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

PubMed

Lynch, Henry T; Lanspa, Stephen; Shaw, Trudy; Casey, Murray Joseph; Rendell, Marc; Stacey, Mark; Townley, Theresa; Snyder, Carrie; Hitchins, Megan; Bailey-Wilson, Joan

2018-07-01

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

PubMed Central

Hutchinson, John N.; Raj, Towfique; Fagerness, Jes; Stahl, Eli; Viloria, Fernando T.; Gimelbrant, Alexander; Seddon, Johanna; Daly, Mark; Chess, Andrew; Plenge, Robert

2014-01-01

We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results. PMID:24911414

High-Risk Screening for Fabry Disease: Analysis by Tandem Mass Spectrometry of Globotriaosylceramide (Gb3 ) in Urine Collected on Filter Paper.

PubMed

Auray-Blais, Christiane; Lavoie, Pamela; Boutin, Michel; Abaoui, Mona

2017-04-06

Fabry disease is a complex, panethnic lysosomal storage disorder. It is characterized by the accumulation of glycosphingolipids in tissues, organs, the vascular endothelium, and biological fluids. The reported incidence in different populations is quite variable, ranging from 1:1400 to 1:117,000. Its complexity lies in the marked genotypic and phenotypic heterogeneity. Despite the fact that it is an X-linked disease, more than 600 mutations affect both males and females. In fact, some females may be affected as severely as males. The purpose of this protocol is to focus on the high-risk screening of patients who might have Fabry disease using a simple, rapid, non-invasive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for urinary globotriaosylceramide (Gb 3 ) analysis. Urine filter paper samples are easily collected at home by patients and sent by regular mail. This method has been successfully used for high-risk screening of patients with ophthalmologic manifestations and in an on-going study for high-risk screening of Fabry disease in patients with chronic kidney diseases. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Loss of Gnas imprinting differentially affects REM/NREM sleep and cognition in mice.

PubMed

Lassi, Glenda; Ball, Simon T; Maggi, Silvia; Colonna, Giovanni; Nieus, Thierry; Cero, Cheryl; Bartolomucci, Alessandro; Peters, Jo; Tucci, Valter

2012-01-01

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM-linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM-dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes.

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

PubMed Central

Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

2018-01-01

Abstract Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1−/y) and contactin-associated (CNTNAP2−/−) knockout mice. Young Fmr1−/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2−/− mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes. PMID:29901787

Exploiting Differential Gene Expression and Epistasis to Discover Candidate Genes for Drought-Associated QTLs in Arabidopsis thaliana.

PubMed

Lovell, John T; Mullen, Jack L; Lowry, David B; Awole, Kedija; Richards, James H; Sen, Saunak; Verslues, Paul E; Juenger, Thomas E; McKay, John K

2015-04-01

Soil water availability represents one of the most important selective agents for plants in nature and the single greatest abiotic determinant of agricultural productivity, yet the genetic bases of drought acclimation responses remain poorly understood. Here, we developed a systems-genetic approach to characterize quantitative trait loci (QTLs), physiological traits and genes that affect responses to soil moisture deficit in the TSUxKAS mapping population of Arabidopsis thaliana. To determine the effects of candidate genes underlying QTLs, we analyzed gene expression as a covariate within the QTL model in an effort to mechanistically link markers, RNA expression, and the phenotype. This strategy produced ranked lists of candidate genes for several drought-associated traits, including water use efficiency, growth, abscisic acid concentration (ABA), and proline concentration. As a proof of concept, we recovered known causal loci for several QTLs. For other traits, including ABA, we identified novel loci not previously associated with drought. Furthermore, we documented natural variation at two key steps in proline metabolism and demonstrated that the mitochondrial genome differentially affects genomic QTLs to influence proline accumulation. These findings demonstrate that linking genome, transcriptome, and phenotype data holds great promise to extend the utility of genetic mapping, even when QTL effects are modest or complex. © 2015 American Society of Plant Biologists. All rights reserved.

Ex vivo isolation protocols differentially affect the phenotype of human CD4+ T cells.

PubMed

Bernard, Frédéric; Jaleco, Sara; Dardalhon, Valérie; Steinberg, Marcos; Yssel, Hans; Noraz, Nelly; Taylor, Naomi; Kinet, Sandrina

2002-12-20

Leukemic T cell lines have facilitated signal transduction studies but their physiological relevance is restricted. The use of primary T lymphocytes overcomes this limitation but it has long been speculated that methodological aspects of blood collection and the isolation procedure modify the phenotype of the cell. Here we demonstrate that several characteristics of human peripheral T cells are affected by the selection conditions. A significantly higher induction of the chemokine receptor CXCR4 was observed on CD4+ lymphocytes isolated by sheep red blood cell (SRBC) rosetting and CD4 MicroBeads as compared with positively selected CD4+ cells where the antibody/bead complex was immediately detached. These latter cells expressed CXCR4 at levels equivalent to that observed on CD4+ lymphocytes obtained by negative antibody-mediated selection. Furthermore, CD4+ cells isolated by SRBC rosetting and CD4 MicroBeads formed aggregates upon in vitro culture. CD4+ lymphocytes obtained by SRBC rosetting as well as those isolated following positive selection demonstrated basal phosphorylation of the extracellular signal-regulated kinase (ERK)-2. Altogether these data suggest that certain discrepancies concerning signal transduction in primary human T cells can be attributed to the selection conditions. Thus, it is essential to establish the parameters influenced by the isolation protocol in order to fully interpret T cell responses to antigens, chemokines, and cytokines.

Social chromosome variants differentially affect queen determination and the survival of workers in the fire ant Solenopsis invicta.

PubMed

Buechel, Séverine D; Wurm, Yanick; Keller, Laurent

2014-10-01

Intraspecific variation in social organization is common, yet the underlying causes are rarely known. An exception is the fire ant Solenopsis invicta in which the existence of two distinct forms of social colony organization is under the control of the two variants of a pair of social chromosomes, SB and Sb. Colonies containing exclusively SB/SB workers accept only one single queen and she must be SB/SB. By contrast, when colonies contain more than 10% of SB/Sb workers, they accept several queens but only SB/Sb queens. The variants of the social chromosome are associated with several additional important phenotypic differences, including the size, fecundity and dispersal strategies of queens, aggressiveness of workers, and sperm count in males. However, little is known about whether social chromosome variants affect fitness in other life stages. Here, we perform experiments to determine whether differential selection occurs during development and in adult workers. We find evidence that the Sb variant of the social chromosome increases the likelihood of female brood to develop into queens and that adult SB/Sb workers, the workers that cull SB/SB queens, are overrepresented in comparison to SB/SB workers. This demonstrates that supergenes such as the social chromosome can have complex effects on phenotypes at various stages of development. © 2014 John Wiley & Sons Ltd.

Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis.

PubMed

Quélin, Chloé; Loget, Philippe; Boutaud, Lucile; Elkhartoufi, Nadia; Milon, Joelle; Odent, Sylvie; Fradin, Mélanie; Demurger, Florence; Pasquier, Laurent; Thomas, Sophie; Attié-Bitach, Tania

2018-04-27

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype. © 2018 Wiley Periodicals, Inc.

Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes

PubMed Central

Watkins-Chow, Dawn E.; Cooke, Joanna; Pidsley, Ruth; Edwards, Andrew; Slotkin, Rebecca; Leeds, Karen E.; Mullen, Raymond; Baxter, Laura L.; Campbell, Thomas G.; Salzer, Marion C.; Biondini, Laura; Gibney, Gretchen; Phan Dinh Tuy, Françoise; Chelly, Jamel; Morris, H. Douglas; Riegler, Johannes; Lythgoe, Mark F.; Arkell, Ruth M.; Loreni, Fabrizio; Flint, Jonathan

2013-01-01

The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7Mtu and Rps7Zma) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes. PMID:23382688

Testing cross-phenotype effects of rare variants in longitudinal studies of complex traits.

PubMed

Rudra, Pratyaydipta; Broadaway, K Alaine; Ware, Erin B; Jhun, Min A; Bielak, Lawrence F; Zhao, Wei; Smith, Jennifer A; Peyser, Patricia A; Kardia, Sharon L R; Epstein, Michael P; Ghosh, Debashis

2018-06-01

Many gene mapping studies of complex traits have identified genes or variants that influence multiple phenotypes. With the advent of next-generation sequencing technology, there has been substantial interest in identifying rare variants in genes that possess cross-phenotype effects. In the presence of such effects, modeling both the phenotypes and rare variants collectively using multivariate models can achieve higher statistical power compared to univariate methods that either model each phenotype separately or perform separate tests for each variant. Several studies collect phenotypic data over time and using such longitudinal data can further increase the power to detect genetic associations. Although rare-variant approaches exist for testing cross-phenotype effects at a single time point, there is no analogous method for performing such analyses using longitudinal outcomes. In order to fill this important gap, we propose an extension of Gene Association with Multiple Traits (GAMuT) test, a method for cross-phenotype analysis of rare variants using a framework based on the distance covariance. The approach allows for both binary and continuous phenotypes and can also adjust for covariates. Our simple adjustment to the GAMuT test allows it to handle longitudinal data and to gain power by exploiting temporal correlation. The approach is computationally efficient and applicable on a genome-wide scale due to the use of a closed-form test whose significance can be evaluated analytically. We use simulated data to demonstrate that our method has favorable power over competing approaches and also apply our approach to exome chip data from the Genetic Epidemiology Network of Arteriopathy. © 2018 WILEY PERIODICALS, INC.

Exhaustive Analysis of a Genotype Space Comprising 1015 Central Carbon Metabolisms Reveals an Organization Conducive to Metabolic Innovation

PubMed Central

Hosseini, Sayed-Rzgar; Barve, Aditya; Wagner, Andreas

2015-01-01

All biological evolution takes place in a space of possible genotypes and their phenotypes. The structure of this space defines the evolutionary potential and limitations of an evolving system. Metabolism is one of the most ancient and fundamental evolving systems, sustaining life by extracting energy from extracellular nutrients. Here we study metabolism’s potential for innovation by analyzing an exhaustive genotype-phenotype map for a space of 1015 metabolisms that encodes all possible subsets of 51 reactions in central carbon metabolism. Using flux balance analysis, we predict the viability of these metabolisms on 10 different carbon sources which give rise to 1024 potential metabolic phenotypes. Although viable metabolisms with any one phenotype comprise a tiny fraction of genotype space, their absolute numbers exceed 109 for some phenotypes. Metabolisms with any one phenotype typically form a single network of genotypes that extends far or all the way through metabolic genotype space, where any two genotypes can be reached from each other through a series of single reaction changes. The minimal distance of genotype networks associated with different phenotypes is small, such that one can reach metabolisms with novel phenotypes – viable on new carbon sources – through one or few genotypic changes. Exceptions to these principles exist for those metabolisms whose complexity (number of reactions) is close to the minimum needed for viability. Increasing metabolic complexity enhances the potential for both evolutionary conservation and evolutionary innovation. PMID:26252881

Family background of Diabetes Mellitus, obesity and hypertension affects the phenotype and first symptom of patients with PCOS.

PubMed

Kulshreshtha, Bindu; Singh, Seerat; Arora, Arpita

2013-12-01

The phenotypic variability among PCOS could be due to differences in insulin patterns. Hyperinsulinemia commonly accompanies Diabetes Mellitus (DM), obesity, hypertension and CAD, though, to a variable degree. We speculate that a family history of these diseases could differentially affect the phenotype of PCOS. To study the effect of DM/CAD/HT and obesity on the phenotype of PCOS. PCOS patients and age matched controls were enquired for a family background of DM, hypertension, CAD and obesity among parents and grandparents. Regression modelling was employed to examine predictors of obesity and first symptom in PCOS patients. There were 88 PCOS women and 77 age-matched controls (46 lean, 31 obese). A high prevalence of DM, CAD, obesity and hypertension was observed among parents and grandparents of women with PCOS compared to controls. Hypertension and CAD manifested more in father's side of family. BMI of PCOS subjects was significantly related to parental DM and obesity after correcting for age. First symptom of weight gain was significantly associated with number of parents with DM (p = 0.02) and first symptom of irregular periods was associated with number of parents with hypertension (p = 0.06). A family background of DM/HT and obesity diseases affects the phenotype of PCOS.

Chromosomal rearrangements, phenotypic variation and modularity: a case study from a contact zone between house mouse Robertsonian races in Central Italy.

PubMed

Franchini, Paolo; Colangelo, Paolo; Meyer, Axel; Fruciano, Carmelo

2016-03-01

The Western European house mouse, Mus musculus domesticus, is well-known for the high frequency of Robertsonian fusions that have rapidly produced more than 50 karyotipic races, making it an ideal model for studying the mechanisms of chromosomal speciation. The mouse mandible is one of the traits studied most intensively to investigate the effect of Robertsonian fusions on phenotypic variation within and between populations. This complex bone structure has also been widely used to study the level of integration between different morphogenetic units. Here, with the aim of testing the effect of different karyotypic assets on the morphology of the mouse mandible and on its level of modularity, we performed morphometric analyses of mice from a contact area between two highly metacentric races in Central Italy. We found no difference in size, while the mandible shape was found to be different between the two Robertsonian races, even after accounting for the genetic relationships among individuals and geographic proximity. Our results support the existence of two modules that indicate a certain degree of evolutionary independence, but no difference in the strength of modularity between chromosomal races. Moreover, the ascending ramus showed more pronounced interpopulation/race phenotypic differences than the alveolar region, an effect that could be associated to their different polygenic architecture. This study suggests that chromosomal rearrangements play a role in the house mouse phenotypic divergence, and that the two modules of the mouse mandible are differentially affected by environmental factors and genetic makeup.

Immobilized heavy chain-hyaluronic acid polarizes lipopolysaccharide-activated macrophages toward M2 phenotype.

PubMed

He, Hua; Zhang, Suzhen; Tighe, Sean; Son, Ji; Tseng, Scheffer C G

2013-09-06

Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-α-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPS-activated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-α, and NO synthase 2. Additionally, IL-10, TGF-β1, peroxisome proliferator-activated receptor γ, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes.

Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.

PubMed

Piccini, Barbara; Artuso, Rosangela; Lenzi, Lorenzo; Guasti, Monica; Braccesi, Giulia; Barni, Federica; Casalini, Emilio; Giglio, Sabrina; Toni, Sonia

2016-11-01

Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

PubMed

Kawarai, Toshitaka; Miyamoto, Ryosuke; Nakagawa, Eiji; Koichihara, Reiko; Sakamoto, Takashi; Mure, Hideo; Morigaki, Ryoma; Koizumi, Hidetaka; Oki, Ryosuke; Montecchiani, Celeste; Caltagirone, Carlo; Orlacchio, Antonio; Hattori, Ayako; Mashimo, Hideaki; Izumi, Yuishin; Mezaki, Takahiro; Kumada, Satoko; Taniguchi, Makoto; Yokochi, Fusako; Saitoh, Shinji; Goto, Satoshi; Kaji, Ryuji

2018-04-05

Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation.

PubMed

Blumenthal, Edward M

2008-01-01

Mutations in the Drosophila gene drop-dead (drd) result in early adult lethality and neurodegeneration, but the molecular identity of the drd gene and its mechanism of action are not known. This paper describes the characterization of a new X-linked recessive adult-lethal mutation, originally called lot's wife (lwf(1)) but subsequently identified as an allele of drd (drd(lwf)); drd(lwf) mutants die within two weeks of eclosion. Through mapping and complementation, the drd gene has been identified as CG33968, which encodes a putative integral membrane protein of unknown function. The drd(lwf) allele is associated with a nonsense mutation that eliminates nearly 80% of the CG33968 gene product; mutations in the same gene were also found in two previously described drd alleles. Characterization of drd (lwf) flies revealed additional phenotypes of drd, most notably, defects in food processing by the digestive system and in oogenesis. Mutant flies store significantly more food in their crops and defecate less than wild-type flies, suggesting that normal transfer of ingested food from the crop into the midgut is dependent upon the DRD gene product. The defect in oogenesis results in the sterility of homozygous mutant females and is associated with a reduction in the number of vitellogenic egg chambers. The disruption in vitellogenesis is far more severe than that seen in starved flies and so is unlikely to be a secondary consequence of the digestive phenotype. This study demonstrates that mutation of the drd gene CG33968 results in a complex phenotype affecting multiple physiological systems within the fly.

Changes in Muscle Metabolism are Associated with Phenotypic Variability in Golden Retriever Muscular Dystrophy




PubMed Central

Nghiem, Peter P.; Bello, Luca; Stoughton, William B.; López, Sara Mata; Vidal, Alexander H.; Hernandez, Briana V.; Hulbert, Katherine N.; Gourley, Taylor R.; Bettis, Amanda K.; Balog-Alvarez, Cynthia J.; Heath-Barnett, Heather; Kornegay, Joe N.

2017-01-01

Duchenne muscular dystrophy (DMD) is an X-chromosome-linked disorder and the most common monogenic disease in people. Affected boys are diagnosed at a young age, become non-ambulatory by their early teens, and succumb to cardiorespiratory failure by their thirties. Despite being a monogenic condition resulting from mutations in the DMD gene, affected boys have noteworthy phenotypic variability. Efforts have identified genetic modifiers that could modify disease progression and be pharmacologic targets. Dogs affected with golden retriever muscular dystrophy (GRMD) have absent dystrophin and demonstrate phenotypic variability at the functional, histopathological, and molecular level. Our laboratory is particularly interested in muscle metabolism changes in dystrophin-deficient muscle. We identified several metabolic alterations, including myofiber type switching from fast (type II) to slow (type I), reduced glycolytic enzyme expression, reduced and morphologically abnormal mitochondria, and differential AMP-kinase phosphorylation (activation) between hypertrophied and wasted muscle. We hypothesize that muscle metabolism changes are, in part, responsible for phenotypic variability in GRMD. Pharmacological therapies aimed at modulating muscle metabolism can be tested in GRMD dogs for efficacy. PMID:28955176

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

PubMed

Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

2015-10-01

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes

PubMed Central

Miller, Frederick W.; Chen, Wei; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R.; Isenberg, David A.; Chinoy, Hector; Ollier, William E.R.; Scheet, Paul; Peng, Bo; Lee, Annette; Byun, Jinyoung; Lamb, Janine A.; Gregersen, Peter K.; Amos, Christopher I.

2016-01-01

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1haplotype comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

The impact of nectar chemical features on phenotypic variation in two related nectar yeasts.

PubMed

Pozo, María I; Herrera, Carlos M; Van den Ende, Wim; Verstrepen, Kevin; Lievens, Bart; Jacquemyn, Hans

2015-06-01

Floral nectars become easily colonized by microbes, most often species of the ascomycetous yeast genus Metschnikowia. Although it is known that nectar composition can vary tremendously among plant species, most probably corresponding to the nutritional requirements of their main pollinators, far less is known about how variation in nectar chemistry affects intraspecific variation in nectarivorous yeasts. Because variation in nectar traits probably affects growth and abundance of nectar yeasts, nectar yeasts can be expected to display large phenotypic variation in order to cope with varying nectar conditions. To test this hypothesis, we related variation in the phenotypic landscape of a vast collection of nectar-living yeast isolates from two Metschnikowia species (M. reukaufii and M. gruessii) to nectar chemical traits using non-linear redundancy analyses. Nectar yeasts were collected from 19 plant species from different plant families to include as much variation in nectar chemical traits as possible. As expected, nectar yeasts displayed large variation in phenotypic traits, particularly in traits related to growth performance in carbon sources and inhibitors, which was significantly related to the host plant from which they were isolated. Total sugar concentration and relative fructose content significantly explained the observed variation in the phenotypic profile of the investigated yeast species, indicating that sugar concentration and composition are the key traits that affect phenotypic variation in nectarivorous yeasts. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Complex Homology and the Evolution of Nervous Systems.

PubMed

Liebeskind, Benjamin J; Hillis, David M; Zakon, Harold H; Hofmann, Hans A

2016-02-01

We examine the complex evolution of animal nervous systems and discuss the ramifications of this complexity for inferring the nature of early animals. Although reconstructing the origins of nervous systems remains a central challenge in biology, and the phenotypic complexity of early animals remains controversial, a compelling picture is emerging. We now know that the nervous system and other key animal innovations contain a large degree of homoplasy, at least on the molecular level. Conflicting hypotheses about early nervous system evolution are due primarily to differences in the interpretation of this homoplasy. We highlight the need for explicit discussion of assumptions and discuss the limitations of current approaches for inferring ancient phenotypic states. Copyright © 2015. Published by Elsevier Ltd.

Quantification and clustering of phenotypic screening data using time-series analysis for chemotherapy of schistosomiasis.

PubMed

Lee, Hyokyeong; Moody-Davis, Asher; Saha, Utsab; Suzuki, Brian M; Asarnow, Daniel; Chen, Steven; Arkin, Michelle; Caffrey, Conor R; Singh, Rahul

2012-01-01

Neglected tropical diseases, especially those caused by helminths, constitute some of the most common infections of the world's poorest people. Development of techniques for automated, high-throughput drug screening against these diseases, especially in whole-organism settings, constitutes one of the great challenges of modern drug discovery. We present a method for enabling high-throughput phenotypic drug screening against diseases caused by helminths with a focus on schistosomiasis. The proposed method allows for a quantitative analysis of the systemic impact of a drug molecule on the pathogen as exhibited by the complex continuum of its phenotypic responses. This method consists of two key parts: first, biological image analysis is employed to automatically monitor and quantify shape-, appearance-, and motion-based phenotypes of the parasites. Next, we represent these phenotypes as time-series and show how to compare, cluster, and quantitatively reason about them using techniques of time-series analysis. We present results on a number of algorithmic issues pertinent to the time-series representation of phenotypes. These include results on appropriate representation of phenotypic time-series, analysis of different time-series similarity measures for comparing phenotypic responses over time, and techniques for clustering such responses by similarity. Finally, we show how these algorithmic techniques can be used for quantifying the complex continuum of phenotypic responses of parasites. An important corollary is the ability of our method to recognize and rigorously group parasites based on the variability of their phenotypic response to different drugs. The methods and results presented in this paper enable automatic and quantitative scoring of high-throughput phenotypic screens focused on helmintic diseases. Furthermore, these methods allow us to analyze and stratify parasites based on their phenotypic response to drugs. Together, these advancements represent a significant breakthrough for the process of drug discovery against schistosomiasis in particular and can be extended to other helmintic diseases which together afflict a large part of humankind.

Quantification and clustering of phenotypic screening data using time-series analysis for chemotherapy of schistosomiasis

PubMed Central

2012-01-01

Background Neglected tropical diseases, especially those caused by helminths, constitute some of the most common infections of the world's poorest people. Development of techniques for automated, high-throughput drug screening against these diseases, especially in whole-organism settings, constitutes one of the great challenges of modern drug discovery. Method We present a method for enabling high-throughput phenotypic drug screening against diseases caused by helminths with a focus on schistosomiasis. The proposed method allows for a quantitative analysis of the systemic impact of a drug molecule on the pathogen as exhibited by the complex continuum of its phenotypic responses. This method consists of two key parts: first, biological image analysis is employed to automatically monitor and quantify shape-, appearance-, and motion-based phenotypes of the parasites. Next, we represent these phenotypes as time-series and show how to compare, cluster, and quantitatively reason about them using techniques of time-series analysis. Results We present results on a number of algorithmic issues pertinent to the time-series representation of phenotypes. These include results on appropriate representation of phenotypic time-series, analysis of different time-series similarity measures for comparing phenotypic responses over time, and techniques for clustering such responses by similarity. Finally, we show how these algorithmic techniques can be used for quantifying the complex continuum of phenotypic responses of parasites. An important corollary is the ability of our method to recognize and rigorously group parasites based on the variability of their phenotypic response to different drugs. Conclusions The methods and results presented in this paper enable automatic and quantitative scoring of high-throughput phenotypic screens focused on helmintic diseases. Furthermore, these methods allow us to analyze and stratify parasites based on their phenotypic response to drugs. Together, these advancements represent a significant breakthrough for the process of drug discovery against schistosomiasis in particular and can be extended to other helmintic diseases which together afflict a large part of humankind. PMID:22369037

Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation

PubMed Central

Veltri, Tiago; Landim-Vieira, Maicon; Parvatiyar, Michelle S.; Gonzalez-Martinez, David; Dieseldorff Jones, Karissa M.; Michell, Clara A.; Dweck, David; Landstrom, Andrew P.; Chase, P. Bryant; Pinto, Jose R.

2017-01-01

Mutations in TNNC1—the gene encoding cardiac troponin C (cTnC)—that have been associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction may also affect Ca2+-regulation and function of slow skeletal muscle since the same gene is expressed in both cardiac and slow skeletal muscle. Therefore, we reconstituted rabbit soleus fibers and bovine masseter myofibrils with mutant cTnCs (A8V, C84Y, E134D, and D145E) associated with HCM to investigate their effects on contractile force and ATPase rates, respectively. Previously, we showed that these HCM cTnC mutants, except for E134D, increased the Ca2+ sensitivity of force development in cardiac preparations. In the current study, an increase in Ca2+ sensitivity of isometric force was only observed for the C84Y mutant when reconstituted in soleus fibers. Incorporation of cTnC C84Y in bovine masseter myofibrils reduced the ATPase activity at saturating [Ca2+], whereas, incorporation of cTnC D145E increased the ATPase activity at inhibiting and saturating [Ca2+]. We also tested whether reconstitution of cardiac fibers with troponin complexes containing the cTnC mutants and slow skeletal troponin I (ssTnI) could emulate the slow skeletal functional phenotype. Reconstitution of cardiac fibers with troponin complexes containing ssTnI attenuated the Ca2+ sensitization of isometric force when cTnC A8V and D145E were present; however, it was enhanced for C84Y. In summary, although the A8V and D145E mutants are present in both muscle types, their functional phenotype is more prominent in cardiac muscle than in slow skeletal muscle, which has implications for the protein-protein interactions within the troponin complex. The C84Y mutant warrants further investigation since it drastically alters the properties of both muscle types and may account for the earlier clinical onset in the proband. PMID:28473771

A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.

PubMed

Kytövuori, Laura; Lipponen, Joonas; Rusanen, Harri; Komulainen, Tuomas; Martikainen, Mika H; Majamaa, Kari

2016-11-01

Defects in the respiratory chain or mitochondrial ATP synthase (complex V) result in mitochondrial dysfunction that is an important cause of inherited neurological disease. Two of the subunits of complex V are encoded by MT-ATP6 and MT-ATP8 in the mitochondrial genome. Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease. We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism. As the phenotype was suggestive of mitochondrial disease, mitochondrial DNA was sequenced and a novel heteroplasmic mutation m.8561C>G in the overlapping region of the MT-ATP6 and MT-ATP8 was found. The mutation changed amino acids in both subunits. Mutation heteroplasmy correlated with the disease phenotype in five family members. An additional assembly intermediate of complex V and increased amount of subcomplex F 1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected. Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production. We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.

The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures.

PubMed

Klein, Karl Martin; Pendziwiat, Manuela; Eilam, Anda; Gilad, Ronit; Blatt, Ilan; Rosenow, Felix; Kanaan, Moien; Helbig, Ingo; Afawi, Zaid

2017-07-01

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

PubMed

Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

2005-12-30

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy.

PubMed

Lipton, Jonathan O; Boyle, Lara M; Yuan, Elizabeth D; Hochstrasser, Kevin J; Chifamba, Fortunate F; Nathan, Ashwin; Tsai, Peter T; Davis, Fred; Sahin, Mustafa

2017-07-25

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer.

PubMed

Has, C; Burger, B; Volz, A; Kohlhase, J; Bruckner-Tuderman, L; Itin, P

2010-01-01

Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy. Here we describe 2 siblings with KS, who are, to the best of our knowledge, the oldest patients reported so far in the literature. The diagnosis was established in their seventh and eighth decades of life, and confirmed by mutation analysis. Both patients were homozygous for the recurrent FERMT1 mutation, c.328C→T, p.R110X. Because of a relatively mild course of the disease, mucosal membranes in the eyes and oesophagus being predominantly affected in recent years, they had been treated under other diagnoses, such as scleroderma. Cutaneous precancerous lesions and epithelial skin cancer arose in both siblings after the age of 50 years and were treated in an early stage. Taken together, we describe the natural course of KS, the morphological abnormalities occurring in the skin of older KS patients, we discuss the differential diagnosis and the association between KS and squamous cell carcinoma. Copyright © 2010 S. Karger AG, Basel.

Phenotypic engineering unveils the function of genital morphology.

PubMed

Hotzy, Cosima; Polak, Michal; Rönn, Johanna L; Arnqvist, Göran

2012-12-04

The rapidly evolving and often extraordinarily complex appearance of male genital morphology of internally fertilizing animals has been recognized for centuries. Postcopulatory sexual selection is regarded as the likely evolutionary engine of this diversity, but direct support for this hypothesis is limited. We used two complementary approaches, evolution through artificial selection and microscale laser surgery, to experimentally manipulate genital morphology in an insect model system. We then assessed the competitive fertilization success of these phenotypically manipulated males and studied the fate of their ejaculate in females using high-resolution radioisotopic labeling of ejaculates. Males with longer genital spines were more successful in gaining fertilizations, providing experimental evidence that male genital morphology influences success in postcopulatory reproductive competition. Furthermore, a larger proportion of the ejaculate moved from the reproductive tract into the female body following mating with males with longer spines, suggesting that genital spines increase the rate at which seminal fluid passes into the female hemolymph. Our results show that genital morphology affects male competitive fertilization success and imply that sexual selection on genital morphology may be mediated in part through seminal fluid. Copyright © 2012 Elsevier Ltd. All rights reserved.

Reproducibility and replicability of rodent phenotyping in preclinical studies.

PubMed

Kafkafi, Neri; Agassi, Joseph; Chesler, Elissa J; Crabbe, John C; Crusio, Wim E; Eilam, David; Gerlai, Robert; Golani, Ilan; Gomez-Marin, Alex; Heller, Ruth; Iraqi, Fuad; Jaljuli, Iman; Karp, Natasha A; Morgan, Hugh; Nicholson, George; Pfaff, Donald W; Richter, S Helene; Stark, Philip B; Stiedl, Oliver; Stodden, Victoria; Tarantino, Lisa M; Tucci, Valter; Valdar, William; Williams, Robert W; Würbel, Hanno; Benjamini, Yoav

2018-04-01

The scientific community is increasingly concerned with the proportion of published "discoveries" that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex interaction between genotype and environment; the definitions of behavioral constructs; and the use of laboratory mice and rats as model species for investigating human health and disease mechanisms. In January 2015, researchers from various disciplines gathered at Tel Aviv University to discuss these issues. The general consensus was that the issue is prevalent and of concern, and should be addressed at the statistical, methodological and policy levels, but is not so severe as to call into question the validity and the usefulness of model organisms as a whole. Well-organized community efforts, coupled with improved data and metadata sharing, have a key role in identifying specific problems and promoting effective solutions. Replicability is closely related to validity, may affect generalizability and translation of findings, and has important ethical implications. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency.

PubMed

Bénit, Paule; Pelhaître, Alice; Saunier, Elise; Bortoli, Sylvie; Coulibaly, Assetou; Rak, Malgorzata; Schiff, Manuel; Kroemer, Guido; Zeviani, Massimo; Rustin, Pierre

2017-03-01

Mice with the hypomorphic AIF-Harlequin mutation exhibit a highly heterogeneous mitochondriopathy that mostly affects respiratory chain complex I, causing a cerebral pathology that resembles that found in patients with AIF loss-of-function mutations. Here we describe that the antidiabetic drug pioglitazone (PIO) can improve the phenotype of a mouse Harlequin (Hq) subgroup, presumably due to an inhibition of glycolysis that causes an increase in blood glucose levels. This glycolysis-inhibitory PIO effect was observed in cultured astrocytes from Hq mice, as well as in human skin fibroblasts from patients with AIF mutation. Glycolysis inhibition by PIO resulted from direct competitive inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, GAPDH protein levels were reduced in the cerebellum and in the muscle from Hq mice that exhibited an improved phenotype upon PIO treatment. Altogether, our results suggest that excessive glycolysis participates to the pathogenesis of mitochondriopathies and that pharmacological inhibition of glycolysis may have beneficial effects in this condition. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, L.; Fuss, J.O.; Cheng, Q.J.

2009-05-18

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tainer, John; Fan, Li; Fuss, Jill O.

2008-06-02

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

Human inversions and their functional consequences

PubMed Central

Puig, Marta; Casillas, Sònia; Villatoro, Sergi

2015-01-01

Polymorphic inversions are a type of structural variants that are difficult to analyze owing to their balanced nature and the location of breakpoints within complex repeated regions. So far, only a handful of inversions have been studied in detail in humans and current knowledge about their possible functional effects is still limited. However, inversions have been related to phenotypic changes and adaptation in multiple species. In this review, we summarize the evidences of the functional impact of inversions in the human genome. First, given that inversions have been shown to inhibit recombination in heterokaryotes, chromosomes displaying different orientation are expected to evolve independently and this may lead to distinct gene-expression patterns. Second, inversions have a role as disease-causing mutations both by directly affecting gene structure or regulation in different ways, and by predisposing to other secondary arrangements in the offspring of inversion carriers. Finally, several inversions show signals of being selected during human evolution. These findings illustrate the potential of inversions to have phenotypic consequences also in humans and emphasize the importance of their inclusion in genome-wide association studies. PMID:25998059

Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

PubMed Central

Khare, Sanjay D.; Sarosi, Ildiko; Xia, Xing-Zhong; McCabe, Susan; Miner, Kent; Solovyev, Irina; Hawkins, Nessa; Kelley, Michael; Chang, David; Van, Gwyneth; Ross, Larry; Delaney, John; Wang, Ling; Lacey, David; Boyle, William J.; Hsu, Hailing

2000-01-01

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a β-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases. PMID:10716715

A large GLC1C Greek family with a myocilin T377M mutation: inheritance and phenotypic variability.

PubMed

Petersen, Michael B; Kitsos, George; Samples, John R; Gaudette, N Donna; Economou-Petersen, Effrosini; Sykes, Renée; Rust, Kristal; Grigoriadou, Maria; Aperis, George; Choi, Dongseok; Psilas, Konstantinos; Craig, Jamie E; Kramer, Patricia L; Mackey, David A; Wirtz, Mary K

2006-02-01

POAG is a complex disease; therefore, families in which a glaucoma gene has been mapped may carry additional POAG genes. The goal of this study was to determine whether mutations in the myocilin (MYOC) gene on chromosome 1 are present in two POAG families, which have previously been mapped to the GLC1C locus on chromosome 3. The three exons of MYOC were screened by denaturing (d)HPLC. Samples with heteroduplex peaks were sequenced. Clinical findings were compared with genotype status in all available family members over the age of 20 years. A T377M coding sequence change in MYOC was identified in family members of the Greek GLC1C family but not in the Oregon GLC1C family. Individuals carrying both the MYOC T377M variant and the GLC1C haplotype were more severely affected at an earlier age than individuals with just one of the POAG genes, suggesting that these two genes interact or that both contribute to the POAG phenotype in a cumulative way.

Heterotropic Effect of β-lactam Antibiotics on Antioxidant Property of Haptoglobin (2-2)-Hemoglobin Complex.

PubMed

Tayari, Masoumeh; Moosavi-Nejad, Zahra; Moosavi Nejad, Fatemeh; Rezaei-Tavirani, Mostafa; Dehghan Shasaltaneh, Marzieh

2011-01-01

Haptoglobin (Hp) is a mammalian serum glycoprotein showing a genetic polymorphism with three types, 1-1, 2-2 and 1-2. Hp appears to conserve the recycling of heme-iron by forming an essentially irreversible but non-covalent complex with hemoglobin which is released into the plasma by erythrocyte lysis. As an important consequence, Haptoglobin-Hemoglobin complex (Hp-Hb) shows considerable antioxidant property. In this study, antioxidant activity of Hp (2-2)-Hb complex on hydrogen peroxide has been studied and analyzed in the absence and presence of two beta-lactam antibiotics in-vitro. For this purpose, non-Michaelis behavior of peroxidase activity of Hp (2-2)-Hb complex was analyzed using Eadie-Hofstee, Clearance and Hill plots, in the absence and presence of pharmaceutical dose of ampicillin and coamoxiclav. The results have shown that peroxidase activity of Hp (2-2)-Hb complex is modulated via homotropic effect of hydrogen peroxide as an allostric substrate. On the other hand antioxidant property of Hp (2-2)-Hb complex increased via heterotropic effect of both antibiotics on the peroxidase activity of the complex. Both drugs also have mild effect on quality of homotropic property of the peroxidase activity of Hp (2-2)-Hb complex. Therefore, it can be concluded from our study that both beta-lactam antibiotics can increase peroxidase activity of Hp (2-2)-Hb complex via heterotropic effect. Thus, the two antibiotics (especially ampicillin) may help those individuals with Hp (2-2) phenotype to improve the Hp-Hb complex efficiency of removing hydrogen peroxide from serum under oxidative stress. This can be important in the individuals with phenotype Hp 2-2 who have less antioxidant activity relative to other phenotypes and are susceptible to cardiovascular disorders, as has been reported by other researchers.

Glacial history affected phenotypic differentiation in the alpine plant, Campanula thyrsoides.

PubMed

Scheepens, J F; Frei, Eva S; Stöcklin, Jürg

2013-01-01

Numerous widespread Alpine plant species show molecular differentiation among populations from distinct regions. This has been explained as the result of genetic drift during glacial survival in isolated refugia along the border of the European Alps. Since genetic drift may affect molecular markers and phenotypic traits alike, we asked whether phenotypic differentiation mirrors molecular patterns among Alpine plant populations from different regions. Phenotypic traits can be under selection, so we additionally investigated whether part of the phenotypic differentiation can be explained by past selection and/or current adaptation. Using the monocarpic Campanula thyrsoides as our study species, a common garden experiment with plants from 21 populations from four phylogeographic groups located in regions across the Alps and the Jura Mountains was performed to test for differentiation in morphological and phenological traits. Past selection was investigated by comparing phenotypic differentiation among and within regions with molecular differentiation among and within regions. The common garden results indicated regional differentiation among populations for all investigated phenotypic traits, particularly in phenology. Delayed flowering in plants from the South-eastern Alps suggested adaptation to long sub-mediterranean summers and contrasted with earlier flowering of plants experiencing shorter growing seasons in regions with higher elevation to the West. Comparisons between molecular and phenotypic differentiation revealed diversifying selection among regions in height and biomass, which is consistent with adaptation to environmental conditions in glacial refugia. Within regions, past selection acted against strong diversification for most phenotypic traits, causing restricted postglacial adaptation. Evidence consistent with post-glacial adaptation was also given by negative correlation coefficients between several phenotypic traits and elevation of the population's origin. In conclusion, our study suggests that, irrespective of adaptation of plants to their current environment, glacial history can have a strong and long-lasting influence on the phenotypic evolution of Alpine plants.

The Human Phenotype Ontology in 2017

PubMed Central

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; Foster, Erin; McMurry, Julie; Aymé, Ségolène; Baynam, Gareth; Bello, Susan M.; Boerkoel, Cornelius F.; Boycott, Kym M.; Brudno, Michael; Buske, Orion J.; Chinnery, Patrick F.; Cipriani, Valentina; Connell, Laureen E.; Dawkins, Hugh J.S.; DeMare, Laura E.; Devereau, Andrew D.; de Vries, Bert B.A.; Firth, Helen V.; Freson, Kathleen; Greene, Daniel; Hamosh, Ada; Helbig, Ingo; Hum, Courtney; Jähn, Johanna A.; James, Roger; Krause, Roland; F. Laulederkind, Stanley J.; Lochmüller, Hanns; Lyon, Gholson J.; Ogishima, Soichi; Olry, Annie; Ouwehand, Willem H.; Pontikos, Nikolas; Rath, Ana; Schaefer, Franz; Scott, Richard H.; Segal, Michael; Sergouniotis, Panagiotis I.; Sever, Richard; Smith, Cynthia L.; Straub, Volker; Thompson, Rachel; Turner, Catherine; Turro, Ernest; Veltman, Marijcke W.M.; Vulliamy, Tom; Yu, Jing; von Ziegenweidt, Julie; Zankl, Andreas; Züchner, Stephan; Zemojtel, Tomasz; Jacobsen, Julius O.B.; Groza, Tudor; Smedley, Damian; Mungall, Christopher J.; Haendel, Melissa; Robinson, Peter N.

2017-01-01

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. PMID:27899602

The Human Phenotype Ontology in 2017

DOE PAGES

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; ...

2016-11-24

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human PhenotypeOntology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical softwaremore » tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.« less

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes.

PubMed

Hwang, Grace; Sun, Fengyun; O'Brien, Marilyn; Eppig, John J; Handel, Mary Ann; Jordan, Philip W

2017-05-01

SMC complexes include three major classes: cohesin, condensin and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis have not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre -driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase IIα to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females. © 2017. Published by The Company of Biologists Ltd.

Changing phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation--a 5 year follow up.

PubMed

Schinwelski, M; Kierdaszuk, B; Dulski, J; Tońska, K; Kodroń, A; Sitek, E J; Bartnik, E; Kamińska, A; Kwieciński, H; Sławek, J

2015-08-01

Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.

The NuRD complex component p66 suppresses photoreceptor neuron regeneration in planarians.

PubMed

Vásquez-Doorman, Constanza; Petersen, Christian P

2016-06-01

Regeneration involves precise control of cell fate to produce an appropriate complement of tissues formed within a blastema. Several chromatin-modifying complexes have been identified as required for regeneration in planarians, but it is unclear whether this class of molecules uniformly promotes the production of differentiated cells. We identify a function for p66, encoding a DNA-binding protein component of the NuRD (nucleosome remodeling and deacetylase) complex, as well as the chromodomain helicase chd4, in suppressing production of photoreceptor neurons (PRNs) in planarians. This suppressive effect appeared restricted to PRNs because p66 inhibition did not influence numbers of eye pigment cup cells (PCCs) and decreased numbers of brain neurons and epidermal progenitors. PRNs from p66(RNAi) animals differentiated with some abnormalities but nonetheless produced arrestin+ projections to the brain. p66 inhibition produced excess ovo+otxA+ PRN progenitors without affecting numbers of ovo+otxA- PCC progenitors, and ovo and otxA were each required for the p66(RNAi) excess PRN phenotype. Together these results suggest that p66 acts through the NuRD complex to suppress PRN production by limiting expression of lineage-specific transcription factors.

Mouse models of ageing and their relevance to disease.

PubMed

Kõks, Sulev; Dogan, Soner; Tuna, Bilge Guvenc; González-Navarro, Herminia; Potter, Paul; Vandenbroucke, Roosmarijn E

2016-12-01

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Redox regulation of the MED28 and MED32 mediator subunits is important for development and senescence.

PubMed

Shaikhali, Jehad; Davoine, Céline; Björklund, Stefan; Wingsle, Gunnar

2016-05-01

Mediator is a conserved multi-protein complex that acts as a bridge between promoter-bound transcriptional regulators and RNA polymerase II. While redox signaling is important in adjusting plant metabolism and development, the involvement of Mediator in redox homeostasis and regulation only recently started to emerge. Our previous results show that the MED10a, MED28, and MED32 Mediator subunits form various types of covalent oligomers linked by intermolecular disulfide bonds in vitro. To link that with biological significance we have characterized Arabidopsis med32 and med28 mutants and found that they are affected in root development and senescence, phenotypes possibly associated to redox changes.

Prediction of reduction in aggressive behaviour of growing pigs using skin lesion traits as selection criteria.

PubMed

Desire, S; Turner, S P; D'Eath, R B; Doeschl-Wilson, A B; Lewis, C R G; Roehe, R

2016-08-01

Aggression at regrouping is a common issue in pig farming. Skin lesions are genetically and phenotypically correlated with aggression and have been shown to have a significant heritable component. This study predicts the magnitude of reduction in complex aggressive behavioural traits when using lesion numbers on different body regions at two different time points as selection criteria, to identify the optimum skin lesion trait for selection purposes. In total, 1146 pigs were mixed into new social groups, and skin lesions were counted 24 h (SL24h) and 3 weeks (SL3wk) post-mixing, on the anterior, centre and posterior regions of the body. An animal model was used to estimate genetic parameters for skin lesion traits and 14 aggressive behavioural traits. Estimated breeding values (EBVs) and phenotypic values were scaled and standardised to allow direct comparison across multiple traits. Individuals with SL24h and SL3wk EBVs in the least aggressive 10% of the population were compared with the population mean to predict the expected genetic and phenotypic response in aggressive behaviour to selection. At mixing, selection for low anterior lesions was predicted to affect substantially more behavioural traits of aggressiveness than lesions obtained on other body parts, with EBVs between -0.21 and -1.17 SD below the population mean. Individuals with low central SL24h EBVs also had low EBVs for aggressive traits (-0.33 to -0.55). Individuals with high SL3wk EBVs had low EBVs for aggression at mixing (between -0.24 and -0.53 SD below the population mean), although this was predicted to affect fewer traits than selection against SL24h. These results suggest that selection against anterior SL24h would result in the greatest genetic and phenotypic reduction in aggressive behaviour recorded at mixing. Selection for increased SL3wk was predicted to reduce aggression at mixing; however, current understanding about aggressive behaviour under stable social conditions is insufficient to recommend using this trait for selection purposes.

Linking amphibian call structure to the environment: the interplay between phenotypic flexibility and individual attributes.

PubMed

Ziegler, Lucía; Arim, Matías; Narins, Peter M

2011-05-01

The structure of the environment surrounding signal emission produces different patterns of degradation and attenuation. The expected adjustment of calls to ensure signal transmission in an environment was formalized in the acoustic adaptation hypothesis. Within this framework, most studies considered anuran calls as fixed attributes determined by local adaptations. However, variability in vocalizations as a product of phenotypic expression has also been reported. Empirical evidence supporting the association between environment and call structure has been inconsistent, particularly in anurans. Here, we identify a plausible causal structure connecting environment, individual attributes, and temporal and spectral adjustments as direct or indirect determinants of the observed variation in call attributes of the frog Hypsiboas pulchellus. For that purpose, we recorded the calls of 40 males in the field, together with vegetation density and other environmental descriptors of the calling site. Path analysis revealed a strong effect of habitat structure on the temporal parameters of the call, and an effect of site temperature conditioning the size of organisms calling at each site and thus indirectly affecting the dominant frequency of the call. Experimental habitat modification with a styrofoam enclosure yielded results consistent with field observations, highlighting the potential role of call flexibility on detected call patterns. Both, experimental and correlative results indicate the need to incorporate the so far poorly considered role of phenotypic plasticity in the complex connection between environmental structure and individual call attributes.

Genetic and environmental factors affecting cryptic variations in gene regulatory networks

PubMed Central

2013-01-01

Background Cryptic genetic variation (CGV) is considered to facilitate phenotypic evolution by producing visible variations in response to changes in the internal and/or external environment. Several mechanisms enabling the accumulation and release of CGVs have been proposed. In this study, we focused on gene regulatory networks (GRNs) as an important mechanism for producing CGVs, and examined how interactions between GRNs and the environment influence the number of CGVs by using individual-based simulations. Results Populations of GRNs were allowed to evolve under various stabilizing selections, and we then measured the number of genetic and phenotypic variations that had arisen. Our results showed that CGVs were not depleted irrespective of the strength of the stabilizing selection for each phenotype, whereas the visible fraction of genetic variation in a population decreased with increasing strength of selection. On the other hand, increasing the number of different environments that individuals encountered within their lifetime (i.e., entailing plastic responses to multiple environments) suppressed the accumulation of CGVs, whereas the GRNs with more genes and interactions were favored in such heterogeneous environments. Conclusions Given the findings that the number of CGVs in a population was largely determined by the size (order) of GRNs, we propose that expansion of GRNs and adaptation to novel environments are mutually facilitating and sustainable sources of evolvability and hence the origins of biological diversity and complexity. PMID:23622056

Genetic and environmental factors affecting cryptic variations in gene regulatory networks.

PubMed

Iwasaki, Watal M; Tsuda, Masaki E; Kawata, Masakado

2013-04-26

Cryptic genetic variation (CGV) is considered to facilitate phenotypic evolution by producing visible variations in response to changes in the internal and/or external environment. Several mechanisms enabling the accumulation and release of CGVs have been proposed. In this study, we focused on gene regulatory networks (GRNs) as an important mechanism for producing CGVs, and examined how interactions between GRNs and the environment influence the number of CGVs by using individual-based simulations. Populations of GRNs were allowed to evolve under various stabilizing selections, and we then measured the number of genetic and phenotypic variations that had arisen. Our results showed that CGVs were not depleted irrespective of the strength of the stabilizing selection for each phenotype, whereas the visible fraction of genetic variation in a population decreased with increasing strength of selection. On the other hand, increasing the number of different environments that individuals encountered within their lifetime (i.e., entailing plastic responses to multiple environments) suppressed the accumulation of CGVs, whereas the GRNs with more genes and interactions were favored in such heterogeneous environments. Given the findings that the number of CGVs in a population was largely determined by the size (order) of GRNs, we propose that expansion of GRNs and adaptation to novel environments are mutually facilitating and sustainable sources of evolvability and hence the origins of biological diversity and complexity.

Nature versus nurture in determining athletic ability.

PubMed

Brutsaert, Tom D; Parra, Esteban J

2009-01-01

This chapter provides an overview of the truism that both nature and nurture determine human athletic ability. The major thesis developed is that environmental effects work through the process of growth and development and interact with an individual's genetic background to produce a specific adult phenotype, i.e. an athletic or nonathletic phenotype. On the nature side (genetics), a brief historical review is provided with emphasis on several areas that are likely to command future attention including the rise of genome-wide association as a mapping strategy, the problem of false positives using association approaches, as well as the relatively unknown effects of gene-gene interaction(epistasis), gene-environment interaction, and genome structure on complex trait variance. On the nurture side (environment), common environmental effects such as training-level and sports nutrition are largely ignored in favor of developmental environmental effects that are channeled through growth and development processes. Developmental effects are difficult to distinguish from genetic effects as phenotypic plasticity in response to early life environmental perturbation can produce lasting effects into adulthood. In this regard, the fetal programming (FP) hypothesis is reviewed in some detail as FP provides an excellent example of how developmental effects work and also interact with genetics. In general, FP has well-documented effects on adult body composition and the risk for adult chronic disease, but there is emerging evidence that FP affects human athletic performance as well. 2009 S. Karger AG, Basel

Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex".

PubMed

Castori, Marco; Scarciolla, Oronzo; Morlino, Silvia; Manente, Liborio; Biscaglia, Assunta; Fragasso, Alberto; Grammatico, Paola

2012-02-01

The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. Copyright © 2012 Wiley Periodicals, Inc.

Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa

PubMed Central

Johansen, Helle Krogh; Molin, Søren

2018-01-01

ABSTRACT Evolution by natural selection under complex and dynamic environmental conditions occurs through intricate and often counterintuitive trajectories affecting many genes and metabolic solutions. To study short- and long-term evolution of bacteria in vivo, we used the natural model system of cystic fibrosis (CF) infection. In this work, we investigated how and through which trajectories evolution of Pseudomonas aeruginosa occurs when migrating from the environment to the airways of CF patients, and specifically, we determined reduction of growth rate and metabolic specialization as signatures of adaptive evolution. We show that central metabolic pathways of three distinct Pseudomonas aeruginosa lineages coevolving within the same environment become restructured at the cost of versatility during long-term colonization. Cell physiology changes from naive to adapted phenotypes resulted in (i) alteration of growth potential that particularly converged to a slow-growth phenotype, (ii) alteration of nutritional requirements due to auxotrophy, (iii) tailored preference for carbon source assimilation from CF sputum, (iv) reduced arginine and pyruvate fermentation processes, and (v) increased oxygen requirements. Interestingly, although convergence was evidenced at the phenotypic level of metabolic specialization, comparative genomics disclosed diverse mutational patterns underlying the different evolutionary trajectories. Therefore, distinct combinations of genetic and regulatory changes converge to common metabolic adaptive trajectories leading to within-host metabolic specialization. This study gives new insight into bacterial metabolic evolution during long-term colonization of a new environmental niche. PMID:29636437

Phenotypic expression of the HLA-linked iron-loading gene in the Afrikaner population of the western Cape.

PubMed

Meyer, T E; Baynes, R D; Bothwell, T H; Jenkins, T; Ballot, D; Jooste, P L; Green, A; Du Toit, E; Jacobs, P

1988-03-05

A previous study conducted on a group of Afrikaans-speaking subjects in the south-western Cape indicated a high frequency (0.115) of the HLA-linked iron-loading gene which causes idiopathic haemochromatosis. The results of phenotypic and genotypic studies on the first degree relatives of identified homozygotes and heterozygotes are now reported. There was considerable heterogeneity of phenotypic expression in the group of heterozygotes, with overlap between the homozygous and heterozygous subjects. The heterozygous relatives of heterozygous index cases, who had been identified on the basis of a serum ferritin concentration greater than 400 micrograms/l, appeared to have more frequent and more marked abnormalities of iron measurements than the heterozygote relatives of homozygous index cases (serum ferritin value greater than 400 micrograms/l, percentage transferrin saturation greater than 60). This suggests that the screening test was identifying a group of more significantly affected heterozygotes, with biochemical abnormalities that overlapped with the identified homozygotes. The index cases were followed up over a period of 5 years and during this time the 7 subjects diagnosed as heterozygotes showed a progressive increase in serum ferritin concentrations, which suggests some iron accumulation. Individual pedigrees included instances of gene recombination within the major histocompatibility complex, and of probable false-positive genotype assignment. The overall results confirm a high frequency of the gene in this particular community.

RotundRacGAP Functions with Ras during Spermatogenesis and Retinal Differentiation in Drosophila melanogaster

PubMed Central

Bergeret, Evelyne; Pignot-Paintrand, Isabelle; Guichard, Annabel; Raymond, Karine; Fauvarque, Marie-Odile; Cazemajor, Michel; Griffin-Shea, Ruth

2001-01-01

Our analysis of rotund (rn) null mutations in Drosophila melanogaster revealed that deletion of the rn locus affects both spermatid and retinal differentiation. In the male reproductive system, the absence of RnRacGAP induced small testes, empty seminal vesicles, short testicular cysts, reduced amounts of interspermatid membrane, the absence of individualization complexes, and incomplete mitochondrial condensation. Flagellar growth continued within the short rn null cysts to produce large bulbous terminations of intertwined mature flagella. Organization of the retina was also severely perturbed as evidenced by grossly misshapen ommatidia containing reduced numbers of photoreceptor and pigment cells. These morphological phenotypes were rescued by genomic rnRacGAP transgenes, demonstrating that RnRacGAP function is critical to spermatid and retinal differentiation. The testicular phenotypes were suppressed by heterozygous hypomorphic mutations in the Dras1 and drk genes, indicating cross talk between RacGAP-regulated signaling and that of the Ras pathway. The observed genetic interactions are consistent with a model in which Rac signaling is activated by Ras and negatively regulated by RnRacGAP during spermatid differentiation. RnRacGAP and Ras cross talk also operated during retinal differentiation; however, while the heterozygous hypomorphic drk mutation continued to act as a suppressor of the rn null mutation, the heterozygous hypomorphic Dras1 mutation induced novel retinal phenotypes. PMID:11509670

SM2PH-db: an interactive system for the integrated analysis of phenotypic consequences of missense mutations in proteins involved in human genetic diseases.

PubMed

Friedrich, Anne; Garnier, Nicolas; Gagnière, Nicolas; Nguyen, Hoan; Albou, Laurent-Philippe; Biancalana, Valérie; Bettler, Emmanuel; Deléage, Gilbert; Lecompte, Odile; Muller, Jean; Moras, Dino; Mandel, Jean-Louis; Toursel, Thierry; Moulinier, Luc; Poch, Olivier

2010-02-01

Understanding how genetic alterations affect gene products at the molecular level represents a first step in the elucidation of the complex relationships between genotypic and phenotypic variations, and is thus a major challenge in the postgenomic era. Here, we present SM2PH-db (http://decrypthon.igbmc.fr/sm2ph), a new database designed to investigate structural and functional impacts of missense mutations and their phenotypic effects in the context of human genetic diseases. A wealth of up-to-date interconnected information is provided for each of the 2,249 disease-related entry proteins (August 2009), including data retrieved from biological databases and data generated from a Sequence-Structure-Evolution Inference in Systems-based approach, such as multiple alignments, three-dimensional structural models, and multidimensional (physicochemical, functional, structural, and evolutionary) characterizations of mutations. SM2PH-db provides a robust infrastructure associated with interactive analysis tools supporting in-depth study and interpretation of the molecular consequences of mutations, with the more long-term goal of elucidating the chain of events leading from a molecular defect to its pathology. The entire content of SM2PH-db is regularly and automatically updated thanks to a computational grid data federation facilities provided in the context of the Decrypthon program. (c) 2009 Wiley-Liss, Inc.

A novel locus on chromosome 1 underlies the evolution of a melanic plumage polymorphism in a wild songbird

PubMed Central

Delahaie, Boris; Gautier, Mathieu; Malé, Pierre-Jean G.; Bertrand, Joris A. M.; Cornuault, Josselin; Wakamatsu, Kazumasa; Bouchez, Olivier; Mould, Claire; Bruxaux, Jade; Holota, Hélène; Milá, Borja; Thébaud, Christophe

2017-01-01

Understanding the mechanisms responsible for phenotypic diversification within and among species ultimately rests with linking naturally occurring mutations to functionally and ecologically significant traits. Colour polymorphisms are of great interest in this context because discrete colour patterns within a population are often controlled by just a few genes in a common environment. We investigated how and why phenotypic diversity arose and persists in the Zosterops borbonicus white-eye of Reunion (Mascarene archipelago), a colour polymorphic songbird in which all highland populations contain individuals belonging to either a brown or a grey plumage morph. Using extensive phenotypic and genomic data, we demonstrate that this melanin-based colour polymorphism is controlled by a single locus on chromosome 1 with two large-effect alleles, which was not previously described as affecting hair or feather colour. Differences between colour morphs appear to rely upon complex cis-regulatory variation that either prevents the synthesis of pheomelanin in grey feathers, or increases its production in brown ones. We used coalescent analyses to show that, from a ‘brown’ ancestral population, the dominant ‘grey’ allele spread quickly once it arose from a new mutation. Since colour morphs are always found in mixture, this implies that the selected allele does not go to fixation, but instead reaches an intermediate frequency, as would be expected under balancing selection. PMID:28386436

Female receptivity phenotype of icebox mutants caused by a mutation in the L1-type cell adhesion molecule neuroglian.

PubMed

Carhan, A; Allen, F; Armstrong, J D; Hortsch, M; Goodwin, S F; O'Dell, K M C

2005-11-01

Relatively little is known about the genes and brain structures that enable virgin female Drosophila to make the decision to mate or not. Classical genetic approaches have identified several mutant females that have a reluctance-to-mate phenotype, but most of these have additional behavioral defects. However, the icebox (ibx) mutation was previously reported to lower the sexual receptivity of females, without apparently affecting any other aspect of female behavior. We have shown that the ibx mutation maps to the 7F region of the Drosophila X chromosome to form a complex complementation group with both lethal and viable alleles of neuroglian (nrg). The L1-type cell adhesion molecule encoded by nrg consists of six immunoglobulin-like domains, five fibronectin-like domains, one transmembrane domain and one alternatively spliced intracellular domain. The ibx strain has a missense mutation causing a glycine-to-arginine change at amino acid 92 in the first immunoglobulin domain of nrg. Defects in the central brain of ibx mutants are similar to those observed in another nrg mutant, central brain deranged(1) (ceb(1)). However, both ceb(1) homozygous and ceb(1)/ibx heterozygous females are receptive. The expression of a transgene containing the non-neural isoform of nrg rescues both the receptivity and the brain structure phenotypes of ibx females.

Advanced phenotyping and phenotype data analysis for the study of plant growth and development.

PubMed

Rahaman, Md Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

2015-01-01

Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis.

The pharmacogenetics of body odor: as easy as ABCC?

PubMed

Brown, Sara

2013-07-01

ABCC11 genotype affects apocrine secretory cell function and determines individual body odor phenotype. Rodriguez et al. have applied genetic epidemiology using predetermined phenotype data to demonstrate an association between a single-nucleotide polymorphism (rs17822931) and the human behavior of deodorant application. Individuals with the ABCC11 genotype predicting a nonodorous phenotype report a significantly lower frequency of deodorant use.

Daddy issues: paternal effects on phenotype.

PubMed

Rando, Oliver J

2012-11-09

The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. Copyright © 2012 Elsevier Inc. All rights reserved.

Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex.

PubMed

de Vries, Petrus J

2010-07-01

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation. (c) 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.

Behavioral Genetic Toolkits: Toward the Evolutionary Origins of Complex Phenotypes.

PubMed

Rittschof, C C; Robinson, G E

2016-01-01

The discovery of toolkit genes, which are highly conserved genes that consistently regulate the development of similar morphological phenotypes across diverse species, is one of the most well-known observations in the field of evolutionary developmental biology. Surprisingly, this phenomenon is also relevant for a wide array of behavioral phenotypes, despite the fact that these phenotypes are highly complex and regulated by many genes operating in diverse tissues. In this chapter, we review the use of the toolkit concept in the context of behavior, noting the challenges of comparing behaviors and genes across diverse species, but emphasizing the successes in identifying genetic toolkits for behavior; these successes are largely attributable to the creative research approaches fueled by advances in behavioral genomics. We have two general goals: (1) to acknowledge the groundbreaking progress in this field, which offers new approaches to the difficult but exciting challenge of understanding the evolutionary genetic basis of behaviors, some of the most complex phenotypes known, and (2) to provide a theoretical framework that encompasses the scope of behavioral genetic toolkit studies in order to clearly articulate the research questions relevant to the toolkit concept. We emphasize areas for growth and highlight the emerging approaches that are being used to drive the field forward. Behavioral genetic toolkit research has elevated the use of integrative and comparative approaches in the study of behavior, with potentially broad implications for evolutionary biologists and behavioral ecologists alike. © 2016 Elsevier Inc. All rights reserved.

Integrative approaches for large-scale transcriptome-wide association studies

PubMed Central

Gusev, Alexander; Ko, Arthur; Shi, Huwenbo; Bhatia, Gaurav; Chung, Wonil; Penninx, Brenda W J H; Jansen, Rick; de Geus, Eco JC; Boomsma, Dorret I; Wright, Fred A; Sullivan, Patrick F; Nikkola, Elina; Alvarez, Marcus; Civelek, Mete; Lusis, Aldons J.; Lehtimäki, Terho; Raitoharju, Emma; Kähönen, Mika; Seppälä, Ilkka; Raitakari, Olli T.; Kuusisto, Johanna; Laakso, Markku; Price, Alkes L.; Pajukanta, Päivi; Pasaniuc, Bogdan

2016-01-01

Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance levels of one or multiple proteins. Here, we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated to complex traits. We leverage expression imputation to perform a transcriptome wide association scan (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ~3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 novel genes significantly associated to obesity-related traits (BMI, lipids, and height). Many of the novel genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits. PMID:26854917

Expansion of phenotype and genotypic data in CRB2-related syndrome.

PubMed

Lamont, Ryan E; Tan, Wen-Hann; Innes, A Micheil; Parboosingh, Jillian S; Schneidman-Duhovny, Dina; Rajkovic, Aleksandar; Pappas, John; Altschwager, Pablo; DeWard, Stephanie; Fulton, Anne; Gray, Kathryn J; Krall, Max; Mehta, Lakshmi; Rodan, Lance H; Saller, Devereux N; Steele, Deanna; Stein, Deborah; Yatsenko, Svetlana A; Bernier, François P; Slavotinek, Anne M

2016-10-01

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

Interactome Analyses of Mature γ-Secretase Complexes Reveal Distinct Molecular Environments of Presenilin (PS) Paralogs and Preferential Binding of Signal Peptide Peptidase to PS2*

PubMed Central

Jeon, Amy Hye Won; Böhm, Christopher; Chen, Fusheng; Huo, Hairu; Ruan, Xueying; Ren, Carl He; Ho, Keith; Qamar, Seema; Mathews, Paul M.; Fraser, Paul E.; Mount, Howard T. J.; St George-Hyslop, Peter; Schmitt-Ulms, Gerold

2013-01-01

γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptides (Aβ) in Alzheimer disease (AD) and consists of a heterotetrameric core complex that includes the aspartyl intramembrane protease presenilin (PS). The human genome codes for two presenilin paralogs. To understand the causes for distinct phenotypes of PS paralog-deficient mice and elucidate whether PS mutations associated with early-onset AD affect the molecular environment of mature γ-secretase complexes, quantitative interactome comparisons were undertaken. Brains of mice engineered to express wild-type or mutant PS1, or HEK293 cells stably expressing PS paralogs with N-terminal tandem-affinity purification tags served as biological source materials. The analyses revealed novel interactions of the γ-secretase core complex with a molecular machinery that targets and fuses synaptic vesicles to cellular membranes and with the H+-transporting lysosomal ATPase macrocomplex but uncovered no differences in the interactomes of wild-type and mutant PS1. The catenin/cadherin network was almost exclusively found associated with PS1. Another intramembrane protease, signal peptide peptidase, predominantly co-purified with PS2-containing γ-secretase complexes and was observed to influence Aβ production. PMID:23589300

New insights from monogenic diabetes for “common” type 2 diabetes

PubMed Central

Tallapragada, Divya Sri Priyanka; Bhaskar, Seema; Chandak, Giriraj R.

2015-01-01

Boundaries between monogenic and complex genetic diseases are becoming increasingly blurred, as a result of better understanding of phenotypes and their genetic determinants. This had a large impact on the way complex disease genetics is now being investigated. Starting with conventional approaches like familial linkage, positional cloning and candidate genes strategies, the scope of complex disease genetics has grown exponentially with scientific and technological advances in recent times. Despite identification of multiple loci harboring common and rare variants associated with complex diseases, interpreting and evaluating their functional role has proven to be difficult. Information from monogenic diseases, especially related to the intermediate traits associated with complex diseases comes handy. The significant overlap between traits and phenotypes of monogenic diseases with related complex diseases provides a platform to understand the disease biology better. In this review, we would discuss about one such complex disease, type 2 diabetes, which shares marked similarity of intermediate traits with different forms of monogenic diabetes. PMID:26300908

DOE Office of Scientific and Technical Information (OSTI.GOV)

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human PhenotypeOntology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical softwaremore » tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.« less

Octamer-binding protein 4 affects the cell biology and phenotypic transition of lung cancer cells involving β-catenin/E-cadherin complex degradation.

PubMed

Chen, Zhong-Shu; Ling, Dong-Jin; Zhang, Yang-De; Feng, Jian-Xiong; Zhang, Xue-Yu; Shi, Tian-Sheng

2015-03-01

Clinical studies have reported evidence for the involvement of octamer‑binding protein 4 (Oct4) in the tumorigenicity and progression of lung cancer; however, the role of Oct4 in lung cancer cell biology in vitro and its mechanism of action remain to be elucidated. Mortality among lung cancer patients is more frequently due to metastasis rather than their primary tumors. Epithelial‑mesenchymal transition (EMT) is a prominent biological event for the induction of epithelial cancer metastasis. The aim of the present study was to investigate whether Oct4 had the capacity to induce lung cancer cell metastasis via the promoting the EMT in vitro. Moreover, the effect of Oct4 on the β‑catenin/E‑cadherin complex, associated with EMT, was examined using immunofluorescence and immunoprecipitation assays as well as western blot analysis. The results demonstrated that Oct4 enhanced cell invasion and adhesion accompanied by the downregulation of epithelial marker cytokeratin, and upregulation of the mesenchymal markers vimentin and N‑cadherin. Furthermore, Oct4 induced EMT of lung cancer cells by promoting β‑catenin/E‑cadherin complex degradation and regulating nuclear localization of β‑catenin. In conclusion, the present study indicated that Oct4 affected the cell biology of lung cancer cells in vitro through promoting lung cancer cell metastasis via EMT; in addition, the results suggested that the association and degradation of the β‑catenin/E‑cadherin complex was regulated by Oct4 during the process of EMT.

[Genotype/phenotype correlation in autism: genetic models and phenotypic characterization].

PubMed

Bonnet-Brilhault, F

2011-02-01

Autism spectrum disorders are a class of conditions categorized by communication problems, ritualistic behaviors, and deficits in social behaviors. This class of disorders merges a heterogeneous group of neurodevelopmental disorders regarding some phenotypic and probably physiopathological aspects. Genetic basis is well admitted, however, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be established. To better identify such correspondences, genetic models have to be identified and phenotypic markers have to be characterized. Recent insights show that a variety of genetic mechanisms may be involved in autism spectrum disorders, i.e. single gene disorders, copy number variations and polygenic mechanisms. These current genetic models are described. Regarding clinical aspects, several approaches can be used in genetic studies. Nosographical approach, especially with the concept of autism spectrum disorders, merges a large group of disorders with clinical heterogeneity and may fail to identify clear genotype/phenotype correlations. Dimensional approach referred in genetic studies to the notion of "Broad Autism Phenotype" related to a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype may provide a potentially important complementary approach for detecting the genes involved in these domains. However, control population used in those studies need to be well characterized too. Identification of endophenotypes seems to offer more promising results. Endophenotypes, which are supposed to be more proximal markers of gene action in the same biological pathway, linking genes and complex clinical symptoms, are thought to be less genetically complex than the broader disease phenotype, indexing a limited aspect of genetic risk for the disorder as a whole. However, strategies useful to characterize such phenotypic markers (for example, electrophysiological markers) have to take into account that autism is an early neurodevelopmental disorder occurring during childhood when brain development and maturation are in process. Recent genetic results have improved our knowledge in genetic basis in autism. Nevertheless, correspondences with phenotypic markers remain challenging according to phenotypic and genotypic heterogeneity. Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Addressing the challenges of phenotyping pediatric pulmonary vascular disease

PubMed Central

Goss, Kara N.; Everett, Allen D.; Mourani, Peter M.; Baker, Christopher D.; Abman, Steven H.

2017-01-01

Pediatric pulmonary vascular disease (PVD) and pulmonary hypertension (PH) represent phenotypically and pathophysiologically diverse disease categories, contributing substantial morbidity and mortality to a complex array of pediatric conditions. Here, we review the multifactorial nature of pediatric PVD, with an emphasis on improved recognition, phenotyping, and endotyping strategies for pediatric PH. Novel tailored approaches to diagnosis and treatment in pediatric PVD, as well as the implications for long-term outcomes, are highlighted. PMID:28680562

Beta-lactam resistance in the gram negatives: increasing complexity of conditional, composite and multiply resistant phenotypes.

PubMed

Iredell, Jon; Thomas, Lee; Espedido, Björn

2006-12-01

The greatest impact of microbiology data on clinical care is in the critically ill. Unfortunately, this is also the area in which microbiology laboratories are most often non-contributive. Attempts to move to rapid, culture-independent diagnostics are driven by the need to expedite urgent results. This is difficult in Gram-negative infection because of the complexity of the antibiotic resistance phenotype. Here, we discuss resistance to modern beta-lactams as a case in point. Recent outbreaks of transmissible carbapenem resistance among Gram-negative enteric pathogens in Sydney and Melbourne serve to illustrate the pitfalls of traditional phenotypical approaches. A better understanding of the epidemiology and mosaic nature of antibiotic resistance elements in the microflora is needed for us to move forward.

Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype.

PubMed

Loland, Sigmund

2015-09-01

New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype.

Shade avoidance components and pathways in adult plants revealed by phenotypic profiling.

PubMed

Nozue, Kazunari; Tat, An V; Kumar Devisetty, Upendra; Robinson, Matthew; Mumbach, Maxwell R; Ichihashi, Yasunori; Lekkala, Saradadevi; Maloof, Julin N

2015-04-01

Shade from neighboring plants limits light for photosynthesis; as a consequence, plants have a variety of strategies to avoid canopy shade and compete with their neighbors for light. Collectively the response to foliar shade is called the shade avoidance syndrome (SAS). The SAS includes elongation of a variety of organs, acceleration of flowering time, and additional physiological responses, which are seen throughout the plant life cycle. However, current mechanistic knowledge is mainly limited to shade-induced elongation of seedlings. Here we use phenotypic profiling of seedling, leaf, and flowering time traits to untangle complex SAS networks. We used over-representation analysis (ORA) of shade-responsive genes, combined with previous annotation, to logically select 59 known and candidate novel mutants for phenotyping. Our analysis reveals shared and separate pathways for each shade avoidance response. In particular, auxin pathway components were required for shade avoidance responses in hypocotyl, petiole, and flowering time, whereas jasmonic acid pathway components were only required for petiole and flowering time responses. Our phenotypic profiling allowed discovery of seventeen novel shade avoidance mutants. Our results demonstrate that logical selection of mutants increased success of phenotypic profiling to dissect complex traits and discover novel components.

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

PubMed

Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

2018-05-01

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

Functional Regression Models for Epistasis Analysis of Multiple Quantitative Traits.

PubMed

Zhang, Futao; Xie, Dan; Liang, Meimei; Xiong, Momiao

2016-04-01

To date, most genetic analyses of phenotypes have focused on analyzing single traits or analyzing each phenotype independently. However, joint epistasis analysis of multiple complementary traits will increase statistical power and improve our understanding of the complicated genetic structure of the complex diseases. Despite their importance in uncovering the genetic structure of complex traits, the statistical methods for identifying epistasis in multiple phenotypes remains fundamentally unexplored. To fill this gap, we formulate a test for interaction between two genes in multiple quantitative trait analysis as a multiple functional regression (MFRG) in which the genotype functions (genetic variant profiles) are defined as a function of the genomic position of the genetic variants. We use large-scale simulations to calculate Type I error rates for testing interaction between two genes with multiple phenotypes and to compare the power with multivariate pairwise interaction analysis and single trait interaction analysis by a single variate functional regression model. To further evaluate performance, the MFRG for epistasis analysis is applied to five phenotypes of exome sequence data from the NHLBI's Exome Sequencing Project (ESP) to detect pleiotropic epistasis. A total of 267 pairs of genes that formed a genetic interaction network showed significant evidence of epistasis influencing five traits. The results demonstrate that the joint interaction analysis of multiple phenotypes has a much higher power to detect interaction than the interaction analysis of a single trait and may open a new direction to fully uncovering the genetic structure of multiple phenotypes.

A strategy to apply quantitative epistasis analysis on developmental traits.

PubMed

Labocha, Marta K; Yuan, Wang; Aleman-Meza, Boanerges; Zhong, Weiwei

2017-05-15

Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement. Using two different C. elegans developmental phenotypes, body length and sex ratio, as examples, we showed that this method could accommodate various metazoan phenotypes with performances comparable to those methods in single cell growth studies. Comparing with qualitative observations, this method of quantitative epistasis enabled detection of new interactions involving subtle phenotypes. For example, several sex-ratio genes were found to interact with brc-1 and brd-1, the orthologs of the human breast cancer genes BRCA1 and BARD1, respectively. We confirmed the brc-1 interactions with the following genes in DNA damage response: C34F6.1, him-3 (ortholog of HORMAD1, HORMAD2), sdc-1, and set-2 (ortholog of SETD1A, SETD1B, KMT2C, KMT2D), validating the effectiveness of our method in detecting genetic interactions. We developed a reliable, high-throughput method for quantitative epistasis analysis of developmental phenotypes.

19q13.12 microdeletion syndrome fibroblasts display abnormal storage of cholesterol and sphingolipids in the endo-lysosomal system.

PubMed

Zhao, Kexin; van der Spoel, Aarnoud; Castiglioni, Claudia; Gale, Sarah; Fujiwara, Hideji; Ory, Daniel S; Ridgway, Neale D

2018-06-01

Microdeletions in 19q12q13.12 cause a rare and complex haploinsufficiency syndrome characterized by intellectual deficiency, developmental delays, and neurological movement disorders. Variability in the size and interval of the deletions makes it difficult to attribute the complex clinical phenotype of this syndrome to an underlying gene(s). As an alternate approach, we examined the biochemical and metabolic features of fibroblasts from an affected individual to derive clues as to the molecular basis for the syndrome. Immunofluorescence and electron microscopy of affected fibroblasts revealed an abnormal endo-lysosomal compartment that was characterized by rapid accumulation of lysosomotropic dyes, elevated LAMP1 and LAMP2 expression and vacuoles containing membrane whorls, common features of lysosomal lipid storage disorders. The late endosomes-lysosomes (LE/LY) of affected fibroblasts accumulated low-density lipoprotein cholesterol, and displayed reduced cholesterol esterification and increased de novo cholesterol synthesis, indicative of defective cholesterol transport to the endoplasmic reticulum. Affected fibroblasts also had increased ceramide and sphingolipid mass, altered glycosphingolipid species and accumulation of a fluorescent lactosylceramide probe in LE/LY. Autophagosomes also accumulated in affected fibroblasts because of decreased fusion with autolysosomes, a defect associated with other lysosomal storage diseases. Attempts to correct the cholesterol/sphingolipid storage defect in fibroblasts with cyclodextrin, sphingolipid synthesis inhibitors or by altering ion transport were unsuccessful. Our data show that 19q13.12 deletion fibroblasts have abnormal accumulation of cholesterol and sphingolipids in the endo-lysosomal system that compromises organelle function and could be an underlying cause of the clinical features of the syndrome. Copyright © 2018 Elsevier B.V. All rights reserved.

Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice.

PubMed

Wolff, G L; Kodell, R L; Moore, S R; Cooney, C A

1998-08-01

'Viable yellow' (Avy/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epigenetic mosaics ranging from a yellow phenotype with maximum ectopic agouti overexpression, through a continuum of mottled agouti/yellow phenotypes with partial agouti overexpression, to a pseudoagouti phenotype with minimal ectopic expression. Pseudoagouti Avy/a mice are lean, healthy, and longer lived than their yellow siblings. Here we report that feeding pregnant black a/a dams methyl-supplemented diets alters epigenetic regulation of agouti expression in their offspring, as indicated by increased agouti/black mottling in the direction of the pseudoagouti phenotype. We also present confirmatory evidence that epigenetic phenotypes are maternally heritable. Thus Avy expression, already known to be modulated by imprinting, strain-specific modification, and maternal epigenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epigenetic mechanisms, especially DNA methylation, in developing embryos.

The lncRNA CASC9 and RNA binding protein HNRNPL form a complex and co-regulate genes linked to AKT signaling.

PubMed

Klingenberg, Marcel; Groß, Matthias; Goyal, Ashish; Polycarpou-Schwarz, Maria; Miersch, Thilo; Ernst, Anne-Sophie; Leupold, Jörg; Patil, Nitin; Warnken, Uwe; Allgayer, Heike; Longerich, Thomas; Schirmacher, Peter; Boutros, Michael; Diederichs, Sven

2018-05-23

The identification of viability-associated long non-coding RNAs (lncRNA) might be a promising rationale for new therapeutic approaches in liver cancer. Here, we applied the first RNAi screening approach in hepatocellular carcinoma (HCC) cell lines to find viability-associated lncRNAs. Among the multiple identified lncRNAs with a significant impact on HCC cell viability, we selected CASC9 (Cancer Susceptibility 9) due to the strength of its phenotype, expression, and upregulation in HCC versus normal liver. CASC9 regulated viability across multiple HCC cell lines as shown by CRISPR interference, single siRNA- and siPOOL-mediated depletion of CASC9. Further, CASC9 depletion caused an increase in apoptosis and decrease of proliferation. We identified the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a CASC9 interacting protein by RNA affinity purification (RAP) and validated it by native RNA immunoprecipitation (RIP). Knockdown of HNRNPL mimicked the loss-of-viability phenotype observed upon CASC9 depletion. Analysis of the proteome (SILAC) of CASC9- and HNRNPL-depleted cells revealed a set of co-regulated genes which implied a role of the CASC9:HNRNPL complex in AKT-signaling and DNA damage sensing. CASC9 expression levels were elevated in patient-derived tumor samples compared to normal control tissue and had a significant association with overall survival of HCC patients. In a xenograft chicken chorioallantoic membrane model, we measured a decreased tumor size after knockdown of CASC9. Taken together, we provide a comprehensive list of viability-associated lncRNAs in HCC. We identified the CASC9:HNRNPL complex as a clinically relevant viability-associated lncRNA/protein complex which affects AKT-signaling and DNA damage sensing in HCC. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Genetics of healthy aging and longevity.

PubMed

Brooks-Wilson, Angela R

2013-12-01

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

Creative Activities in Music--A Genome-Wide Linkage Analysis.

PubMed

Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

2016-01-01

Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose a common genetic background for music-related creative behaviour and musical abilities at chromosome 4.

Quantification of Dynamic Morphological Drug Responses in 3D Organotypic Cell Cultures by Automated Image Analysis

PubMed Central

Härmä, Ville; Schukov, Hannu-Pekka; Happonen, Antti; Ahonen, Ilmari; Virtanen, Johannes; Siitari, Harri; Åkerfelt, Malin; Lötjönen, Jyrki; Nees, Matthias

2014-01-01

Glandular epithelial cells differentiate into complex multicellular or acinar structures, when embedded in three-dimensional (3D) extracellular matrix. The spectrum of different multicellular morphologies formed in 3D is a sensitive indicator for the differentiation potential of normal, non-transformed cells compared to different stages of malignant progression. In addition, single cells or cell aggregates may actively invade the matrix, utilizing epithelial, mesenchymal or mixed modes of motility. Dynamic phenotypic changes involved in 3D tumor cell invasion are sensitive to specific small-molecule inhibitors that target the actin cytoskeleton. We have used a panel of inhibitors to demonstrate the power of automated image analysis as a phenotypic or morphometric readout in cell-based assays. We introduce a streamlined stand-alone software solution that supports large-scale high-content screens, based on complex and organotypic cultures. AMIDA (Automated Morphometric Image Data Analysis) allows quantitative measurements of large numbers of images and structures, with a multitude of different spheroid shapes, sizes, and textures. AMIDA supports an automated workflow, and can be combined with quality control and statistical tools for data interpretation and visualization. We have used a representative panel of 12 prostate and breast cancer lines that display a broad spectrum of different spheroid morphologies and modes of invasion, challenged by a library of 19 direct or indirect modulators of the actin cytoskeleton which induce systematic changes in spheroid morphology and differentiation versus invasion. These results were independently validated by 2D proliferation, apoptosis and cell motility assays. We identified three drugs that primarily attenuated the invasion and formation of invasive processes in 3D, without affecting proliferation or apoptosis. Two of these compounds block Rac signalling, one affects cellular cAMP/cGMP accumulation. Our approach supports the growing needs for user-friendly, straightforward solutions that facilitate large-scale, cell-based 3D assays in basic research, drug discovery, and target validation. PMID:24810913

Novel FAM20A mutation causes autosomal recessive amelogenesis imperfecta.

PubMed

Volodarsky, Michael; Zilberman, Uri; Birk, Ohad S

2015-06-01

To relate the peculiar phenotype of amelogenesis imperfecta in a large Bedouin family to the genotype determined by whole genome linkage analysis. Amelogenesis imperfecta (AI) is a broad group of inherited pathologies affecting enamel formation, characterized by variability in phenotypes, causing mutations and modes of inheritance. Autosomal recessive or compound heterozygous mutations in FAM20A, encoding sequence similarity 20, member A, have been shown to cause several AI phenotypes. Five members from a large consanguineous Bedouin family presented with hypoplastic amelogenesis imperfecta with unerupted and resorbed permanent molars. Following Soroka Medical Center IRB approval and informed consent, blood samples were obtained from six affected offspring, five obligatory carriers and two unaffected siblings. Whole genome linkage analysis was performed followed by Sanger sequencing of FAM20A. The sequencing unravelled a novel homozygous deletion mutation in exon 11 (c.1523delC), predicted to insert a premature stop codon (p.Thr508Lysfs*6). We provide an interesting case of novel mutation in this rare disorder, in which the affected kindred is unique in the large number of family members sharing a similar phenotype. Copyright © 2015 Elsevier Ltd. All rights reserved.

POB3 is required for both transcription and replication in the yeast Saccharomyces cerevisiae.

PubMed Central

Schlesinger, M B; Formosa, T

2000-01-01

Spt16 and Pob3 form stable heterodimers in Saccharomyces cerevisiae, and homologous proteins have also been purified as complexes from diverse eukaryotes. This conserved factor has been implicated in both transcription and replication and may affect both by altering the characteristics of chromatin. Here we describe the isolation and properties of a set of pob3 mutants and confirm that they have defects in both replication and transcription. Mutation of POB3 caused the Spt(-) phenotype, spt16 and pob3 alleles displayed severe synthetic defects, and elevated levels of Pob3 suppressed some spt16 phenotypes. These results are consistent with previous reports that Spt16 and Pob3 act in a complex that modulates transcription. Additional genetic interactions were observed between pob3 mutations and the genes encoding several DNA replication factors, including POL1, CTF4, DNA2, and CHL12. pob3 alleles caused sensitivity to the ribonucleotide reductase inhibitor hydroxyurea, indicating a defect in a process requiring rapid dNTP synthesis. Mutation of the S phase checkpoint gene MEC1 caused pob3 mutants to lose viability rapidly under restrictive conditions, revealing defects in a process monitored by Mec1. Direct examination of DNA contents by flow cytometry showed that S phase onset and progression were delayed when POB3 was mutated. We conclude that Pob3 is required for normal replication as well as for transcription. PMID:10924459

Variation and Functional Impact of Neanderthal Ancestry in Western Asia

PubMed Central

Taskent, Recep Ozgur; Alioglu, Nursen Duha; Fer, Evrim

2017-01-01

Abstract Neanderthals contributed genetic material to modern humans via multiple admixture events. Initial admixture events presumably occurred in Western Asia shortly after humans migrated out of Africa. Despite being a focal point of admixture, earlier studies indicate lower Neanderthal introgression rates in some Western Asian populations as compared with other Eurasian populations. To better understand the genome-wide and phenotypic impact of Neanderthal introgression in the region, we sequenced whole genomes of nine present-day Europeans, Africans, and the Western Asian Druze at high depth, and analyzed available whole genome data from various other populations, including 16 genomes from present-day Turkey. Our results confirmed previous observations that contemporary Western Asian populations, on an average, have lower levels of Neanderthal-introgressed DNA relative to other Eurasian populations. Modern Western Asians also show comparatively high variability in Neanderthal ancestry, which may be attributed to the complex demographic history of the region. We further replicated the previously described depletion of putatively functional sequences among Neanderthal-introgressed haplotypes. Still, we find dozens of common Neanderthal-introgressed haplotypes in the Turkish sample associated with human phenotypes, including anthropometric and metabolic traits, as well as the immune response. One of these haplotypes is unusually long and harbors variants that affect the expression of members of the CCR gene family and are associated with celiac disease. Overall, our results paint a complex first picture of the genomic impact of Neanderthal introgression in the Western Asian populations. PMID:29040546

Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines.

PubMed

Adalsteinsson, Viktor A; Tahirova, Narmin; Tallapragada, Naren; Yao, Xiaosai; Campion, Liam; Angelini, Alessandro; Douce, Thomas B; Huang, Cindy; Bowman, Brittany; Williamson, Christina A; Kwon, Douglas S; Wittrup, K Dane; Love, J Christopher

2013-10-01

Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors.

Molecular analysis of the XLRS1 gene in 4 females affected with X-linked juvenile retinoschisis.

PubMed

Saleheen, Danish; Ali, Azam; Khanum, Shaheen; Ozair, Mohammad Z; Zaidi, Moazzam; Sethi, Muhammad J; Khan, Nadir; Frossard, Philippe

2008-10-01

X-linked juvenile retinoschisis (XLRS) is the most common cause of juvenile macular degeneration in males. Because of its X-linked mode of transmission, the disease is rare in females. In this article, we describe a mutation screen conducted on a family in which 4 female patients affected with XLRS presented with an unusually severe phenotype. DNA was extracted from peripheral blood, and the XLRS1 gene was amplified on DNA samples of all the available family members. The mutation screen was conducted by performing direct DNA sequencing using an MJ Research PTC-225 Peltier Thermal Cycler. A novel mutation, 588-593ins.C, was identified in exon 6 of the gene. The affected father was found to be heterozygous for the mutation, whereas all the female patients were homozygous for this mutation. The homozygosity of the mutation in the affected females led to severe phenotypes. The defective allele was expressed in infancy in 1 patient, whereas the disease manifested itself at variable ages in the other patients, reflecting a variation in the phenotype. This report describes a novel mutation in a family in which consanguinity has led to XLRS in 4 females. A variation in the phenotype of the disease is consistent with the published literature and suggests the involvement of genetic modifiers or environmental factors in influencing the clinical severity of the disease.

The Treacher Collins syndrome (TCOF1) gene product is involved in pre-rRNA methylation.

PubMed

Gonzales, Bianca; Henning, Dale; So, Rolando B; Dixon, Jill; Dixon, Michael J; Valdez, Benigno C

2005-07-15

Treacher Collins syndrome (TCS) is characterized by defects in craniofacial development, which results from mutations in the TCOF1 gene. TCOF1 encodes the nucleolar phosphoprotein treacle, which interacts with upstream binding factor (UBF) and affects transcription of the ribosomal DNA gene. The present study shows participation of treacle in the 2'-O-methylation of pre-rRNA. Antisense-mediated down-regulation of treacle expression in Xenopus laevis oocytes reduced 2'-O-methylation of pre-rRNA. Analysis of RNA isolated from wild-type and Tcof1+/- heterozygous mice embryos from strains that exhibit a lethal phenotype showed significant reduction in 2'-O-methylation at nucleotide C463 of 18S rRNA. The level of pseudouridylation of U1642 of 18S rRNA from the same RNA samples was not affected suggesting specificity. There is no significant difference in rRNA methylation between wild-type and heterozygous embryos of DBA x BALB/c mice, which have no obvious craniofacial phenotype. The function of treacle in pre-rRNA methylation is most likely mediated by its direct physical interaction with NOP56, a component of the ribonucleoprotein methylation complex. Although treacle co-localizes with UBF throughout mitosis, it co-localizes with NOP56 and fibrillarin, a putative methyl transferase, only during telophase when rDNA gene transcription and pre-rRNA methylation are known to commence. These observations suggest that treacle might link RNA polymerase I-catalyzed transcription and post-transcriptional modification of pre-rRNA. We hypothesize that haploinsufficiency of treacle in TCS patients results in inhibition of production of properly modified mature rRNA in addition to inhibition of rDNA gene transcription, which consequently affects proliferation and proper differentiation of specific embryonic cells during development.

Quantitative trait loci for maternal performance for offspring survival in mice.

PubMed Central

Peripato, Andréa C; De Brito, Reinaldo A; Vaughn, Ty T; Pletscher, L Susan; Matioli, Sergio R; Cheverud, James M

2002-01-01

Maternal performance refers to the effect that the environment provided by mothers has on their offspring's phenotypes, such as offspring survival and growth. Variations in maternal behavior and physiology are responsible for variations in maternal performance, which in turn affects offspring survival. In our study we found females that failed to nurture their offspring and showed abnormal maternal behaviors. The genetic architecture of maternal performance for offspring survival was investigated in 241 females of an F(2) intercross of the SM/J and LG/J inbred mouse strains. Using interval-mapping methods we found two quantitative trait loci (QTL) affecting maternal performance at D2Mit17 + 6 cM and D7Mit21 + 2 cM on chromosomes 2 and 7, respectively. In a two-way genome-wide epistasis scan we found 15 epistatic interactions involving 23 QTL distributed across all chromosomes except 12, 16, and 17. These loci form several small sets of interacting QTL, suggesting a complex set of mechanisms operating to determine maternal performance for offspring survival. Taken all together and correcting for the large number of significant factors, QTL and their interactions explain almost 35% of the phenotypic variation for maternal performance for offspring survival in this cross. This study allowed the identification of many possible candidate genes, as well as the relative size of gene effects and patterns of gene action affecting maternal performance in mice. Detailed behavior observation of mothers from later generations suggests that offspring survival in the first week is related to maternal success in building nests, grooming their pups, providing milk, and/or manifesting aggressive behavior against intruders. PMID:12454078

Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.

PubMed

García-Castillo, Herbert; Vásquez-Velásquez, Ana Isabel; Rivera, Horacio; Barros-Núñez, Patricio

2008-07-01

Mosaic variegated aneuploidy (MVA) is a rare autosomal recessive syndrome related to BUB1B gene mutations and characterized by multiple mosaic aneuploidies, cancer predisposition, and a distinct phenotype. We report on two mildly affected sibs with MVA syndrome but without BUB1B mutation. Both patients exhibited growth retardation, frontal bossing, triangular face and micrognathia but not microcephaly or cancer. Aneuploidies were assessed both in G-banded metaphases from lymphocyte cultures and in interphase nuclei from buccal cells by FISH. Screening of 23 exons and intron-exon boundaries of BUB1B was also carried out. These patients were then compared with other 19 MVA patients screened for BUB1B mutations. Around one half of the cultured lymphocytes from our patients had aneuploidies ranging from nullisomies to heptasomies; the most frequent abnormalities were trisomies (42%) and monosomies (28%). FISH results demonstrated more chromosomal losses than gains. Screening of BUB1B in our two patients failed to identify any mutation. A review of the 21/35 patients screened for BUB1B demonstrated three clinical pictures. Patients with monoallelic BUB1B mutations were severely affected with Dandy-Walker complex (7/8), cataracts (6/6), and Wilms' tumor (7/8); premature chromatid separation (PCS) was observed in 8/8 propositi and 7/7 carrier parents. Patients without BUB1B mutations were mildly affected with no evidence of cancer, Dandy-Walker malformation or cataract, and rarely (1/7) showed PCS. Finally, patients with biallelic BUB1B mutations showed a moderate phenotype. The distinct MVA clinical groups delineated here point to involvement of at least another mitotic spindle checkpoint gene in addition to the BUB1B gene. (c) 2008 Wiley-Liss, Inc.

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress.

PubMed

Palma, Anita; Pugliese, Giusj Monia; Murfuni, Ivana; Marabitti, Veronica; Malacaria, Eva; Rinalducci, Sara; Minoprio, Anna; Sanchez, Massimo; Mazzei, Filomena; Zolla, Lello; Franchitto, Annapaola; Pichierri, Pietro

2018-06-01

The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells. Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis.

The genotypic and phenotypic spectrum of MTO1 deficiency.

PubMed

O'Byrne, James J; Tarailo-Graovac, Maja; Ghani, Aisha; Champion, Michael; Deshpande, Charu; Dursun, Ali; Ozgul, Riza K; Freisinger, Peter; Garber, Ian; Haack, Tobias B; Horvath, Rita; Barić, Ivo; Husain, Ralf A; Kluijtmans, Leo A J; Kotzaeridou, Urania; Morris, Andrew A; Ross, Colin J; Santra, Saikat; Smeitink, Jan; Tarnopolsky, Mark; Wortmann, Saskia B; Mayr, Johannes A; Brunner-Krainz, Michaela; Prokisch, Holger; Wasserman, Wyeth W; Wevers, Ron A; Engelke, Udo F; Rodenburg, Richard J; Ting, Teck Wah; McFarland, Robert; Taylor, Robert W; Salvarinova, Ramona; van Karnebeek, Clara D M

2018-01-01

Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations

PubMed Central

Candille, Sophie I.; Absher, Devin M.; Beleza, Sandra; Bauchet, Marc; McEvoy, Brian; Garrison, Nanibaa’ A.; Li, Jun Z.; Myers, Richard M.; Barsh, Gregory S.; Tang, Hua; Shriver, Mark D.

2012-01-01

Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world. PMID:23118974

Effects of energetic restriction diet on butyrylcholinesterase in obese women from southern Brazil - A longitudinal study.

PubMed

Santos, Willian Dos; Tureck, Luciane Viater; Saliba, Louise Farah; Schenknecht, Caroline Schovanz; Scaraboto, Débora; Souza, Ricardo Lehtonen R; Furtado-Alle, Lupe

2017-01-01

Butyrylcholinesterase (BChE) activity has been associated with obesity, lipid concentrations, and CHE2 locus phenotypes. This, the aim of this study was to evaluate the effects of an energetic restriction diet intervention on anthropometrical and biochemical variables and on absolute and relative BChE activity in CHE2 C5+ and CHE2 C5- individuals. One hundred eleven premenopausal obese women from Southern Brazil participated in an energetic restriction diet intervention (deficit of 2500 kJ/day) for 8 weeks. Their anthropometric and biochemical parameters were evaluated before and after the intervention. Plasma BChE activity was measured, and BChE bands in plasma and CHE2 locus phenotypes were detected by electrophoresis. The dietetic intervention decreased anthropometric and biochemical parameters as well as absolute BChE activity and relative activity of the G4 band. The CHE2 C5+ phenotype presented a different effect when compared with the CHE2 C5- phenotype. The CHE2 C5+ phenotype showed an effect in absolute BChE activity and in the relative activity of the G4 form, maintaining higher BChE activity regardless of the metabolic changes. In our study, 8 weeks was not sufficient time to lower the body mass index to normal, but it was enough to significantly reduce the absolute BChE activity, which became similar to the levels in nonobese individuals. CHE2 C5+ individuals were resistant to the decrease in BChE activity compared to CHE2 C5- individuals. This shows that the diet did not affect the CHE2 and G4 fraction complex and that the products of the CHE2 locus in association with BChE have a role in energy metabolism, maintaining high levels of enzymatic activity even after dietary intervention.

The integrated phenotype and plasticity of Cuphea PSR23: A semi-domesticated oilseed crop

USDA-ARS?s Scientific Manuscript database

Cuphea PSR23, a semi-domesticated potential oilseed crop, is a selection from an interspecific cross between the wild species Cuphea lanceolata and C. viscosissima. Understanding the extent to which its phenotype is integrated, by studying complex trait interactions and interdependencies, is critica...

Affective temperament and personal identity.

PubMed

Stanghellini, Giovanni; Rosfort, René

2010-10-01

The complex relationship between temperament and personal identity, and between these and mental disorders, is of critical interest to both philosophy and psychopathology. More than other living creatures, human beings are constituted and characterized by the interplay of their genotype and phenotype. There appears to be an explanatory gap between the almost perfect genetic identity and the individual differences among humans. One reason for this gap is that a human being is a person besides a physiological organism. We propose an outline of a theoretical model that might somewhat mitigate the explanatory discrepancies between physiological mechanisms and individual human emotional experience and behaviour. Arguing for the pervasive nature of human affectivity, i.e., for the assumption that human consciousness and behaviour is characterised by being permeated by affectivity; to envisage the dynamics of emotional experience, we make use of a three-levelled model of human personal identity that differentiates between factors that are simultaneously at work in the constitution of the individual human person: 1) core emotions, 2) affective temperament types/affective character traits, and 3) personhood. These levels are investigated separately in order to respect the methodological diversity among them (neuroscience, psychopathology, and philosophy), but they are eventually brought together in a hermeneutical account of human personhood. Copyright 2010 Elsevier B.V. All rights reserved.

Strategy Revealing Phenotypic Differences among Synthetic Oscillator Designs

PubMed Central

2015-01-01

Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID:25019938

Linking stream ecology with morphological variability in a native freshwater fish from semi-arid Australia

PubMed Central

Lostrom, Samantha; Evans, Jonathan P; Grierson, Pauline F; Collin, Shaun P; Davies, Peter M; Kelley, Jennifer L

2015-01-01

Environmental variation is a potent force affecting phenotypic expression. While freshwater fishes have provided a compelling example of the link between the environment and phenotypic diversity, few studies have been conducted with arid-zone fishes, particularly those that occur in geographically isolated regions where species typically inhabit intermittent and ephemeral creeks. We investigated morphological variation of a freshwater fish (the western rainbowfish, Melanotaenia australis) inhabiting creeks in the Pilbara region of northwest Australia to determine whether body shape variation correlated with local environmental characteristics, including water velocity, habitat complexity, predator presence, and food availability. We expected that the geographic isolation of creeks within this arid region would result in habitat-specific morphological specializations. We used landmark-based geometric morphometrics to quantify the level of morphological variability in fish captured from 14 locations within three distinct subcatchments of a major river system. Western rainbowfish exhibited a range of morphologies, with variation in body depth accounting for a significant proportion (>42%) of the total variance in shape. Sexual dimorphism was also apparent, with males displaying deeper bodies than females. While the measured local habitat characteristics explained little of the observed morphological variation, fish displayed significant morphological differentiation at the level of the subcatchment. Local adaptation may partly explain the geographic patterns of body shape variation, but fine-scale genetic studies are required to disentangle the effects of genetic differentiation from environmentally determined phenotypic plasticity in body shape. Developing a better understanding of environment–phenotype relationships in species from arid regions will provide important insights into ecological and evolutionary processes in these unique and understudied habitats. PMID:26380663

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women.

PubMed

Ellefsen, S; Vikmoen, O; Slettaløkken, G; Whist, J E; Nygaard, H; Hollan, I; Rauk, I; Vegge, G; Strand, T A; Raastad, T; Rønnestad, B R

2014-09-01

To investigate the effects of strength training on abundances of irisin-related biomarkers in skeletal muscle and blood of untrained young women, and their associations with body mass composition, muscle phenotype and levels of thyroid hormones. Eighteen untrained women performed 12 weeks of progressive whole-body heavy strength training, with measurement of strength, body composition, expression of irisin-related genes (FNDC5 and PGC1α) in two different skeletal muscles, and levels of serum-irisin and -thyroid hormones, before and after the training intervention. The strength training intervention did not result in changes in serum-irisin or muscle FNDC5 expression, despite considerable effects on strength, lean body mass (LBM) and skeletal muscle phenotype. Our data indicate that training affects irisin biology in a LBM-dependent manner. However, no association was found between steady-state serum-irisin or training-associated changes in serum-irisin and alterations in body composition. FNDC5 expression was higher in m.Biceps brachii than in m.Vastus lateralis, with individual expression levels being closely correlated, suggesting a systemic mode of transcriptional regulation. In pre-biopsies, FNDC5 expression was correlated with proportions of aerobic muscle fibers, a relationship that disappeared in post-biopsies. No association was found between serum-thyroid hormones and FNDC5 expression or serum-irisin. No evidence was found for an effect of strength training on irisin biology in untrained women, though indications were found for a complex interrelationship between irisin, body mass composition and muscle phenotype. FNDC5 expression was closely associated with muscle fiber composition in untrained muscle.

Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

PubMed Central

Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija H.; Hansen, Mark S. T.; Lawley, Cindy T.; Karlsson, Elinor K.; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis; Fredholm, Merete; Häggström, Jens; Hedhammar, Åke; André, Catherine; Lindblad-Toh, Kerstin; Hitte, Christophe; Webster, Matthew T.

2011-01-01

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease. PMID:22022279

Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

PubMed

Vaysse, Amaury; Ratnakumar, Abhirami; Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija H; Hansen, Mark S T; Lawley, Cindy T; Karlsson, Elinor K; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis; Fredholm, Merete; Häggström, Jens; Hedhammar, Ake; André, Catherine; Lindblad-Toh, Kerstin; Hitte, Christophe; Webster, Matthew T

2011-10-01

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

Evolutionary trade-offs and the structure of polymorphisms.

PubMed

Sheftel, Hila; Szekely, Pablo; Mayo, Avi; Sella, Guy; Alon, Uri

2018-05-26

Populations of organisms show genetic differences called polymorphisms. Understanding the effects of polymorphisms is important for biology and medicine. Here, we ask which polymorphisms occur at high frequency when organisms evolve under trade-offs between multiple tasks. Multiple tasks present a problem, because it is not possible to be optimal at all tasks simultaneously and hence compromises are necessary. Recent work indicates that trade-offs lead to a simple geometry of phenotypes in the space of traits: phenotypes fall on the Pareto front, which is shaped as a polytope: a line, triangle, tetrahedron etc. The vertices of these polytopes are the optimal phenotypes for a single task. Up to now, work on this Pareto approach has not considered its genetic underpinnings. Here, we address this by asking how the polymorphism structure of a population is affected by evolution under trade-offs. We simulate a multi-task selection scenario, in which the population evolves to the Pareto front: the line segment between two archetypes or the triangle between three archetypes. We find that polymorphisms that become prevalent in the population have pleiotropic phenotypic effects that align with the Pareto front. Similarly, epistatic effects between prevalent polymorphisms are parallel to the front. Alignment with the front occurs also for asexual mating. Alignment is reduced when drift or linkage is strong, and is replaced by a more complex structure in which many perpendicular allele effects cancel out. Aligned polymorphism structure allows mating to produce offspring that stand a good chance of being optimal multi-taskers in at least one of the locales available to the species.This article is part of the theme issue 'Self-organization in cell biology'. © 2018 The Author(s).

DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.

PubMed

Xu, Wang-Yang; Zhu, Houbao; Shen, Yan; Wan, Ying-Han; Tu, Xiao-Die; Wu, Wen-Ting; Tang, Lingyun; Zhang, Hong-Xin; Lu, Shun-Yuan; Jin, Xiao-Long; Fei, Jian; Wang, Zhu-Gang

2018-07-01

DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 that we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive. Here, we show that Dhtkd1 -/- mice mimic the major aspects of CMT2 phenotypes, characterized by progressive weakness and atrophy in the distal parts of limbs with motor and sensory dysfunctions, which are accompanied with decreased nerve conduction velocity. Moreover, DHTKD1 deficiency causes severe metabolic abnormalities and dramatically increased levels of 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) in urine. Further studies revealed that both 2-KAA and 2-AAA could stimulate insulin biosynthesis and secretion. Subsequently, elevated insulin regulates myelin protein zero ( Mpz ) transcription in Schwann cells via upregulating the expression of early growth response 2 (Egr2), leading to myelin structure damage and axonal degeneration. Finally, 2-AAA-fed mice do reproduce phenotypes similar to CMT2Q phenotypes. In conclusion, we have demonstrated that loss of DHTKD1 causes CMT2Q-like phenotypes through dysregulation of Mpz mRNA and protein zero (P 0 ) which are closely associated with elevated DHTKD1 substrate and insulin levels. These findings further indicate an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies. Copyright © 2018 American Society for Microbiology.

Systematic identification of an integrative network module during senescence from time-series gene expression.

PubMed

Park, Chihyun; Yun, So Jeong; Ryu, Sung Jin; Lee, Soyoung; Lee, Young-Sam; Yoon, Youngmi; Park, Sang Chul

2017-03-15

Cellular senescence irreversibly arrests growth of human diploid cells. In addition, recent studies have indicated that senescence is a multi-step evolving process related to important complex biological processes. Most studies analyzed only the genes and their functions representing each senescence phase without considering gene-level interactions and continuously perturbed genes. It is necessary to reveal the genotypic mechanism inferred by affected genes and their interaction underlying the senescence process. We suggested a novel computational approach to identify an integrative network which profiles an underlying genotypic signature from time-series gene expression data. The relatively perturbed genes were selected for each time point based on the proposed scoring measure denominated as perturbation scores. Then, the selected genes were integrated with protein-protein interactions to construct time point specific network. From these constructed networks, the conserved edges across time point were extracted for the common network and statistical test was performed to demonstrate that the network could explain the phenotypic alteration. As a result, it was confirmed that the difference of average perturbation scores of common networks at both two time points could explain the phenotypic alteration. We also performed functional enrichment on the common network and identified high association with phenotypic alteration. Remarkably, we observed that the identified cell cycle specific common network played an important role in replicative senescence as a key regulator. Heretofore, the network analysis from time series gene expression data has been focused on what topological structure was changed over time point. Conversely, we focused on the conserved structure but its context was changed in course of time and showed it was available to explain the phenotypic changes. We expect that the proposed method will help to elucidate the biological mechanism unrevealed by the existing approaches.

Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

PubMed Central

Pendergrass, Sarah A.; Brown-Gentry, Kristin; Dudek, Scott; Frase, Alex; Torstenson, Eric S.; Goodloe, Robert; Ambite, Jose Luis; Avery, Christy L.; Buyske, Steve; Bůžková, Petra; Deelman, Ewa; Fesinmeyer, Megan D.; Haiman, Christopher A.; Heiss, Gerardo; Hindorff, Lucia A.; Hsu, Chu-Nan; Jackson, Rebecca D.; Kooperberg, Charles; Le Marchand, Loic; Lin, Yi; Matise, Tara C.; Monroe, Kristine R.; Moreland, Larry; Park, Sungshim L.; Reiner, Alex; Wallace, Robert; Wilkens, Lynn R.; Crawford, Dana C.; Ritchie, Marylyn D.

2013-01-01

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype–phenotype associations, 26 represented phenotypes closely related to previously known genotype–phenotype associations, and 33 represented potentially novel genotype–phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits. PMID:23382687

The RDoC initiative and the structure of psychopathology.

PubMed

Krueger, Robert F; DeYoung, Colin G

2016-03-01

The NIMH Research Domain Criteria (RDoC) project represents a welcome effort to circumvent the limitations of psychiatric categories as phenotypes for psychopathology research. Here, we describe the hierarchical and dimensional structure of phenotypic psychopathology and illustrate how this structure provides phenotypes suitable for RDoC research on neural correlates of psychopathology. A hierarchical and dimensional approach to psychopathology phenotypes holds great promise for delineating connections between neuroscience constructs and the patterns of affect, cognition, and behavior that constitute manifest psychopathology. © 2016 Society for Psychophysiological Research.

Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes.

PubMed

Gollasch, Benjamin; Basmanav, Fitnat Buket; Nanda, Arti; Fritz, Günter; Mahmoudi, Hassnaa; Thiele, Holger; Wehner, Maria; Wolf, Sabrina; Altmüller, Janine; Nürnberg, Peter; Frank, Jorge; Betz, Regina C

2015-11-01

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging. © 2015 Wiley Periodicals, Inc.

MUM ENHANCERS are important for seed coat mucilage production and mucilage secretory cell differentiation in Arabidopsis thaliana

PubMed Central

Arsovski, Andrej A.; Villota, Maria M.; Rowland, Owen; Subramaniam, Rajagopal; Western, Tamara L.

2009-01-01

Pollination triggers not only embryo development but also the differentiation of the ovule integuments to form a specialized seed coat. The mucilage secretory cells of the Arabidopsis thaliana seed coat undergo a complex differentiation process in which cell growth is followed by the synthesis and secretion of pectinaceous mucilage. A number of genes have been identified affecting mucilage secretory cell differentiation, including MUCILAGE-MODIFIED4 (MUM4). mum4 mutants produce a reduced amount of mucilage and cloning of MUM4 revealed that it encodes a UDP-L-rhamnose synthase that is developmentally up-regulated to provide rhamnose for mucilage pectin synthesis. To identify additional genes acting in mucilage synthesis and secretion, a screen for enhancers of the mum4 phenotype was performed. Eight mum enhancers (men) have been identified, two of which result from defects in known mucilage secretory cell genes (MUM2 and MYB61). Our results show that, in a mum4 background, mutations in MEN1, MEN4, and MEN5 lead to further reductions in mucilage compared to mum4 single mutants, suggesting that they are involved in mucilage synthesis or secretion. Conversely, mutations in MEN2 and MEN6 appear to affect mucilage release rather than quantity. With the exception of men4, whose single mutant exhibits reduced mucilage, none of these genes have a single mutant phenotype, suggesting that they would not have been identified outside the compromised mum4 background. PMID:19401413

Subtle effect of Xenos vesparum (Xenidae, Strepsiptera) on the reproductive apparatus of its male host: Parasite or parasitoid?

PubMed

Beani, L; Marchini, D; Cappa, F; Petrocelli, I; Gottardo, M; Manfredini, F; Giusti, F; Dallai, R

2017-08-01

Parasitic castration is an adaptive strategy where parasites usurp the hosts' reproductive physiology to complete their life cycle. The alterations in the host traits vary in their magnitude, from subtle changes in the host morpho-physiology and behaviour to the production of complex aberrant phenotypes, which often depend on the host gender. The strepsipteran macroparasite Xenos vesparum induces dramatic behavioural and physiological changes in its female host, the paper wasp Polistes dominula, while its effect on the male phenotype is largely unknown. In this study we investigated how a single X. vesparum parasite influences the functional morphology of P. dominula male reproductive apparatus. We performed morphometry and ultrastructure characterization of corpora allata, testes, seminal vesicles and accessory glands in parasitized and unparasitized males, and also in young and old males to control for the effect of age on the natural deterioration of these organs. Our results show that age significantly affects the development of male reproductive apparatus. A low parasite load - one parasite per host is the common prevalence in the field - has only a marginal impact on the reproductive morphology of P. dominula males, affecting quantitatively but not qualitatively the protein content of male accessory glands. Thus, in male P. dominula wasps, X. vesparum appears to behave as a true "parasite", in clear opposition to the role of "parasitoid" that it takes in female hosts where castration causes the reproductive death. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protein Kinase Cδ Deficiency Causes Mendelian Systemic Lupus Erythematosus With B Cell–Defective Apoptosis and Hyperproliferation

PubMed Central

Belot, Alexandre; Kasher, Paul R.; Trotter, Eleanor W.; Foray, Anne-Perrine; Debaud, Anne-Laure; Rice, Gillian I.; Szynkiewicz, Marcin; Zabot, Marie-Therese; Rouvet, Isabelle; Bhaskar, Sanjeev S.; Daly, Sarah B.; Dickerson, Jonathan E.; Mayer, Josephine; O’Sullivan, James; Juillard, Laurent; Urquhart, Jill E.; Fawdar, Shameem; Marusiak, Anna A.; Stephenson, Natalie; Waszkowycz, Bohdan; Beresford, Michael W.; Biesecker, Leslie G.; Black, Graeme C. M.; René, Céline; Eliaou, Jean-François; Fabien, Nicole; Ranchin, Bruno; Cochat, Pierre; Gaffney, Patrick M.; Rozenberg, Flore; Lebon, Pierre; Malcus, Christophe; Crow, Yanick J.; Brognard, John; Bonnefoy, Nathalie

2014-01-01

Objective Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. Methods We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. Results We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor– and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. Conclusion Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE. PMID:23666743

Markov Logic Networks in the Analysis of Genetic Data

PubMed Central

Sakhanenko, Nikita A.

2010-01-01

Abstract Complex, non-additive genetic interactions are common and can be critical in determining phenotypes. Genome-wide association studies (GWAS) and similar statistical studies of linkage data, however, assume additive models of gene interactions in looking for genotype-phenotype associations. These statistical methods view the compound effects of multiple genes on a phenotype as a sum of influences of each gene and often miss a substantial part of the heritable effect. Such methods do not use any biological knowledge about underlying mechanisms. Modeling approaches from the artificial intelligence (AI) field that incorporate deterministic knowledge into models to perform statistical analysis can be applied to include prior knowledge in genetic analysis. We chose to use the most general such approach, Markov Logic Networks (MLNs), for combining deterministic knowledge with statistical analysis. Using simple, logistic regression-type MLNs we can replicate the results of traditional statistical methods, but we also show that we are able to go beyond finding independent markers linked to a phenotype by using joint inference without an independence assumption. The method is applied to genetic data on yeast sporulation, a complex phenotype with gene interactions. In addition to detecting all of the previously identified loci associated with sporulation, our method identifies four loci with smaller effects. Since their effect on sporulation is small, these four loci were not detected with methods that do not account for dependence between markers due to gene interactions. We show how gene interactions can be detected using more complex models, which can be used as a general framework for incorporating systems biology with genetics. PMID:20958249

Analysis of Polygenic Mutants Suggests a Role for Mediator in Regulating Transcriptional Activation Distance in Saccharomyces cerevisiae.

PubMed

Reavey, Caitlin T; Hickman, Mark J; Dobi, Krista C; Botstein, David; Winston, Fred

2015-10-01

Studies of natural populations of many organisms have shown that traits are often complex, caused by contributions of mutations in multiple genes. In contrast, genetic studies in the laboratory primarily focus on studying the phenotypes caused by mutations in a single gene. However, the single mutation approach may be limited with respect to the breadth and degree of new phenotypes that can be found. We have taken the approach of isolating complex, or polygenic mutants in the lab to study the regulation of transcriptional activation distance in yeast. While most aspects of eukaryotic transcription are conserved from yeast to human, transcriptional activation distance is not. In Saccharomyces cerevisiae, the upstream activating sequence (UAS) is generally found within 450 base pairs of the transcription start site (TSS) and when the UAS is moved too far away, activation no longer occurs. In contrast, metazoan enhancers can activate from as far as several hundred kilobases from the TSS. Previously, we identified single mutations that allow transcription activation to occur at a greater-than-normal distance from the GAL1 UAS. As the single mutant phenotypes were weak, we have now isolated polygenic mutants that possess strong long-distance phenotypes. By identification of the causative mutations we have accounted for most of the heritability of the phenotype in each strain and have provided evidence that the Mediator coactivator complex plays both positive and negative roles in the regulation of transcription activation distance. Copyright © 2015 by the Genetics Society of America.

Phenotyping: Using Machine Learning for Improved Pairwise Genotype Classification Based on Root Traits

PubMed Central

Zhao, Jiangsan; Bodner, Gernot; Rewald, Boris

2016-01-01

Phenotyping local crop cultivars is becoming more and more important, as they are an important genetic source for breeding – especially in regard to inherent root system architectures. Machine learning algorithms are promising tools to assist in the analysis of complex data sets; novel approaches are need to apply them on root phenotyping data of mature plants. A greenhouse experiment was conducted in large, sand-filled columns to differentiate 16 European Pisum sativum cultivars based on 36 manually derived root traits. Through combining random forest and support vector machine models, machine learning algorithms were successfully used for unbiased identification of most distinguishing root traits and subsequent pairwise cultivar differentiation. Up to 86% of pea cultivar pairs could be distinguished based on top five important root traits (Timp5) – Timp5 differed widely between cultivar pairs. Selecting top important root traits (Timp) provided a significant improved classification compared to using all available traits or randomly selected trait sets. The most frequent Timp of mature pea cultivars was total surface area of lateral roots originating from tap root segments at 0–5 cm depth. The high classification rate implies that culturing did not lead to a major loss of variability in root system architecture in the studied pea cultivars. Our results illustrate the potential of machine learning approaches for unbiased (root) trait selection and cultivar classification based on rather small, complex phenotypic data sets derived from pot experiments. Powerful statistical approaches are essential to make use of the increasing amount of (root) phenotyping information, integrating the complex trait sets describing crop cultivars. PMID:27999587

Advanced phenotyping and phenotype data analysis for the study of plant growth and development

PubMed Central

Rahaman, Md. Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

2015-01-01

Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060

A Role for the TOC Complex in Arabidopsis Root Gravitropism1[W][OA

PubMed Central

Stanga, John P.; Boonsirichai, Kanokporn; Sedbrook, John C.; Otegui, Marisa S.; Masson, Patrick H.

2009-01-01

Arabidopsis (Arabidopsis thaliana) roots perceive gravity and reorient their growth accordingly. Starch-dense amyloplasts within the columella cells of the root cap are important for gravitropism, and starchless mutants such as pgm1 display an attenuated response to gravistimulation. The altered response to gravity1 (arg1) mutant is known to be involved with the early phases of gravity signal transduction. arg1 responds slowly to gravistimulation and is in a genetically distinct pathway from pgm1, as pgm1 mutants enhance the gravitropic defect of arg1. arg1 seeds were mutagenized with ethylmethane sulfonate to identify new mutants that enhance the gravitropic defect of arg1. Two modifier of arg1 mutants (mar1 and mar2) grow in random directions only when arg1 is present, do not affect phototropism, and respond like the wild type to application of phytohormones. Both have mutations affecting different components of the Translocon of Outer Membrane of Chloroplasts (TOC) complex. mar1 possesses a mutation in the TOC75-III gene; mar2 possesses a mutation in the TOC132 gene. Overexpression of TOC132 rescues the random growth phenotype of mar2 arg1 roots. Root cap amyloplasts in mar2 arg1 appear ultrastructurally normal. They saltate like the wild type and sediment at wild-type rates upon gravistimulation. These data point to a role for the plastidic TOC complex in gravity signal transduction within the statocytes. PMID:19211693

A role for the TOC complex in Arabidopsis root gravitropism.

PubMed

Stanga, John P; Boonsirichai, Kanokporn; Sedbrook, John C; Otegui, Marisa S; Masson, Patrick H

2009-04-01

Arabidopsis (Arabidopsis thaliana) roots perceive gravity and reorient their growth accordingly. Starch-dense amyloplasts within the columella cells of the root cap are important for gravitropism, and starchless mutants such as pgm1 display an attenuated response to gravistimulation. The altered response to gravity1 (arg1) mutant is known to be involved with the early phases of gravity signal transduction. arg1 responds slowly to gravistimulation and is in a genetically distinct pathway from pgm1, as pgm1 mutants enhance the gravitropic defect of arg1. arg1 seeds were mutagenized with ethylmethane sulfonate to identify new mutants that enhance the gravitropic defect of arg1. Two modifier of arg1 mutants (mar1 and mar2) grow in random directions only when arg1 is present, do not affect phototropism, and respond like the wild type to application of phytohormones. Both have mutations affecting different components of the Translocon of Outer Membrane of Chloroplasts (TOC) complex. mar1 possesses a mutation in the TOC75-III gene; mar2 possesses a mutation in the TOC132 gene. Overexpression of TOC132 rescues the random growth phenotype of mar2 arg1 roots. Root cap amyloplasts in mar2 arg1 appear ultrastructurally normal. They saltate like the wild type and sediment at wild-type rates upon gravistimulation. These data point to a role for the plastidic TOC complex in gravity signal transduction within the statocytes.

Disruption of the ndhF1 gene affects Chl fluorescence through state transition in the Cyanobacterium Synechocystis sp. PCC 6803, resulting in apparent high efficiency of photosynthesis.

PubMed

Ogawa, Takako; Harada, Tetsuyuki; Ozaki, Hiroshi; Sonoike, Kintake

2013-07-01

In Synechocystis sp. PCC 6803, the disruption of the ndhF1 gene (slr0844), which encodes a subunit of one of the NDH-1 complexes (NDH-1L complex) serving for respiratory electron transfer, causes the largest change in Chl fluorescence induction kinetics among the kinetics of 750 disruptants searched in the Fluorome, the cyanobacterial Chl fluorescence database. The cause of the explicit phenotype of the ndhF1 disruptant was examined by measurements of the photosynthetic rate, Chl fluorescence and state transition. The results demonstrate that the defects in respiratory electron transfer obviously have great impact on Chl fluorescence in cyanobacteria. The inactivation of NDH-1L complexes involving electron transfer from NDH-1 to plastoquinone (PQ) would result in the oxidation of the PQ pool, leading to the transition to State 1, where the yield of Chl fluorescence is high. Apparently, respiration, although its rate is far lower than that of photosynthesis, could affect Chl fluorescence through the state transition as leverage. The disruption of the ndhF1 gene caused lower oxygen-evolving activity but the estimated electron transport rate from Chl fluorescence measurements was faster in the mutant than in the wild-type cells. The discrepancy could be ascribed to the decreased level of non-photochemical quenching due to state transition. One must be cautious when using the Chl fluorescence parameter to estimate photosynthesis in mutants defective in state transition.

Arabidopsis thaliana plants lacking the ARP2/3 complex show defects in cell wall assembly and auxin distribution.

PubMed

Pratap Sahi, Vaidurya; Cifrová, Petra; García-González, Judith; Kotannal Baby, Innu; Mouillé, Gregory; Gineau, Emilie; Müller, Karel; Baluška, František; Soukup, Aleš; Petrášek, Jan; Schwarzerová, Katerina

2017-12-25

The cytoskeleton plays an important role in the synthesis of plant cell walls. Both microtubules and actin cytoskeleton are known to be involved in the morphogenesis of plant cells through their role in cell wall building. The role of ARP2/3-nucleated actin cytoskeleton in the morphogenesis of cotyledon pavement cells has been described before. Seedlings of Arabidopsis mutants lacking a functional ARP2/3 complex display specific cell wall-associated defects. In three independent Arabidopsis mutant lines lacking subunits of the ARP2/3 complex, phenotypes associated with the loss of the complex were analysed throughout plant development. Organ size and anatomy, cell wall composition, and auxin distribution were investigated. ARP2/3-related phenotype is associated with changes in cell wall composition, and the phenotype is manifested especially in mature tissues. Cell walls of mature plants contain less cellulose and a higher amount of homogalacturonan, and display changes in cell wall lignification. Vascular bundles of mutant inflorescence stems show a changed pattern of AUX1-YFP expression. Plants lacking a functional ARP2/3 complex have decreased basipetal auxin transport. The results suggest that the ARP2/3 complex has a morphogenetic function related to cell wall synthesis and auxin transport. © The Author(s) 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Maternal allergic disease does not affect the phenotype of T and B cells or the immune response to allergens in neonates.

PubMed

Rindsjö, E; Joerink, M; Johansson, C; Bremme, K; Malmström, V; Scheynius, A

2010-07-01

It is hypothesized that the in utero environment in allergic mothers can affect the neonatal immune responses. The aim of this study was to analyse the effect of maternal allergic disease on cord blood mononuclear cell (CBMC) phenotype and proliferative responses upon allergen stimulation. Peripheral blood mononuclear cells (PBMC) from 12 allergic and 14 nonallergic mothers and CBMC from their children were analysed. In the mothers, we determined cell proliferation, production of IL-4 and expression of FOXP3 in response to allergen stimulation. In the children, we evaluated cell proliferation and FOXP3 expression following allergen stimulation. Furthermore, expression of different homing markers on T cells and regulatory T cells and maturity of the T cells and B cell subsets were evaluated directly ex vivo. The timothy- and birch-allergic mothers responded with increased proliferation and/or IL-4 production towards timothy and birch extract, respectively, when compared to nonallergic mothers. This could not be explained by impairment of FOXP3(+) regulatory T cells in the allergic mothers. CBMC proliferation and FOXP3 expression in response to allergens were not affected by the allergic status of the mother. Also, phenotype of T cells, FOXP3(+) regulatory T cells and B cells was not affected by the allergic status of the mother. Our results suggest that maternal allergic disease has no effect on the neonatal response to allergens or the phenotype of neonatal lymphocytes. The factors studied here could, however, still affect later development of allergy.

Cyclin C influences the timing of mitosis in fission yeast.

PubMed

Banyai, Gabor; Szilagyi, Zsolt; Baraznenok, Vera; Khorosjutina, Olga; Gustafsson, Claes M

2017-07-01

The multiprotein Mediator complex is required for the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator contains the Cdk8 regulatory subcomplex, which directs periodic transcription and influences cell cycle progression in fission yeast. Here we investigate the role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control. Previous reports suggested that CycC interacts with other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle phenotypes. We find that Cdk8 and CycC interactions are stabilized within the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components. Analysis of a mutant yeast strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into S phase. © 2017 Banyai et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Distinct promoter activation mechanisms modulate noise-driven HIV gene expression

NASA Astrophysics Data System (ADS)

Chavali, Arvind K.; Wong, Victor C.; Miller-Jensen, Kathryn

2015-12-01

Latent human immunodeficiency virus (HIV) infections occur when the virus occupies a transcriptionally silent but reversible state, presenting a major obstacle to cure. There is experimental evidence that random fluctuations in gene expression, when coupled to the strong positive feedback encoded by the HIV genetic circuit, act as a ‘molecular switch’ controlling cell fate, i.e., viral replication versus latency. Here, we implemented a stochastic computational modeling approach to explore how different promoter activation mechanisms in the presence of positive feedback would affect noise-driven activation from latency. We modeled the HIV promoter as existing in one, two, or three states that are representative of increasingly complex mechanisms of promoter repression underlying latency. We demonstrate that two-state and three-state models are associated with greater variability in noisy activation behaviors, and we find that Fano factor (defined as variance over mean) proves to be a useful noise metric to compare variability across model structures and parameter values. Finally, we show how three-state promoter models can be used to qualitatively describe complex reactivation phenotypes in response to therapeutic perturbations that we observe experimentally. Ultimately, our analysis suggests that multi-state models more accurately reflect observed heterogeneous reactivation and may be better suited to evaluate how noise affects viral clearance.

Recent advancements to study flowering time in almond and other Prunus species

PubMed Central

Sánchez-Pérez, Raquel; Del Cueto, Jorge; Dicenta, Federico; Martínez-Gómez, Pedro

2014-01-01

Flowering time is an important agronomic trait in almond since it is decisive to avoid the late frosts that affect production in early flowering cultivars. Evaluation of this complex trait is a long process because of the prolonged juvenile period of trees and the influence of environmental conditions affecting gene expression year by year. Consequently, flowering time has to be studied for several years to have statistical significant results. This trait is the result of the interaction between chilling and heat requirements. Flowering time is a polygenic trait with high heritability, although a major gene Late blooming (Lb) was described in “Tardy Nonpareil.” Molecular studies at DNA level confirmed this polygenic nature identifying several genome regions (Quantitative Trait Loci, QTL) involved. Studies about regulation of gene expression are scarcer although several transcription factors have been described as responsible for flowering time. From the metabolomic point of view, the integrated analysis of the mechanisms of accumulation of cyanogenic glucosides and flowering regulation through transcription factors open new possibilities in the analysis of this complex trait in almond and in other Prunus species (apricot, cherry, peach, plum). New opportunities are arising from the integration of recent advancements including phenotypic, genetic, genomic, transcriptomic, and metabolomics studies from the beginning of dormancy until flowering. PMID:25071812

“Forward Genetics” as a Method to Maximize Power and Cost-Efficiency in Studies of Human Complex Traits

PubMed Central

Derks, E. M.; Dolan, C. V.; Kahn, R. S.; Ophoff, R. A.

2010-01-01

There is increasing interest in methods to disentangle the relationship between genotype and (endo)phenotypes in human complex traits. We present a population-based method of increasing the power and cost-efficiency of studies by selecting random individuals with a particular genotype and then assessing the accompanying quantitative phenotypes. Using statistical derivations, power- and cost graphs we show that such a “forward genetics” approach can lead to a marked reduction in sample size and costs. This approach is particularly apt for implementing in epidemiological studies for which DNA is already available but the phenotyping costs are high. Electronic supplementary material The online version of this article (doi:10.1007/s10519-010-9348-y) contains supplementary material, which is available to authorized users. PMID:20232132

The Val{sup 192}Leu mutation in the {alpha}-subunit of {beta}-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou, Y.; Vavougios, G.; Hinek, A.

1996-07-01

Substitution mutations adversely affecting the {alpha}-subunit of {beta}-hexosaminidase A ({alpha}{beta}) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-{alpha} chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an {open_quotes}active-site{close_quotes} residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all {alpha}-specific activity. This biochemical phenotype is referred to as the {open_quotes}B1-variant form{close_quotes} of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and bothmore » subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, {alpha}-Val{sup 192}Leu. Chinese hamster ovary cells were permanently cotransfected with an {alpha}-cDNA-construct encoding the substitution and a mutant {beta}-cDNA ({beta}-Arg{sup 211}Lys), encoding a {beta}-subunit that is inactive but normal in all other respects. We were surprised to find that the Val{sup 192}Leu substitution produced a pro-{alpha} chain that did not form {alpha}-{beta} dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val{sup 192}Leu substitution does not specifically affect the {alpha}-active site. 23 refs., 4 figs., 2 tabs.« less

Control of flowering time and cold response by a NAC-domain protein in Arabidopsis.

PubMed

Yoo, So Yeon; Kim, Yunhee; Kim, Soo Young; Lee, Jong Seob; Ahn, Ji Hoon

2007-07-25

Plants must integrate complex signals from environmental and endogenous cues to fine-tune the timing of flowering. Low temperature is one of the most common environmental stresses that affect flowering time; however, molecular mechanisms underlying the cold temperature regulation of flowering time are not fully understood. We report the identification of a novel regulator, LONG VEGETATIVE PHASE 1 (LOV1), that controls flowering time and cold response. An Arabidopsis mutant, longvegetative phase 1-1D (lov1-1D) showing the late-flowering phenotype, was isolated by activation tagging screening. Subsequent analyses demonstrated that the phenotype of the mutant resulted from the overexpression of a NAC-domain protein gene (At2g02450). Both gain- and loss-of-function alleles of LOV1 affected flowering time predominantly under long-day but not short-day conditions, suggesting that LOV1 may act within the photoperiod pathway. The expression of CONSTANS (CO), a floral promoter, was affected by LOV1 level, suggesting that LOV1 controls flowering time by negatively regulating CO expression. The epistatic relationship between CO and LOV1 was consistent with this proposed regulatory pathway. Physiological analyses to elucidate upstream signalling pathways revealed that LOV1 regulates the cold response in plants. Loss of LOV1 function resulted in hypersensitivity to cold temperature, whereas a gain-of-function allele conferred cold tolerance. The freezing tolerance was accompanied by upregulation of cold response genes, COLD-REGULATED 15A (COR15A) and COLD INDUCED 1 (KIN1) without affecting expression of the C-repeat-binding factor/dehydration responsive element-binding factor 1 (CBF/DREB1) family of genes. Our study shows that LOV1 functions as a floral repressor that negatively regulates CO expression under long-day conditions and acts as a common regulator of two intersecting pathways that regulate flowering time and the cold response, respectively. Our results suggest an overlapping pathway for controlling cold stress response and flowering time in plants.

Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound

PubMed Central

Fitzgerald, Kevin; Tertyshnikova, Svetlana; Moore, Lisa; Bjerke, Lynn; Burley, Ben; Cao, Jian; Carroll, Pamela; Choy, Robert; Doberstein, Steve; Dubaquie, Yves; Franke, Yvonne; Kopczynski, Jenny; Korswagen, Hendrik; Krystek, Stanley R; Lodge, Nicholas J; Plasterk, Ronald; Starrett, John; Stouch, Terry; Thalody, George; Wayne, Honey; van der Linden, Alexander; Zhang, Yongmei; Walker, Stephen G; Cockett, Mark; Wardwell-Swanson, Judi; Ross-Macdonald, Petra; Kindt, Rachel M

2006-01-01

We report here on a chemical genetic screen designed to address the mechanism of action of a small molecule. Small molecules that were active in models of urinary incontinence were tested on the nematode Caenorhabditis elegans, and the resulting phenotypes were used as readouts in a genetic screen to identify possible molecular targets. The mutations giving resistance to compound were found to affect members of the RGS protein/G-protein complex. Studies in mammalian systems confirmed that the small molecules inhibit muscarinic G-protein coupled receptor (GPCR) signaling involving G-αq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-αq signaling complex, and define new mutations in both RGS and G-αq, including a unique hypo-adapation allele of G-αq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation. PMID:16683034

Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3.

PubMed

Korenke, Georg-Christoph; Eggert, Marlene; Thiele, Holger; Nürnberg, Peter; Sander, Thomas; Steinlein, Ortrud K

2016-03-01

Mutations in NPRL3, one of three genes that encode proteins of the mTORC1-regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel- or DEPDC5-associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Understanding Plant Nitrogen Metabolism through Metabolomics and Computational Approaches

PubMed Central

Beatty, Perrin H.; Klein, Matthias S.; Fischer, Jeffrey J.; Lewis, Ian A.; Muench, Douglas G.; Good, Allen G.

2016-01-01

A comprehensive understanding of plant metabolism could provide a direct mechanism for improving nitrogen use efficiency (NUE) in crops. One of the major barriers to achieving this outcome is our poor understanding of the complex metabolic networks, physiological factors, and signaling mechanisms that affect NUE in agricultural settings. However, an exciting collection of computational and experimental approaches has begun to elucidate whole-plant nitrogen usage and provides an avenue for connecting nitrogen-related phenotypes to genes. Herein, we describe how metabolomics, computational models of metabolism, and flux balance analysis have been harnessed to advance our understanding of plant nitrogen metabolism. We introduce a model describing the complex flow of nitrogen through crops in a real-world agricultural setting and describe how experimental metabolomics data, such as isotope labeling rates and analyses of nutrient uptake, can be used to refine these models. In summary, the metabolomics/computational approach offers an exciting mechanism for understanding NUE that may ultimately lead to more effective crop management and engineered plants with higher yields. PMID:27735856

Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

PubMed

Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M

2013-05-10

A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

Coevolutionary dynamics of phenotypic diversity and contingent cooperation

PubMed Central

Wang, Long

2017-01-01

Phenotypic diversity is considered beneficial to the evolution of contingent cooperation, in which cooperators channel their help preferentially towards others of similar phenotypes. However, it remains largely unclear how phenotypic variation arises in the first place and thus leads to the construction of phenotypic complexity. Here we propose a mathematical model to study the coevolutionary dynamics of phenotypic diversity and contingent cooperation. Unlike previous models, our model does not assume any prescribed level of phenotypic diversity, but rather lets it be an evolvable trait. Each individual expresses one phenotype at a time and only the phenotypes expressed are visible to others. Moreover, individuals can differ in their potential of phenotypic variation, which is characterized by the number of distinct phenotypes they can randomly switch to. Each individual incurs a cost proportional to the number of potentially expressible phenotypes so as to retain phenotypic variation and expression. Our results show that phenotypic diversity coevolves with contingent cooperation under a wide range of conditions and that there exists an optimal level of phenotypic diversity best promoting contingent cooperation. It pays for contingent cooperators to elevate their potential of phenotypic variation, thereby increasing their opportunities of establishing cooperation via novel phenotypes, as these new phenotypes serve as secret tags that are difficult for defector to discover and chase after. We also find that evolved high levels of phenotypic diversity can occasionally collapse due to the invasion of defector mutants, suggesting that cooperation and phenotypic diversity can mutually reinforce each other. Thus, our results provide new insights into better understanding the coevolution of cooperation and phenotypic diversity. PMID:28141806

AtSIG6 and other members of the sigma gene family jointly but differentially determine plastid target gene expression in Arabidopsis thaliana

PubMed Central

Bock, Sylvia; Ortelt, Jennifer; Link, Gerhard

2014-01-01

Plants contain a nuclear gene family for plastid sigma factors, i.e., proteins that associate with the “bacterial-type” organellar RNA polymerase and confer the ability for correct promoter binding and transcription initiation. Questions that are still unresolved relate to the “division of labor” among members of the sigma family, both in terms of their range of target genes and their temporal and spatial activity during development. Clues to the in vivo role of individual sigma genes have mainly come from studies of sigma knockout lines. Despite its obvious strengths, however, this strategy does not necessarily trace-down causal relationships between mutant phenotype and a single sigma gene, if other family members act in a redundant and/or compensatory manner. We made efforts to reduce the complexity by genetic crosses of Arabidopsis single mutants (with focus on a chlorophyll-deficient sig6 line) to generate double knockout lines. The latter typically had a similar visible phenotype as the parental lines, but tended to be more strongly affected in the transcript patterns of both plastid and sigma genes. Because triple mutants were lethal under our growth conditions, we exploited a strategy of transformation of single and double mutants with RNAi constructs that contained sequences from the unconserved sigma region (UCR). These RNAi/knockout lines phenotypically resembled their parental lines, but were even more strongly affected in their plastid transcript patterns. Expression patterns of sigma genes revealed both similarities and differences compared to the parental lines, with transcripts at reduced or unchanged amounts and others that were found to be present in higher (perhaps compensatory) amounts. Together, our results reveal considerable flexibility of gene activity at the levels of both sigma and plastid gene expression. A (still viable) “basal state” seems to be reached, if 2–3 of the 6 Arabidopsis sigma genes are functionally compromised. PMID:25505479

Asymmetric Facial Bone Fragmentation Mirrors Asymmetric Distribution of Cranial Neuromasts in Blind Mexican Cavefish.

PubMed

Gross, Joshua B; Gangidine, Andrew; Powers, Amanda K

2016-11-01

Craniofacial asymmetry is a convergent trait widely distributed across animals that colonize the extreme cave environment. Although craniofacial asymmetry can be discerned easily, other complex phenotypes (such as sensory organ position and numerical variation) are challenging to score and compare. Certain bones of the craniofacial complex demonstrate substantial asymmetry, and co-localize to regions harboring dramatically expanded numbers of mechanosensory neuromasts. To determine if a relationship exists between this expansion and bone fragmentation in cavefish, we developed a quantitative measure of positional symmetry across the left-right axis. We found that three different cave-dwelling populations were significantly more asymmetric compared to surface-dwelling fish. Moreover, cave populations did not differ in the degree of neuromast asymmetry. This work establishes a method for quantifying symmetry of a complex phenotype, and demonstrates that facial bone fragmentation mirrors the asymmetric distribution of neuromasts in different cavefish populations. Further developmental studies will provide a clearer picture of the developmental and cellular changes that accompany this extreme phenotype, and help illuminate the genetic basis for facial asymmetry in vertebrates.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PubMed

Allen, R C; Russell, S R; Streb, L M; Alsheikheh, A; Stone, E M

2006-02-01

To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. Longitudinal cohort study. A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

PubMed

Brinkmeyer-Langford, Candice; Balog-Alvarez, Cynthia; Cai, James J; Davis, Brian W; Kornegay, Joe N

2016-08-22

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.

Precision and Error of Three-dimensional Phenotypic Measures Acquired from 3dMD Photogrammetric Images

PubMed Central

Aldridge, Kristina; Boyadjiev, Simeon A.; Capone, George T.; DeLeon, Valerie B.; Richtsmeier, Joan T.

2015-01-01

The genetic basis for complex phenotypes is currently of great interest for both clinical investigators and basic scientists. In order to acquire a thorough understanding of the translation from genotype to phenotype, highly precise measures of phenotypic variation are required. New technologies, such as 3D photogrammetry are being implemented in phenotypic studies due to their ability to collect data rapidly and non-invasively. Before these systems can be broadly implemented the error associated with data collected from images acquired using these technologies must be assessed. This study investigates the precision, error, and repeatability associated with anthropometric landmark coordinate data collected from 3D digital photogrammetric images acquired with the 3dMDface System. Precision, error due to the imaging system, error due to digitization of the images, and repeatability are assessed in a sample of children and adults (N=15). Results show that data collected from images with the 3dMDface System are highly repeatable and precise. The average error associated with the placement of landmarks is sub-millimeter; both the error due to digitization and to the imaging system are very low. The few measures showing a higher degree of error include those crossing the labial fissure, which are influenced by even subtle movement of the mandible. These results suggest that 3D anthropometric data collected using the 3dMDface System are highly reliable and therefore useful for evaluation of clinical dysmorphology and surgery, analyses of genotype-phenotype correlations, and inheritance of complex phenotypes. PMID:16158436

A functional U-statistic method for association analysis of sequencing data.

PubMed

Jadhav, Sneha; Tong, Xiaoran; Lu, Qing

2017-11-01

Although sequencing studies hold great promise for uncovering novel variants predisposing to human diseases, the high dimensionality of the sequencing data brings tremendous challenges to data analysis. Moreover, for many complex diseases (e.g., psychiatric disorders) multiple related phenotypes are collected. These phenotypes can be different measurements of an underlying disease, or measurements characterizing multiple related diseases for studying common genetic mechanism. Although jointly analyzing these phenotypes could potentially increase the power of identifying disease-associated genes, the different types of phenotypes pose challenges for association analysis. To address these challenges, we propose a nonparametric method, functional U-statistic method (FU), for multivariate analysis of sequencing data. It first constructs smooth functions from individuals' sequencing data, and then tests the association of these functions with multiple phenotypes by using a U-statistic. The method provides a general framework for analyzing various types of phenotypes (e.g., binary and continuous phenotypes) with unknown distributions. Fitting the genetic variants within a gene using a smoothing function also allows us to capture complexities of gene structure (e.g., linkage disequilibrium, LD), which could potentially increase the power of association analysis. Through simulations, we compared our method to the multivariate outcome score test (MOST), and found that our test attained better performance than MOST. In a real data application, we apply our method to the sequencing data from Minnesota Twin Study (MTS) and found potential associations of several nicotine receptor subunit (CHRN) genes, including CHRNB3, associated with nicotine dependence and/or alcohol dependence. © 2017 WILEY PERIODICALS, INC.

CONAN: copy number variation analysis software for genome-wide association studies

PubMed Central

2010-01-01

Background Genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs) promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs. Results CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data. Conclusions CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at. PMID:20546565

A generalized association test based on U statistics.

PubMed

Wei, Changshuai; Lu, Qing

2017-07-01

Second generation sequencing technologies are being increasingly used for genetic association studies, where the main research interest is to identify sets of genetic variants that contribute to various phenotypes. The phenotype can be univariate disease status, multivariate responses and even high-dimensional outcomes. Considering the genotype and phenotype as two complex objects, this also poses a general statistical problem of testing association between complex objects. We here proposed a similarity-based test, generalized similarity U (GSU), that can test the association between complex objects. We first studied the theoretical properties of the test in a general setting and then focused on the application of the test to sequencing association studies. Based on theoretical analysis, we proposed to use Laplacian Kernel-based similarity for GSU to boost power and enhance robustness. Through simulation, we found that GSU did have advantages over existing methods in terms of power and robustness. We further performed a whole genome sequencing (WGS) scan for Alzherimer's disease neuroimaging initiative data, identifying three genes, APOE , APOC1 and TOMM40 , associated with imaging phenotype. We developed a C ++ package for analysis of WGS data using GSU. The source codes can be downloaded at https://github.com/changshuaiwei/gsu . weichangshuai@gmail.com ; qlu@epi.msu.edu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Phenotypic changes in laboratory-reared colonies of the maize herbivore, Diabrotica virgifera virgifera

USDA-ARS?s Scientific Manuscript database

The North American and European maize pest Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae) was used to assess whether environmental conditions of the natal field, subsequent laboratory rearing, or genetic population characteristics affect phenotypic traits of fitness, activity, or...

Approaches for geospatial processing of field-based high-throughput plant phenomics data from ground vehicle platforms

USDA-ARS?s Scientific Manuscript database

Understanding the genetic basis of complex plant traits requires connecting genotype to phenotype information, known as the “G2P question.” In the last three decades, genotyping methods have become highly developed. Much less innovation has occurred for measuring plant traits (phenotyping), particul...

Obesity Differentially Affects Phenotypes of Polycystic Ovary Syndrome

PubMed Central

Moran, Carlos; Arriaga, Monica; Rodriguez, Gustavo; Moran, Segundo

2012-01-01

Obesity or overweight affect most of patients with polycystic ovary syndrome (PCOS). Phenotypes are the clinical characteristics produced by the interaction of heredity and environment in a disease or syndrome. Phenotypes of PCOS have been described on the presence of clinical hyperandrogenism, oligoovulation and polycystic ovaries. The insulin resistance is present in the majority of patients with obesity and/or PCOS and it is more frequent and of greater magnitude in obese than in non obese PCOS patients. Levels of sexual hormone binding globulin are decreased, and levels of free androgens are increased in obese PCOS patients. Weight loss treatment is important for overweight or obese PCOS patients, but not necessary for normal weight PCOS patients, who only need to avoid increasing their body weight. Obesity decreases or delays several infertility treatments. The differences in the hormonal and metabolic profile, as well as the different focus and response to treatment between obese and non obese PCOS patients suggest that obesity has to be considered as a characteristic for classification of PCOS phenotypes. PMID:22829818

Phenotypic landscape inference reveals multiple evolutionary paths to C4 photosynthesis

PubMed Central

Williams, Ben P; Johnston, Iain G; Covshoff, Sarah; Hibberd, Julian M

2013-01-01

C4 photosynthesis has independently evolved from the ancestral C3 pathway in at least 60 plant lineages, but, as with other complex traits, how it evolved is unclear. Here we show that the polyphyletic appearance of C4 photosynthesis is associated with diverse and flexible evolutionary paths that group into four major trajectories. We conducted a meta-analysis of 18 lineages containing species that use C3, C4, or intermediate C3–C4 forms of photosynthesis to parameterise a 16-dimensional phenotypic landscape. We then developed and experimentally verified a novel Bayesian approach based on a hidden Markov model that predicts how the C4 phenotype evolved. The alternative evolutionary histories underlying the appearance of C4 photosynthesis were determined by ancestral lineage and initial phenotypic alterations unrelated to photosynthesis. We conclude that the order of C4 trait acquisition is flexible and driven by non-photosynthetic drivers. This flexibility will have facilitated the convergent evolution of this complex trait. DOI: http://dx.doi.org/10.7554/eLife.00961.001 PMID:24082995

Examination of Clock and Adcyap1 gene variation in a neotropical migratory passerine

PubMed Central

Bridge, Eli S.; Ross, Jeremy D.; Shipley, J. Ryan; Kelly, Jeffrey F.

2018-01-01

Complex behavioral traits, such as those making up a migratory phenotype, are regulated by multiple environmental factors and multiple genes. We investigated possible relationships between microsatellite variation at two candidate genes implicated in the control of migratory behavior, Clock and Adcyap1, and several aspects of migratory life-history and evolutionary divergence in the Painted Bunting (Passerina ciris), a species that shows wide variation in migratory and molting strategies across a disjunct distribution. We focused on Clock and Adcyap1 microsatellite variation across three Painted Bunting populations in Oklahoma, Louisiana, and North Carolina, and for the Oklahoma breeding population we used published migration tracking data on adult males to explore phenotypic variation in individual migratory behavior. We found no correlation between microsatellite allele size within either Clock and Adcyap1 relative to the initiation or duration of fall migration in adult males breeding in Oklahoma. We also show the lack of significant correlations with aspects of the migratory phenotype for the Louisiana population. Our research highlights the limitations of studying microsatellite allelic mutations that are of undetermined functional influence relative to complex behavioral phenotypes. PMID:29324772

Understanding the Etiology of Complex Traits: Symbiotic Relationships between Psychology and Genetics

ERIC Educational Resources Information Center

Grigorenko, Elena L.

2007-01-01

The present article offers comments on the infusion of methodologies, approaches, reasoning strategies, and findings from the fields of genetics and genomics into studies of complex human behaviors (hereafter, complex phenotypes). Specifically, I discuss issues of generality and specificity, causality, and replicability as they pertain to…

Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib).

PubMed

Bastepe, Murat; Altug-Teber, Ozge; Agarwal, Chhavi; Oberfield, Sharon E; Bonin, Michael; Jüppner, Harald

2011-03-01

Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end-organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype. Copyright © 2010 Elsevier Inc. All rights reserved.

Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies.

PubMed

Barbato, Ersilia; Traversa, Alice; Guarnieri, Rosanna; Giovannetti, Agnese; Genovesi, Maria Luce; Magliozzi, Maria Rosa; Paolacci, Stefano; Ciolfi, Andrea; Pizzi, Simone; Di Giorgio, Roberto; Tartaglia, Marco; Pizzuti, Antonio; Caputo, Viviana

2018-07-01

The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity. Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis. Prioritization of variants "by function" allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C>T, p.Ser103Phe) and COL5A1 (c.1588G>A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines. This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium-sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development. Copyright © 2018 Elsevier Ltd. All rights reserved.

Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.

PubMed

Deml, B; Reis, L M; Maheshwari, M; Griffis, C; Bick, D; Semina, E V

2014-11-01

Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

RAPTOR controls developmental growth transitions by altering the hormonal and metabolic balance.

PubMed

Salem, Mohamed A; Li, Yan; Bajdzienko, Krzysztof; Fisahn, Joachim; Watanabe, Mutsumi; Hoefgen, Rainer; Schöttler, Mark Aurel; Giavalisco, Patrick

2018-04-23

Vegetative growth requires the systemic coordination of numerous cellular processes, which are controlled by regulatory proteins that monitor extra- and intra-cellular cues and translate them into growth decisions. In eukaryotes, one of the central factors regulating growth is the Ser/Thr protein kinase Target of Rapamycin (TOR), which forms complexes with regulatory proteins. To understand the function of one such regulatory protein, Regulatory-Associated Protein of TOR 1B (RAPTOR1B) in plants, we analyzed the effect of raptor1b mutations on growth and physiology in Arabidopsis thaliana by detailed phenotyping, metabolomic, lipidomic, and proteomic analysis. Mutation of RAPTR1B resulted in a strong reduction of TOR kinase activity, leading to massive changes in central carbon and nitrogen metabolism, accumulation of excess starch, and induction of autophagy. These shifts led to a significant, reduction of plant growth that occurred non-linearly during developmental stage transtions.. This phenotype was accompanied by changes in cell morphology and tissue anatomy. In contrast to previous studies in rice, we found that the Arabidopsis raptor1b mutation did not affect chloroplast development or photosynthetic electron transport efficiency; however, it resulted in decreased CO2 assimilation rate and increased stomatal conductance. The raptor1b mutants also had reduced abscisic acid levels. Surprisingly, ABA feeding experiments resulted in partial complementation of the growth phenotypes, indicating the tight interaction between TOR function and hormone synthesis and signaling in plants. {copyright, serif} 2018 American Society of Plant Biologists. All rights reserved.

Linking amphibian call structure to the environment: the interplay between phenotypic flexibility and individual attributes

PubMed Central

Arim, Matías; Narins, Peter M.

2011-01-01

The structure of the environment surrounding signal emission produces different patterns of degradation and attenuation. The expected adjustment of calls to ensure signal transmission in an environment was formalized in the acoustic adaptation hypothesis. Within this framework, most studies considered anuran calls as fixed attributes determined by local adaptations. However, variability in vocalizations as a product of phenotypic expression has also been reported. Empirical evidence supporting the association between environment and call structure has been inconsistent, particularly in anurans. Here, we identify a plausible causal structure connecting environment, individual attributes, and temporal and spectral adjustments as direct or indirect determinants of the observed variation in call attributes of the frog Hypsiboas pulchellus. For that purpose, we recorded the calls of 40 males in the field, together with vegetation density and other environmental descriptors of the calling site. Path analysis revealed a strong effect of habitat structure on the temporal parameters of the call, and an effect of site temperature conditioning the size of organisms calling at each site and thus indirectly affecting the dominant frequency of the call. Experimental habitat modification with a styrofoam enclosure yielded results consistent with field observations, highlighting the potential role of call flexibility on detected call patterns. Both, experimental and correlative results indicate the need to incorporate the so far poorly considered role of phenotypic plasticity in the complex connection between environmental structure and individual call attributes. PMID:22479134

Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster

PubMed Central

Iyer, Janani; Wang, Qingyu; Le, Thanh; Pizzo, Lucilla; Grönke, Sebastian; Ambegaokar, Surendra S.; Imai, Yuzuru; Srivastava, Ashutosh; Troisí, Beatriz Llamusí; Mardon, Graeme; Artero, Ruben; Jackson, George R.; Isaacs, Adrian M.; Partridge, Linda; Lu, Bingwei; Kumar, Justin P.; Girirajan, Santhosh

2016-01-01

About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (http://flynotyper.sourceforge.net), to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes. Flynotyper utilizes a series of image processing operations to automatically detect the fly eye and the individual ommatidium, and calculates a phenotypic score as a measure of the disorderliness of ommatidial arrangement in the fly eye. As a proof of principle, we tested our method by analyzing the defects due to eye-specific knockdown of Drosophila orthologs of 12 neurodevelopmental genes to accurately document differential sensitivities of these genes to dosage alteration. We also evaluated eye images from six independent studies assessing the effect of overexpression of repeats, candidates from peptide library screens, and modifiers of neurotoxicity and developmental processes on eye morphology, and show strong concordance with the original assessment. We further demonstrate the utility of this method by analyzing 16 modifiers of sine oculis obtained from two genome-wide deficiency screens of Drosophila and accurately quantifying the effect of its enhancers and suppressors during eye development. Our method will complement existing assays for eye phenotypes, and increase the accuracy of studies that use fly eyes for functional evaluation of genes and genetic interactions. PMID:26994292

Phenotypic expression of polycystic ovary syndrome in South Asian women.

PubMed

Mehta, Jaya; Kamdar, Vikram; Dumesic, Daniel

2013-03-01

Polycystic ovary syndrome (PCOS) occurs in 6% to 10% of women and, as the most common worldwide endocrinopathy of reproductive-aged women, is linked to a constellation of reproductive and metabolic abnormalities, including anovulatory infertility, hirsutism, acne, and insulin resistance in association with metabolic syndrome. Despite a genetic component to PCOS, ethnicity plays an important role in the phenotypic expression of PCOS, with South Asian PCOS women having more severe reproductive and metabolic symptoms than other ethnic groups. South Asians with PCOS seek medical care at an earlier age for reproductive abnormalities; have a higher degree of hirsutism, infertility, and acne; and experience lower live birth rates following in vitro fertilization than do whites with PCOS. Similarly, South Asians with PCOS have a higher prevalence of insulin resistance and metabolic syndrome than do other PCOS-related ethnic groups of a similar body mass index. Inheritance of PCOS appears to have a complex genetic basis, including genetic differences based on ethnicity, which interact with lifestyle and other environmental factors to affect PCOS phenotypic expression. Obstetricians and Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to state an ethnic difference in reproductive dysfunction between South Asian and white women with polycystic ovary syndrome (PCOS), state an ethnic difference in metabolic dysfunction between South Asian and white women with PCOS, identify a genetic abnormality found in South Asian women with PCOS, and list 2 environmental factors that predispose South Asian women to metabolic dysfunction.

Plant Phenotyping through the Eyes of Complex Systems: Theoretical Considerations

NASA Astrophysics Data System (ADS)

Kim, J.

2017-12-01

Plant phenotyping is an emerging transdisciplinary research which necessitates not only the communication and collaboration of scientists from different disciplines but also the paradigm shift to a holistic approach. Complex system is defined as a system having a large number of interacting parts (or particles, agents), whose interactions give rise to non-trivial properties like self-organization and emergence. Plant ecosystems are complex systems which are continually morphing dynamical systems, i.e. self-organizing hierarchical open systems. Such systems are composed of many subunits/subsystems with nonlinear interactions and feedback. The throughput such as the flow of energy, matter and information is the key control parameter in complex systems. Information theoretic approaches can be used to understand and identify such interactions, structures and dynamics through reductions in uncertainty (i.e. entropy). The theoretical considerations based on network and thermodynamic thinking and exemplary analyses (e.g. dynamic process network, spectral entropy) of the throughput time series will be presented. These can be used as a framework to develop more discipline-specific fundamental approaches to provide tools for the transferability of traits between measurement scales in plant phenotyping. Acknowledgment: This work was funded by the Weather Information Service Engine Program of the Korea Meteorological Administration under Grant KMIPA-2012-0001.

Domestic animals as models for biomedical research.

PubMed

Andersson, Leif

2016-01-01

Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene.

Domestic animals as models for biomedical research

PubMed Central

Andersson, Leif

2016-01-01

Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene. PMID:26479863

Maternal epigenetics and methyl supplements affect agouti gene expression in A{sup vy}/a mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, G.L.; Kodell, R.L.; Cooney, C.A.

Viable yellow (A{sup vy}/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epigenetic mosaics ranging from a yellow phenotype with maximum ectopic agouti overexpression, through a continuum of mottled agouti/yellow phenotypes with partial agouti overexpression, to a pseudoagouti phenotype with minimal ectopic expression. Pseudoagouti A{sup vy}/a mice are lean, healthy, and longer lived than their yellow siblings. Here the authors report that feeding pregnant black a/a dams methyl-supplemented diets alters epigenetic regulation of agouti expression in their offspring, as indicated by increased agouti/black mottling in the direction ofmore » the pseudoagouti phenotype. They also present confirmatory evidence that epigenetic phenotypes are maternally heritable. Thus A{sup vy} expression, already known to be modulated by imprinting, strain-specific modification, and maternal epigenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epigenetic mechanisms, especially DNA methylation, in developing embryos.« less

Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes.

PubMed

Kagami, Masayo; Sekita, Yoichi; Nishimura, Gen; Irie, Masahito; Kato, Fumiko; Okada, Michiyo; Yamamori, Shunji; Kishimoto, Hiroshi; Nakayama, Masahiro; Tanaka, Yukichi; Matsuoka, Kentarou; Takahashi, Tsutomu; Noguchi, Mika; Tanaka, Yoko; Masumoto, Kouji; Utsunomiya, Takeshi; Kouzan, Hiroko; Komatsu, Yumiko; Ohashi, Hirofumi; Kurosawa, Kenji; Kosaki, Kenjirou; Ferguson-Smith, Anne C; Ishino, Fumitoshi; Ogata, Tsutomu

2008-02-01

Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 and maternally expressed genes (MEGs) such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8 (refs. 1,2), together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes. We studied eight individuals (cases 1-8) with a upd(14)pat-like phenotype and three individuals (cases 9-11) with a upd(14)mat-like phenotype in the absence of upd(14) and identified various deletions and epimutations affecting the imprinted region. The results, together with recent mouse data, imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.

Early Detection of Apathetic Phenotypes in Huntington's Disease Knock-in Mice Using Open Source Tools.

PubMed

Minnig, Shawn; Bragg, Robert M; Tiwana, Hardeep S; Solem, Wes T; Hovander, William S; Vik, Eva-Mari S; Hamilton, Madeline; Legg, Samuel R W; Shuttleworth, Dominic D; Coffey, Sydney R; Cantle, Jeffrey P; Carroll, Jeffrey B

2018-02-02

Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington's disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off-the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test Htt Q111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, Htt Q111/+ mice exhibit reduced PR performance at 9-11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies.

Differential translation efficiency of orthologous genes is involved in phenotypic divergence of yeast species.

PubMed

Man, Orna; Pilpel, Yitzhak

2007-03-01

A major challenge in comparative genomics is to understand how phenotypic differences between species are encoded in their genomes. Phenotypic divergence may result from differential transcription of orthologous genes, yet less is known about the involvement of differential translation regulation in species phenotypic divergence. In order to assess translation effects on divergence, we analyzed approximately 2,800 orthologous genes in nine yeast genomes. For each gene in each species, we predicted translation efficiency, using a measure of the adaptation of its codons to the organism's tRNA pool. Mining this data set, we found hundreds of genes and gene modules with correlated patterns of translational efficiency across the species. One signal encompassed entire modules that are either needed for oxidative respiration or fermentation and are efficiently translated in aerobic or anaerobic species, respectively. In addition, the efficiency of translation of the mRNA splicing machinery strongly correlates with the number of introns in the various genomes. Altogether, we found extensive selection on synonymous codon usage that modulates translation according to gene function and organism phenotype. We conclude that, like factors such as transcription regulation, translation efficiency affects and is affected by the process of species divergence.

A System-Level Pathway-Phenotype Association Analysis Using Synthetic Feature Random Forest

PubMed Central

Pan, Qinxin; Hu, Ting; Malley, James D.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2015-01-01

As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The bladder cancer associated pathways we found are both consistent with existing biological knowledge and reveal novel and plausible hypotheses for future biological validations. PMID:24535726

Genotype–phenotype correlations in individuals with pathogenic RERE variants

PubMed Central

Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

2018-01-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

Genotype-phenotype correlations in individuals with pathogenic RERE variants.

PubMed

Jordan, Valerie K; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J; Balci, Tugce B; Carter, Melissa T; Bernat, John A; Moccia, Amanda N; Srivastava, Anshika; Martin, Donna M; Bielas, Stephanie L; Pappas, John; Svoboda, Melissa D; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M; Scaglia, Fernando; Kohler, Jennefer N; Bernstein, Jonathan A; Dries, Annika M; Rosenfeld, Jill A; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H; Bi, Weimin; Scott, Daryl A

2018-05-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. © 2018 Wiley Periodicals, Inc.

X-linked juvenile retinoschisis in a consanguineous family: phenotypic variability and report of a homozygous female patient.

PubMed

Gliem, Martin; Holz, Frank G; Stöhr, Heidi; Weber, Bernhard H F; Charbel Issa, Peter

2014-12-01

To describe the phenotypic variability in a consanguineous family with genetically confirmed X-linked retinoschisis. Five patients, including one homozygous female, were characterized by clinical examination, optical coherence tomography, fundus autofluorescence, mapping of macular pigment optical density, electroretinography, and DNA testing. The 36-year-old male index patient showed a ring of enhanced autofluorescence and outer retinal atrophy on optical coherence tomography. Electroretinography testing revealed a reduced a/b ratio. His mother presented with a central atrophic retina with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. The 40-year-old brother of the index patient and his 2 sons showed characteristic signs for X-linked retinoschisis, including retinal schisis and a reduced a/b ratio. Genetic testing revealed a c.293C>A mutation in the RS1 gene in all affected family members while the mother of the index patient was homozygous for this mutation. X-linked retinoschisis can present with a wide phenotypic variability. Here, detailed family history and genetic testing established the diagnosis of X-linked retinoschisis despite striking differences in phenotypic presentation in affected subjects, homozygosity of one affected female, and seemingly dominant inheritance in three subsequent generations because of multiple consanguinity.

Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions

PubMed Central

Kraakman-van der Zwet, Maria; Overkamp, Wilhelmina J. I.; van Lange, Rebecca E. E.; Essers, Jeroen; van Duijn-Goedhart, Annemarie; Wiggers, Ingrid; Swaminathan, Srividya; van Buul, Paul P. W.; Errami, Abdellatif; Tan, Raoul T. L.; Jaspers, Nicolaas G. J.; Sharan, Shyam K.; Kanaar, Roland; Zdzienicka, Małgorzata Z.

2002-01-01

We show here that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2. The very complex phenotype of V-C8 cells is complemented by a single human chromosome 13 providing the BRCA2 gene, as well as by the murine Brca2 gene. The Brca2 deficiency in V-C8 cells causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents. Furthermore, V-C8 cells show radioresistant DNA synthesis after ionizing radiation, suggesting that Brca2 deficiency affects cell cycle checkpoint regulation. In addition, V-C8 cells display tremendous chromosomal instability and a high frequency of abnormal centrosomes. The mutation spectrum at the hprt locus showed that the majority of spontaneous mutations in V-C8 cells are deletions, in contrast to wild-type V79 cells. A mechanistic explanation for the genome instability phenotype of Brca2-deficient cells is provided by the observation that the nuclear localization of the central DNA repair protein in homologous recombination, Rad51, is reduced in V-C8 cells. PMID:11756561

Bioelectric modulation of macrophage polarization

NASA Astrophysics Data System (ADS)

Li, Chunmei; Levin, Michael; Kaplan, David L.

2016-02-01

Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. The native roles of polarized macrophages encompass biomaterials and tissue remodeling needs, yet harnessing or directing the polarization response has been largely absent as a potential strategy to exploit in regenerative medicine to date. Recent data have revealed that specific alteration of cells’ resting potential (Vmem) is a powerful tool to direct proliferation and differentiation in a number of complex tissues, such as limb regeneration, craniofacial patterning and tumorigenesis. In this study, we explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP). Glibenclamide (KATP blocker) and pinacidil (KATP opener) treatment not only affect macrophage polarization, but also influence the phenotype of prepolarized macrophages. Furthermore, modulation of cell membrane electrical properties can fine-tune macrophage plasticity. Glibenclamide decreased the secretion and gene expression of selected M1 markers, while pinacidil augmented M1 markers. More interestingly, glibencalmide promoted macrophage alternative activation by enhancing certain M2 markers during M2 polarization. These findings suggest that control of bioelectric properties of macrophages could offer a promising approach to regulate macrophage phenotype as a useful tool in regenerative medicine.

Evolution of Functional Diversification within Quasispecies

PubMed Central

Colizzi, Enrico Sandro; Hogeweg, Paulien

2014-01-01

According to quasispecies theory, high mutation rates limit the amount of information genomes can store (Eigen’s Paradox), whereas genomes with higher degrees of neutrality may be selected even at the expenses of higher replication rates (the “survival of the flattest” effect). Introducing a complex genotype to phenotype map, such as RNA folding, epitomizes such effect because of the existence of neutral networks and their exploitation by evolution, affecting both population structure and genome composition. We reexamine these classical results in the light of an RNA-based system that can evolve its own ecology. Contrary to expectations, we find that quasispecies evolving at high mutation rates are steep and characterized by one master sequence. Importantly, the analysis of the system and the characterization of the evolved quasispecies reveal the emergence of functionalities as phenotypes of nonreplicating genotypes, whose presence is crucial for the overall viability and stability of the system. In other words, the master sequence codes for the information of the entire ecosystem, whereas the decoding happens, stochastically, through mutations. We show that this solution quickly outcompetes strategies based on genomes with a high degree of neutrality. In conclusion, individually coded but ecosystem-based diversity evolves and persists indefinitely close to the Information Threshold. PMID:25056399

The Pseudomonas aeruginosa AlgZR two-component system coordinates multiple phenotypes

PubMed Central

Okkotsu, Yuta; Little, Alexander S.; Schurr, Michael J.

2014-01-01

Pseudomonas aeruginosa is an opportunistic pathogen that causes a multitude of infections. These infections can occur at almost any site in the body and are usually associated with a breach of the innate immune system. One of the prominent sites where P. aeruginosa causes chronic infections is within the lungs of cystic fibrosis patients. P. aeruginosa uses two-component systems that sense environmental changes to differentially express virulence factors that cause both acute and chronic infections. The P. aeruginosa AlgZR two component system is one of its global regulatory systems that affects the organism's fitness in a broad manner. This two-component system is absolutely required for two P. aeruginosa phenotypes: twitching motility and alginate production, indicating its importance in both chronic and acute infections. Additionally, global transcriptome analyses indicate that it regulates the expression of many different genes, including those associated with quorum sensing, type IV pili, type III secretion system, anaerobic metabolism, cyanide and rhamnolipid production. This review examines the complex AlgZR regulatory network, what is known about the structure and function of each protein, and how it relates to the organism's ability to cause infections. PMID:24999454

RomA, A Periplasmic Protein Involved in the Synthesis of the Lipopolysaccharide, Tunes Down the Inflammatory Response Triggered by Brucella.

PubMed

Valguarnera, Ezequiel; Spera, Juan M; Czibener, Cecilia; Fulgenzi, Fabiana R; Casabuono, Adriana C; Altabe, Silvia G; Pasquevich, Karina A; Guaimas, Francisco; Cassataro, Juliana; Couto, Alicia S; Ugalde, Juan E

2018-03-28

Brucellaceae are stealthy pathogens with the ability to survive and replicate in the host in the context of a strong immune response. This capacity relies on several virulence factors that are able to modulate the immune system and in their structural components that have low proinflammatory activities. Lipopolysaccharide (LPS), the main component of the outer membrane, is a central virulence factor of Brucella, and it has been well established that it induces a low inflammatory response. We describe here the identification and characterization of a novel periplasmic protein (RomA) conserved in alpha-proteobacteria, which is involved in the homeostasis of the outer membrane. A mutant in this gene showed several phenotypes, such as membrane defects, altered LPS composition, reduced adhesion, and increased virulence and inflammation. We show that RomA is involved in the synthesis of LPS, probably coordinating part of the biosynthetic complex in the periplasm. Its absence alters the normal synthesis of this macromolecule and affects the homeostasis of the outer membrane, resulting in a strain with a hyperinflammatory phenotype. Our results suggest that the proper synthesis of LPS is central to maximize virulence and minimize inflammation.

Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis

PubMed Central

Aldridge, Bree B; Gaudet, Suzanne; Lauffenburger, Douglas A; Sorger, Peter K

2011-01-01

Receptor-mediated apoptosis proceeds via two pathways: one requiring only a cascade of initiator and effector caspases (type I behavior) and the second requiring an initiator–effector caspase cascade and mitochondrial outer membrane permeabilization (type II behavior). Here, we investigate factors controlling type I versus II phenotypes by performing Lyapunov exponent analysis of an ODE-based model of cell death. The resulting phase diagrams predict that the ratio of XIAP to pro-caspase-3 concentrations plays a key regulatory role: type I behavior predominates when the ratio is low and type II behavior when the ratio is high. Cell-to-cell variability in phenotype is observed when the ratio is close to the type I versus II boundary. By positioning multiple tumor cell lines on the phase diagram we confirm these predictions. We also extend phase space analysis to mutations affecting the rate of caspase-3 ubiquitylation by XIAP, predicting and showing that such mutations abolish all-or-none control over activation of effector caspases. Thus, phase diagrams derived from Lyapunov exponent analysis represent a means to study multi-factorial control over a complex biochemical pathway. PMID:22108795

Avian phenotypic traits related to feeding preferences in two Culex mosquitoes

NASA Astrophysics Data System (ADS)

Yan, Jiayue; Gangoso, Laura; Martínez-de la Puente, Josué; Soriguer, Ramón; Figuerola, Jordi

2017-10-01

Host choice by mosquitoes affects the transmission dynamics of vector-borne infectious diseases. Although asymmetries in mosquito attraction to vertebrate species have been reported, the relative importance of host characteristics in mosquito blood-feeding behavior is still poorly studied. Here, we investigate the relationship between avian phenotypic traits—in particular, morphometry, plumage coloration, and nesting and roosting behavior—and the blood-feeding patterns in two common Culex mosquito species on a North American avian community. Forage ratios of the mosquito species were unrelated to the phylogenetic relationships among bird species. Culex pipiens fed preferably on birds with lighter-colored plumage and longer tarsi; furthermore, solitary roosting avian species were both bitten by Cx. pipiens and Cx. restuans more often than expected. These associations may be explained by greater mosquito attraction towards larger birds with a greater color contrast against the background. Although communally roosting birds may release more cues and attract more mosquitoes, individuals may in fact receive fewer bites due to the encounter-dilution effect. Mosquito feeding behavior is a highly complex phenomenon, and our results may improve understanding of the non-random interaction between birds and mosquitoes in natural communities.

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.

PubMed

Fenwick, Aimee L; Kliszczak, Maciej; Cooper, Fay; Murray, Jennie; Sanchez-Pulido, Luis; Twigg, Stephen R F; Goriely, Anne; McGowan, Simon J; Miller, Kerry A; Taylor, Indira B; Logan, Clare; Bozdogan, Sevcan; Danda, Sumita; Dixon, Joanne; Elsayed, Solaf M; Elsobky, Ezzat; Gardham, Alice; Hoffer, Mariette J V; Koopmans, Marije; McDonald-McGinn, Donna M; Santen, Gijs W E; Savarirayan, Ravi; de Silva, Deepthi; Vanakker, Olivier; Wall, Steven A; Wilson, Louise C; Yuregir, Ozge Ozalp; Zackai, Elaine H; Ponting, Chris P; Jackson, Andrew P; Wilkie, Andrew O M; Niedzwiedz, Wojciech; Bicknell, Louise S

2016-07-07

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

PubMed Central

Knierim, Ellen; Hirata, Hiromi; Wolf, Nicole I.; Morales-Gonzalez, Susanne; Schottmann, Gudrun; Tanaka, Yu; Rudnik-Schöneborn, Sabine; Orgeur, Mickael; Zerres, Klaus; Vogt, Stefanie; van Riesen, Anne; Gill, Esther; Seifert, Franziska; Zwirner, Angelika; Kirschner, Janbernd; Goebel, Hans Hilmar; Hübner, Christoph; Stricker, Sigmar; Meierhofer, David; Stenzel, Werner; Schuelke, Markus

2016-01-01

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system. PMID:26924529

Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster

PubMed Central

Maier, Dieter; Kurth, Patricia; Schulz, Adriana; Russell, Andrew; Yuan, Zhenyu; Gruber, Kim; Kovall, Rhett A.; Preiss, Anette

2011-01-01

In metazoans, the highly conserved Notch pathway drives cellular specification. On receptor activation, the intracellular domain of Notch assembles a transcriptional activator complex that includes the DNA-binding protein CSL, a composite of human C-promoter binding factor 1, Suppressor of Hairless of Drosophila melanogaster [Su(H)], and lin-12 and Glp-1 phenotype of Caenorhabditis elegans. In the absence of ligand, CSL represses Notch target genes. However, despite the structural similarity of CSL orthologues, repression appears largely diverse between organisms. Here we analyze the Notch repressor complex in Drosophila, consisting of the fly CSL protein, Su(H), and the corepressor Hairless, which recruits general repressor proteins. We show that the C-terminal domain of Su(H) is necessary and sufficient for forming a high-affinity complex with Hairless. Mutations in Su(H) that affect interactions with Notch and Mastermind have no effect on Hairless binding. Nonetheless, we demonstrate that Notch and Hairless compete for CSL in vitro and in cell culture. In addition, we identify a site in Hairless that is crucial for binding Su(H) and subsequently show that this Hairless mutant is strongly impaired, failing to properly assemble the repressor complex in vivo. Finally, we demonstrate Hairless-mediated inhibition of Notch signaling in a cell culture assay, which hints at a potentially similar repression mechanism in mammals that might be exploited for therapeutic purposes. PMID:21737682

Design of synthetic bacterial communities for predictable plant phenotypes

PubMed Central

Herrera Paredes, Sur; Gao, Tianxiang; Law, Theresa F.; Finkel, Omri M.; Mucyn, Tatiana; Teixeira, Paulo José Pereira Lima; Salas González, Isaí; Feltcher, Meghan E.; Powers, Matthew J.; Shank, Elizabeth A.; Jones, Corbin D.; Jojic, Vladimir; Dangl, Jeffery L.; Castrillo, Gabriel

2018-01-01

Specific members of complex microbiota can influence host phenotypes, depending on both the abiotic environment and the presence of other microorganisms. Therefore, it is challenging to define bacterial combinations that have predictable host phenotypic outputs. We demonstrate that plant–bacterium binary-association assays inform the design of small synthetic communities with predictable phenotypes in the host. Specifically, we constructed synthetic communities that modified phosphate accumulation in the shoot and induced phosphate starvation–responsive genes in a predictable fashion. We found that bacterial colonization of the plant is not a predictor of the plant phenotypes we analyzed. Finally, we demonstrated that characterizing a subset of all possible bacterial synthetic communities is sufficient to predict the outcome of untested bacterial consortia. Our results demonstrate that it is possible to infer causal relationships between microbiota membership and host phenotypes and to use these inferences to rationally design novel communities. PMID:29462153

Standards-Based Procedural Phenotyping: The Arden Syntax on i2b2.

PubMed

Mate, Sebastian; Castellanos, Ixchel; Ganslandt, Thomas; Prokosch, Hans-Ulrich; Kraus, Stefan

2017-01-01

Phenotyping, or the identification of patient cohorts, is a recurring challenge in medical informatics. While there are open source tools such as i2b2 that address this problem by providing user-friendly querying interfaces, these platforms lack semantic expressiveness to model complex phenotyping algorithms. The Arden Syntax provides procedural programming language construct, designed specifically for medical decision support and knowledge transfer. In this work, we investigate how language constructs of the Arden Syntax can be used for generic phenotyping. We implemented a prototypical tool to integrate i2b2 with an open source Arden execution environment. To demonstrate the applicability of our approach, we used the tool together with an Arden-based phenotyping algorithm to derive statistics about ICU-acquired hypernatremia. Finally, we discuss how the combination of i2b2's user-friendly cohort pre-selection and Arden's procedural expressiveness could benefit phenotyping.

A Review of Imaging Techniques for Plant Phenotyping

PubMed Central

Li, Lei; Zhang, Qin; Huang, Danfeng

2014-01-01

Given the rapid development of plant genomic technologies, a lack of access to plant phenotyping capabilities limits our ability to dissect the genetics of quantitative traits. Effective, high-throughput phenotyping platforms have recently been developed to solve this problem. In high-throughput phenotyping platforms, a variety of imaging methodologies are being used to collect data for quantitative studies of complex traits related to the growth, yield and adaptation to biotic or abiotic stress (disease, insects, drought and salinity). These imaging techniques include visible imaging (machine vision), imaging spectroscopy (multispectral and hyperspectral remote sensing), thermal infrared imaging, fluorescence imaging, 3D imaging and tomographic imaging (MRT, PET and CT). This paper presents a brief review on these imaging techniques and their applications in plant phenotyping. The features used to apply these imaging techniques to plant phenotyping are described and discussed in this review. PMID:25347588

Characterization and consumer acceptance of three muscles from Hampshire x Rambouillet cross sheep expressing the callipyge phenotype.

PubMed

Kerth, C R; Jackson, S P; Ramsey, C B; Miller, M F

2003-09-01

Eight Hampshire x Rambouillet crossbred wethers expressing the callipyge phenotype and eight Hampshire x Rambouillet half-sibling wethers with a normal phenotype were slaughtered when they reached 59 kg. The supraspinatus (SPM), longissimus (LM), and semitendinosus (STM) muscles were analyzed to determine callipyge effects on calpain and calpastatin activities, sarcomere length, percentage of muscle fiber types, and muscle fiber areas. After 14 d of aging, chops were frozen until analyses for trained sensory panel evaluations, Warner-Bratzler shear force values, and consumer perceptions of tenderness, flavor, juiciness, and overall satisfaction of chops were conducted. Calpastatin activity was 57% greater (P < 0.05) and m-calpain activity was 33% greater (P < 0.05) in muscles from carcasses of callipyge than normal sheep. Sarcomeres were shorter (P < 0.001) in the LM than the SPM or STM, regardless of phenotype. Muscle fiber area was 76% larger (P < 0.05) in the LM of callipyge than normal sheep, but muscle fiber area was not affected (P > 0.05) by phenotype in the SPM or STM. Phenotype had no effect (P = 0.12) on the percentage of slow-twitch, oxidative fiber types in any of the three muscles. In STM and LM from callipyge lambs, the percentage of fast-twitch, oxidative/glycolytic fibers was lower (P < 0.05) and that of fast-twitch-glycolytic fibers was higher (P < 0.05) than in their normal counterparts. Phenotype did not affect (P = 0.90) the fiber type percentage in the SPM. Callipyge LM were less tender and normal LM were more tender than other chops (P < 0.05). Callipyge loin chops had higher Warner-Bratzler shear force values than other chops (P < 0.001). Consumers rated fewer (P < 0.05) callipyge loin and shoulder chops acceptable in juiciness, tenderness, and overall acceptability than normal chops, but phenotype did not affect (P > 0.05) consumer acceptability of leg chops. These results indicate that LM from Hampshire x Rambouillet sheep displaying the callipyge phenotype had higher calpastatin activity and were less tender than the LM from normal sheep. In addition, consumer perceptions indicated that only one in 10 leg chops, one in five shoulder chops, and one in four loin chops from callipyge sheep were unacceptable.

Delineation of behavioral phenotypes in genetic syndromes: characteristics of autism spectrum disorder, affect and hyperactivity.

PubMed

Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

2011-08-01

We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in CdLS and FXS. High levels of impulsivity were seen in SMS, AS, CdCS, FXS and adults with CdLS. Negative affect was prominent in adults with CdLS, while positive affect was prominent in adults with AS and FXS. Heightened levels of overactivity and impulsivity were identified in FXS, AS and SMS while low levels were identified in PWS. These findings confirm and extend previously reported behavioral phenotypes.

FIG4 regulates lysosome membrane homeostasis independent of phosphatase function.

PubMed

Bharadwaj, Rajnish; Cunningham, Kathleen M; Zhang, Ke; Lloyd, Thomas E

2016-02-15

FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

FIG4 regulates lysosome membrane homeostasis independent of phosphatase function

PubMed Central

Bharadwaj, Rajnish; Cunningham, Kathleen M.; Zhang, Ke; Lloyd, Thomas E.

2016-01-01

FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS. PMID:26662798

A Bigger Picture: Organismal Function at the Nexus of Development, Ecology, and Evolution: An Introduction to the Symposium.

PubMed

Gignac, P M; Santana, S E

2016-09-01

Over the past 40 years of research, two perspectives have dominated the study of ecomorphology at ontogenetic and evolutionary timescales. For key anatomical complexes (e.g., feeding apparatus, locomotor systems, sensory structures), morphological changes during ontogeny are often interpreted in functional terms and linked to their putative importance for fitness. Across larger timescales, morphological transformations in these complexes are examined through character stability or mutability during cladogenesis. Because the fittest organisms must pass through ontogenetic changes in size and shape, addressing transformations in morphology at different time scales, from life histories to macroevolution, has the potential to illuminate major factors contributing to phenotypic diversity. To date, most studies have relied on the assumption that organismal form is tightly constrained by the adult niche. Although this could be accurate for organisms that rapidly reach and spend a substantial portion of their life history at the adult phenotype (e.g., birds, mammals), it may not always hold true for species that experience substantial growth after one or more major fitness filters during their ontogeny (e.g., some fishes, reptiles). In such circumstances, examining the adult phenotype as the primary result of selective processes may be erroneous as it likely obscures the developmental configuration of morphology that was most critical to early survival. Given this discrepancy-and its potential to mislead interpretations of how selection may shape a taxon's phenotype-this symposium addresses the question: how do we identify such ontogenetic "inertia," and how do we integrate developmental information into our phylogenetic, ecological, and functional interpretations of complex phenotypes? © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

MicroCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system.

PubMed

Hur, Matthew; Gistelinck, Charlotte A; Huber, Philippe; Lee, Jane; Thompson, Marjorie H; Monstad-Rios, Adrian T; Watson, Claire J; McMenamin, Sarah K; Willaert, Andy; Parichy, David M; Coucke, Paul; Kwon, Ronald Y

2017-09-08

Phenomics, which ideally involves in-depth phenotyping at the whole-organism scale, may enhance our functional understanding of genetic variation. Here, we demonstrate methods to profile hundreds of phenotypic measures comprised of morphological and densitometric traits at a large number of sites within the axial skeleton of adult zebrafish. We show the potential for vertebral patterns to confer heightened sensitivity, with similar specificity, in discriminating mutant populations compared to analyzing individual vertebrae in isolation. We identify phenotypes associated with human brittle bone disease and thyroid stimulating hormone receptor hyperactivity. Finally, we develop allometric models and show their potential to aid in the discrimination of mutant phenotypes masked by alterations in growth. Our studies demonstrate virtues of deep phenotyping in a spatially distributed organ system. Analyzing phenotypic patterns may increase productivity in genetic screens, and facilitate the study of genetic variants associated with smaller effect sizes, such as those that underlie complex diseases.

NUCLEAR FACTOR Y Transcription Factors Have Both Opposing and Additive Roles in ABA-Mediated Seed Germination

PubMed Central

Kumimoto, Roderick W.; Siriwardana, Chamindika L.; Gayler, Krystal K.; Risinger, Jan R.; Siefers, Nicholas; Holt, Ben F.

2013-01-01

In the model organism Arabidopsis thaliana the heterotrimeric transcription factor NUCLEAR FACTOR Y (NF-Y) has been shown to play multiple roles in facilitating plant growth and development. Although NF-Y itself represents a multi-protein transcriptional complex, recent studies have shown important interactions with other transcription factors, especially those in the bZIP family. Here we add to the growing evidence that NF-Y and bZIP form common complexes to affect many processes. We carried out transcriptional profiling on nf-yc mutants and through subsequent analyses found an enrichment of bZIP binding sites in the promoter elements of misregulated genes. Using NF-Y as bait, yeast two hybrid assays yielded interactions with bZIP proteins that are known to control ABA signaling. Accordingly, we find that plants mutant for several NF-Y subunits show characteristic phenotypes associated with the disruption of ABA signaling. While previous reports have shown additive roles for NF-YC family members in photoperiodic flowering, we found that they can have opposing roles in ABA signaling. Collectively, these results demonstrated the importance and complexity of NF-Y in the integration of environmental and hormone signals. PMID:23527203

Global urban signatures of phenotypic change in animal and plant populations

PubMed Central

Correa, Cristian; Marzluff, John M.; Hendry, Andrew P.; Palkovacs, Eric P.; Hunt, Victoria M.; Apgar, Travis M.; Zhou, Yuyu

2017-01-01

Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms. This paper presents evidence on the mechanisms linking urban development patterns to rapid evolutionary changes for species that play important functional roles in communities and ecosystems. Through a metaanalysis of experimental and observational studies reporting more than 1,600 phenotypic changes in species across multiple regions, we ask whether we can discriminate an urban signature of phenotypic change beyond the established natural baselines and other anthropogenic signals. We then assess the relative impact of five types of urban disturbances including habitat modifications, biotic interactions, habitat heterogeneity, novel disturbances, and social interactions. Our study shows a clear urban signal; rates of phenotypic change are greater in urbanizing systems compared with natural and nonurban anthropogenic systems. By explicitly linking urban development to traits that affect ecosystem function, we can map potential ecoevolutionary implications of emerging patterns of urban agglomerations and uncover insights for maintaining key ecosystem functions upon which the sustainability of human well-being depends. PMID:28049817

Global urban signatures of phenotypic change in animal and plant populations.

PubMed

Alberti, Marina; Correa, Cristian; Marzluff, John M; Hendry, Andrew P; Palkovacs, Eric P; Gotanda, Kiyoko M; Hunt, Victoria M; Apgar, Travis M; Zhou, Yuyu

2017-08-22

Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms. This paper presents evidence on the mechanisms linking urban development patterns to rapid evolutionary changes for species that play important functional roles in communities and ecosystems. Through a metaanalysis of experimental and observational studies reporting more than 1,600 phenotypic changes in species across multiple regions, we ask whether we can discriminate an urban signature of phenotypic change beyond the established natural baselines and other anthropogenic signals. We then assess the relative impact of five types of urban disturbances including habitat modifications, biotic interactions, habitat heterogeneity, novel disturbances, and social interactions. Our study shows a clear urban signal; rates of phenotypic change are greater in urbanizing systems compared with natural and nonurban anthropogenic systems. By explicitly linking urban development to traits that affect ecosystem function, we can map potential ecoevolutionary implications of emerging patterns of urban agglomerations and uncover insights for maintaining key ecosystem functions upon which the sustainability of human well-being depends.

Comparative Network-Based Recovery Analysis and Proteomic Profiling of Neurological Changes in Valproic Acid-Treated Mice

PubMed Central

2013-01-01

Despite its prominence for characterization of complex mixtures, LC–MS/MS frequently fails to identify many proteins. Network-based analysis methods, based on protein–protein interaction networks (PPINs), biological pathways, and protein complexes, are useful for recovering non-detected proteins, thereby enhancing analytical resolution. However, network-based analysis methods do come in varied flavors for which the respective efficacies are largely unknown. We compare the recovery performance and functional insights from three distinct instances of PPIN-based approaches, viz., Proteomics Expansion Pipeline (PEP), Functional Class Scoring (FCS), and Maxlink, in a test scenario of valproic acid (VPA)-treated mice. We find that the most comprehensive functional insights, as well as best non-detected protein recovery performance, are derived from FCS utilizing real biological complexes. This outstrips other network-based methods such as Maxlink or Proteomics Expansion Pipeline (PEP). From FCS, we identified known biological complexes involved in epigenetic modifications, neuronal system development, and cytoskeletal rearrangements. This is congruent with the observed phenotype where adult mice showed an increase in dendritic branching to allow the rewiring of visual cortical circuitry and an improvement in their visual acuity when tested behaviorally. In addition, PEP also identified a novel complex, comprising YWHAB, NR1, NR2B, ACTB, and TJP1, which is functionally related to the observed phenotype. Although our results suggest different network analysis methods can produce different results, on the whole, the findings are mutually supportive. More critically, the non-overlapping information each provides can provide greater holistic understanding of complex phenotypes. PMID:23557376

Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation.

PubMed

Domschke, Katharina; Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Herrmann, Martin J; Warrings, Bodo; Mühlberger, Andreas; Wosnitza, Katherina; Dlugos, Andrea; Naunin, Swantje; Nienhaus, Kathrin; Fobker, Manfred; Jacob, Christian; Arolt, Volker; Pauli, Paul; Reif, Andreas; Zwanzger, Peter; Deckert, Jürgen

2012-08-01

Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal and anxiety/panic in animal and human studies. Furthermore, a complex interaction of the neuropeptide S and the adenosinergic system has been suggested with administration of the adenosine A2A receptor antagonist caffeine downregulating NPS levels (Lage et al., 2006) and attenuating the stimulatory effects of NPS in rodents (Boeck et al., 2010). Thus, in the present study, the impact of the functional neuropeptide S receptor (NPSR) A/T (Asn(107)Ile; rs324981) variant on affect-modulated (neutral, unpleasant, and pleasant IAPS pictures) startle response depending on the administration of 300 mg caffeine citrate was investigated in a sample of 124 (m = 58, f = 66) healthy probands using a double-blind, placebo-controlled design. ANOVA revealed a significant interaction between NPSR genotype, challenge condition, and picture valence. Comparing startle magnitudes upon stimulation with neutral or emotional pictures between the placebo and caffeine condition, in AA/AT non-risk genotype carriers no significant difference was discerned, while TT risk genotype carriers showed a significantly increased startle magnitude in response to neutral stimuli (p = .02) and a significantly decreased startle magnitude in response to unpleasant stimuli (p = .02) in the caffeine condition as compared to the placebo condition. In summary, the present findings - extending previous evidence from rodent studies - for the first time provide support for a complex, non-linear interaction of the neuropeptide S and adenosinergic systems affecting the affect-modulated startle response as an intermediate phenotype of anxiety in humans.