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

Inferring causal relationships between phenotypes using summary statistics from genome-wide association studies.

PubMed

Meng, Xiang-He; Shen, Hui; Chen, Xiang-Ding; Xiao, Hong-Mei; Deng, Hong-Wen

2018-03-01

Genome-wide association studies (GWAS) have successfully identified numerous genetic variants associated with diverse complex phenotypes and diseases, and provided tremendous opportunities for further analyses using summary association statistics. Recently, Pickrell et al. developed a robust method for causal inference using independent putative causal SNPs. However, this method may fail to infer the causal relationship between two phenotypes when only a limited number of independent putative causal SNPs identified. Here, we extended Pickrell's method to make it more applicable for the general situations. We extended the causal inference method by replacing the putative causal SNPs with the lead SNPs (the set of the most significant SNPs in each independent locus) and tested the performance of our extended method using both simulation and empirical data. Simulations suggested that when the same number of genetic variants is used, our extended method had similar distribution of test statistic under the null model as well as comparable power under the causal model compared with the original method by Pickrell et al. But in practice, our extended method would generally be more powerful because the number of independent lead SNPs was often larger than the number of independent putative causal SNPs. And including more SNPs, on the other hand, would not cause more false positives. By applying our extended method to summary statistics from GWAS for blood metabolites and femoral neck bone mineral density (FN-BMD), we successfully identified ten blood metabolites that may causally influence FN-BMD. We extended a causal inference method for inferring putative causal relationship between two phenotypes using summary statistics from GWAS, and identified a number of potential causal metabolites for FN-BMD, which may provide novel insights into the pathophysiological mechanisms underlying osteoporosis.

Structural and functional analysis of 5S rRNA in Saccharomyces cerevisiae

PubMed Central

Kiparisov, S.; Sergiev, P. V.; Dontsova, O. A.; Petrov, A.; Meskauskas, A.; Dinman, J. D.

2005-01-01

5S rRNA extends from the central protuberance of the large ribosomal subunit, through the A-site finger, and down to the GTPase-associated center. Here, we present a structure-function analysis of seven 5S rRNA alleles which are sufficient for viability in the yeast Saccharomyces cerevisiae when expressed in the absence of wild-type 5S rRNAs, and extend this analysis using a large bank of mutant alleles that show semidominant phenotypes in the presence of wild-type 5S rRNA. This analysis supports the hypothesis that 5S rRNA serves to link together several different functional centers of the ribosome. Data are also presented which suggest that in eukaryotic genomes selection has favored the maintenance of multiple alleles of 5S rRNA, and that these may provide cells with a mechanism to post-transcriptionally regulate gene expression. PMID:16047201

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

Network biology discovers pathogen contact points in host protein-protein interactomes.

PubMed

Ahmed, Hadia; Howton, T C; Sun, Yali; Weinberger, Natascha; Belkhadir, Youssef; Mukhtar, M Shahid

2018-06-13

In all organisms, major biological processes are controlled by complex protein-protein interactions networks (interactomes), yet their structural complexity presents major analytical challenges. Here, we integrate a compendium of over 4300 phenotypes with Arabidopsis interactome (AI-1 MAIN ). We show that nodes with high connectivity and betweenness are enriched and depleted in conditional and essential phenotypes, respectively. Such nodes are located in the innermost layers of AI-1 MAIN and are preferential targets of pathogen effectors. We extend these network-centric analyses to Cell Surface Interactome (CSI LRR ) and predict its 35 most influential nodes. To determine their biological relevance, we show that these proteins physically interact with pathogen effectors and modulate plant immunity. Overall, our findings contrast with centrality-lethality rule, discover fast information spreading nodes, and highlight the structural properties of pathogen targets in two different interactomes. Finally, this theoretical framework could possibly be applicable to other inter-species interactomes to reveal pathogen contact points.

Using electronic patient records to discover disease correlations and stratify patient cohorts.

PubMed

Roque, Francisco S; Jensen, Peter B; Schmock, Henriette; Dalgaard, Marlene; Andreatta, Massimo; Hansen, Thomas; Søeby, Karen; Bredkjær, Søren; Juul, Anders; Werge, Thomas; Jensen, Lars J; Brunak, Søren

2011-08-01

Electronic patient records remain a rather unexplored, but potentially rich data source for discovering correlations between diseases. We describe a general approach for gathering phenotypic descriptions of patients from medical records in a systematic and non-cohort dependent manner. By extracting phenotype information from the free-text in such records we demonstrate that we can extend the information contained in the structured record data, and use it for producing fine-grained patient stratification and disease co-occurrence statistics. The approach uses a dictionary based on the International Classification of Disease ontology and is therefore in principle language independent. As a use case we show how records from a Danish psychiatric hospital lead to the identification of disease correlations, which subsequently can be mapped to systems biology frameworks.

3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes.

PubMed

Lau, Chew L; Kovacevic, Michelle; Tingleff, Tine S; Forsythe, John S; Cate, Holly S; Merlo, Daniel; Cederfur, Cecilia; Maclean, Francesca L; Parish, Clare L; Horne, Malcolm K; Nisbet, David R; Beart, Philip M

2014-07-01

Astrocytes are a target for regenerative neurobiology because in brain injury their phenotype arbitrates brain integrity, neuronal death and subsequent repair and reconstruction. We explored the ability of 3D scaffolds to direct astrocytes into phenotypes with the potential to support neuronal survival. Poly-ε-caprolactone scaffolds were electrospun with random and aligned fibre orientations on which murine astrocytes were sub-cultured and analysed at 4 and 12 DIV. Astrocytes survived, proliferated and migrated into scaffolds adopting 3D morphologies, mimicking in vivo stellated phenotypes. Cells on random poly-ε-caprolactone scaffolds grew as circular colonies extending processes deep within sub-micron fibres, whereas astrocytes on aligned scaffolds exhibited rectangular colonies with processes following not only the direction of fibre alignment but also penetrating the scaffold. Cell viability was maintained over 12 DIV, and cytochemistry for F-/G-actin showed fewer stress fibres on bioscaffolds relative to 2D astrocytes. Reduced cytoskeletal stress was confirmed by the decreased expression of glial fibrillary acidic protein. PCR demonstrated up-regulation of genes (excitatory amino acid transporter 2, brain-derived neurotrophic factor and anti-oxidant) reflecting healthy biologies of mature astrocytes in our extended culture protocol. This study illustrates the therapeutic potential of bioengineering strategies using 3D electrospun scaffolds which direct astrocytes into phenotypes supporting brain repair. Astrocytes exist in phenotypes with pro-survival and destructive components, and their biology can be modulated by changing phenotype. Our findings demonstrate murine astrocytes adopt a healthy phenotype when cultured in 3D. Astrocytes proliferate and extend into poly-ε-caprolactone scaffolds displaying 3D stellated morphologies with reduced GFAP expression and actin stress fibres, plus a cytotrophic gene profile. Bioengineered 3D scaffolds have potential to direct inflammation to aid regenerative neurobiology. © 2014 International Society for Neurochemistry.

Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation.

PubMed

Eklund, Erik A; Sun, Liangwu; Yang, Samuel P; Pasion, Romela M; Thorland, Erik C; Freeze, Hudson H

2006-01-20

We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation.

Heritability of Tic Disorders: a Twin-Family Study

PubMed Central

Zilhao, Nuno R.; Olthof, Maria C.; Smit, Dirk J.A.; Cath, Danielle C.; Ligthart, Lannie; Mathews, Carol A.; Delucchi, Kevin; Boomsma, Dorret I.; Dolan, Conor V.

2017-01-01

Background Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. Methods In an extended twin-family design, we analyzed lifetime tic data reported by adult mono- and dizygotic twins (n= 8,323) and their family members (n=7,164; parents and siblings) from 7,311 families in the Netherlands Twin Register (NTR). We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes (STOBS) (TSAICG, 2007). Heritability was estimated by genetic Structural Equation Modeling (SEM) for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. Results Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between .25 and .37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment, or non-additive genetic effects. Conclusions Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSMIV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies. PMID:27974054

Does rapid evolution matter? Measuring the rate of contemporary evolution and its impacts on ecological dynamics.

PubMed

Ellner, Stephen P; Geber, Monica A; Hairston, Nelson G

2011-06-01

Rapid contemporary evolution due to natural selection is common in the wild, but it remains uncertain whether its effects are an essential component of community and ecosystem structure and function. Previously we showed how to partition change in a population, community or ecosystem property into contributions from environmental and trait change, when trait change is entirely caused by evolution (Hairston et al. 2005). However, when substantial non-heritable trait change occurs (e.g. due to phenotypic plasticity or change in population structure) that approach can mis-estimate both contributions. Here, we demonstrate how to disentangle ecological impacts of evolution vs. non-heritable trait change by combining our previous approach with the Price Equation. This yields a three-way partitioning into effects of evolution, non-heritable phenotypic change and environment. We extend the approach to cases where ecological consequences of trait change are mediated through interspecific interactions. We analyse empirical examples involving fish, birds and zooplankton, finding that the proportional contribution of rapid evolution varies widely (even among different ecological properties affected by the same trait), and that rapid evolution can be important when it acts to oppose and mitigate phenotypic effects of environmental change. Paradoxically, rapid evolution may be most important when it is least evident. © 2011 Blackwell Publishing Ltd/CNRS.

Exploration of structural stability in deleterious nsSNPs of the XPA gene: A molecular dynamics approach.

PubMed

Nagasundaram, N; Priya Doss, C George

2011-01-01

Distinguishing the deleterious from the massive number of non-functional nsSNPs that occur within a single genome is a considerable challenge in mutation research. In this approach, we have used the existing in silico methods to explore the mutation-structure-function relationship in the XPAgene. We used the Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping (PolyPhen), I-Mutant 2.0, and the Protein Analysis THrough Evolutionary Relationships methods to predict the effects of deleterious nsSNPs on protein function and evaluated the impact of mutation on protein stability by Molecular Dynamics simulations. By comparing the scores of all the four in silico methods, nsSNP with an ID rs104894131 at position C108F was predicted to be highly deleterious. We extended our Molecular dynamics approach to gain insight into the impact of this non-synonymous polymorphism on structural changes that may affect the activity of the XPAgene. Based on the in silico methods score, potential energy, root-mean-square deviation, and root-mean-square fluctuation, we predict that deleterious nsSNP at position C108F would play a significant role in causing disease by the XPA gene. Our approach would present the application of in silicotools in understanding the functional variation from the perspective of structure, evolution, and phenotype.

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.

PubMed

Reid, Emma S; Papandreou, Apostolos; Drury, Suzanne; Boustred, Christopher; Yue, Wyatt W; Wedatilake, Yehani; Beesley, Clare; Jacques, Thomas S; Anderson, Glenn; Abulhoul, Lara; Broomfield, Alex; Cleary, Maureen; Grunewald, Stephanie; Varadkar, Sophia M; Lench, Nick; Rahman, Shamima; Gissen, Paul; Clayton, Peter T; Mills, Philippa B

2016-11-01

Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core with the Development of an Addicted Phenotype

PubMed Central

Doyle, Susan E.; Ramôa, Carolina; Garber, Garrett; Newman, Joshua; Toor, Shaun; Lynch, Wendy J.

2014-01-01

Background While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early “non-addicted” stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug-seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a “non-addicted” or an “addicted” phenotype. Methods Following acquisition, male and female Sprague Dawley rats were given either short access (3 fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hr access (10 days; 4 trials/hr; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate AMPA/KA receptor antagonist CNQX (0.0, 0.01, 0.03, 0.1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short versus extended access self-administration. Results Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended versus short access self-administration confirming the development of an addicted phenotype in the extended access group. CNQX dose-dependently reduced motivation for cocaine in the extended access group, but was without effect in the short access group. Conclusions These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in “non-addicted” stages, becomes critical once addiction has developed. PMID:24629536

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.

Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders.

PubMed

de Goede, Christian; Yue, Wyatt W; Yan, Guanhua; Ariyaratnam, Shyamala; Chandler, Kate E; Downes, Laura; Khan, Nasaim; Mohan, Meyyammai; Lowe, Martin; Banka, Siddharth

2016-03-01

Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Exploration of structural stability in deleterious nsSNPs of the XPA gene: A molecular dynamics approach

PubMed Central

NagaSundaram, N; Priya Doss, C George

2011-01-01

Background: Distinguishing the deleterious from the massive number of non-functional nsSNPs that occur within a single genome is a considerable challenge in mutation research. In this approach, we have used the existing in silico methods to explore the mutation-structure-function relationship in the XPAgene. Materials and Methods: We used the Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping (PolyPhen), I-Mutant 2.0, and the Protein Analysis THrough Evolutionary Relationships methods to predict the effects of deleterious nsSNPs on protein function and evaluated the impact of mutation on protein stability by Molecular Dynamics simulations. Results: By comparing the scores of all the four in silico methods, nsSNP with an ID rs104894131 at position C108F was predicted to be highly deleterious. We extended our Molecular dynamics approach to gain insight into the impact of this non-synonymous polymorphism on structural changes that may affect the activity of the XPAgene. Conclusion: Based on the in silico methods score, potential energy, root-mean-square deviation, and root-mean-square fluctuation, we predict that deleterious nsSNP at position C108F would play a significant role in causing disease by the XPA gene. Our approach would present the application of in silicotools in understanding the functional variation from the perspective of structure, evolution, and phenotype. PMID:22190868

Sex-linked phenotypic divergence in the hermaphrodite fungus Neurospora tetrasperma

USDA-ARS?s Scientific Manuscript database

Here we present a study of the molecular phenotype linked to a large region of suppressed recombination (extending over ~ 7 Mbp and >1,500 genes) surrounding the mating-type (mat) locus of the filamentous ascomycete Neurospora tetrasperma. While the remainder of the genome is largely homoallelic, th...

Ligand-Dependent Disorder of Loop Observed in Extended-Spectrum SHV-Type beta-Lactamase

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

J Sampson; W Ke; C Bethel

2011-12-31

Among Gram-negative bacteria, resistance to {beta}-lactams is mediated primarily by {beta}-lactamases (EC 3.2.6.5), periplasmic enzymes that inactivate {beta}-lactam antibiotics. Substitutions at critical amino acid positions in the class A {beta}-lactamase families result in enzymes that can hydrolyze extended-spectrum cephalosporins, thus demonstrating an 'extended-spectrum' {beta}-lactamase (ESBL) phenotype. Using SHV ESBLs with substitutions in the {Omega} loop (R164H and R164S) as target enzymes to understand this enhanced biochemical capability and to serve as a basis for novel {beta}-lactamase inhibitor development, we determined the spectra of activity and crystal structures of these variants. We also studied the inactivation of the R164H and R164Smore » mutants with tazobactam and SA2-13, a unique {beta}-lactamase inhibitor that undergoes a distinctive reaction chemistry in the active site. We noted that the reduced K{sub i} values for the R164H and R164S mutants with SA2-13 are comparable to those with tazobactam (submicromolar). The apo enzyme crystal structures of the R164H and R164S SHV variants revealed an ordered {Omega} loop architecture that became disordered when SA2-13 was bound. Important structural alterations that result from the binding of SA2-13 explain the enhanced susceptibility of these ESBL enzymes to this inhibitor and highlight ligand-dependent {Omega} loop flexibility as a mechanism for accommodating and hydrolyzing {beta}-lactam substrates.« less

Molecular and clinical characterization of two patients with Prader-Willi syndrome and atypical deletions of proximal chromosome 15q.

PubMed

Calounova, Gabriela; Hedvicakova, Petra; Silhanova, Eva; Kreckova, Gabriela; Sedlacek, Zdenek

2008-08-01

Prader-Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11-q13, but the specific contributions of individual genes remain unknown. Most paternal PWS deletions are bracketed by recurrent breakpoints BP1 or BP2 and BP3. Atypical deletions are very rare. In the present work, we describe the molecular analysis of two patients with atypical deletions using microsatellite analysis, methylation-specific MLPA, and microarray CGH. A deletion of about 2 Mb in Patient 1 started at BP2 and ended in the middle of the typically deleted region within the UBE3A gene. The deletion in Patient 2 started 1.3 Mb distal from BP2 within the C15ORF2 gene, extended over 9.5 Mb, and ended within the AVEN gene in proximal 15q14. In Patient 1 both deletion breakpoints involved repetitive regions, which precluded cloning of the junction and pointed to non-allelic homologous recombination as a possible mechanism of this rearrangement. The breakpoints in Patient 2 were sequenced, and their structure suggested non-homologous end joining as the most likely cause of this deletion. The phenotype of both patients did not depart significantly from the typical clinical picture of PWS, although some symptoms in Patient 2 were also reminiscent of the phenotype of individuals with the recently described 15q13.3 microdeletion syndrome. Our findings support previous observations of relatively mild phenotypic effects resulting from deletions that extend distally from the PWS region and observations of the modest effects of different types of genetic defects on the spectrum and severity of symptoms in PWS. Copyright 2008 Wiley-Liss, Inc.

Selective cognitive impairment and tall stature due to chromosome 19 supernumerary ring.

PubMed

Melis, Daniela; Genesio, Rita; Del Giudice, Ennio; Taurisano, Roberta; Mormile, Angela; D'Elia, Federica; Conti, Anna; Imperati, Floriana; Andria, Generoso; Nitsch, Lucio

2012-01-01

Small supernumerary marker chromosomes (sSMC) occur with a frequency of approximately 0.4 per 1000 newborns and are more frequent in the population with mental retardation and/or with dysmorphic signs. Small supernumerary chromosome rings (sSCR) usually occur as apart of a mosaic karyotype (Liehr et al., 2004). Chromosome 19 supernumerary rings are very rare. Almost all cases of sSMC19 have been reported on Thomas Liehr's website (http://www.med.uni-jena.de/fish/sSMC/19.htm#Start19). Of these cases, 14 were with phenotypic abnormalities and a clear characterization of the sSMC; two cases were suitable for comparison with our case with regard to their genetic content, but not with regard to the structure ofthe sSMC (Manvelyan et al., 2008). The phenotype, associated with partial trisomy 19q, includes facial dysmorphism, growth and mental retardation, macrocephaly, heart malformation and anomalies of the genitourinary and gastrointestinal tracts. The phenotype associated with partial trisomy 19p is characterized by dysmorphic features, severe mental retardation, abnormalities of brain morphology and anomalies of the fingers (Tercanli et al., 2000; Qorri et al., 2002; Novelli et al., 2005; Vraneković et al., 2008). Herein, we report the phenotype and molecular cytogenetic analysis in a patient with the smallest de-novo constitutional ring extended from the p12 to q12 region of chromosome 19.

Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges.

PubMed

O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Kirby, Brian P; Waddington, John L

2011-01-01

Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.

Intermediate phenotypes and biomarkers of treatment outcome in major depressive disorder

PubMed Central

Leuchter, Andrew F.; Hunter, Aimee M.; Krantz, David E.; Cook, Ian A.

2014-01-01

Major depressive disorder (MDD) is a pleomorphic illness originating from gene x environment interactions. Patients with differing symptom phenotypes receive the same diagnosis and similar treatment recommendations without regard to genomics, brain structure or function, or other physiologic or psychosocial factors. Using this present approach, only one third of patients enter remission with the first medication prescribed, and patients may take longer than 1 year to enter remission with repeated trials. Research to improve treatment effectiveness recently has focused on identification of intermediate phenotypes (IPs) that could parse the heterogeneous population of patients with MDD into subgroups with more homogeneous responses to treatment. Such IPs could be used to develop biomarkers that could be applied clinically to match patients with the treatment that would be most likely to lead to remission. Putative biomarkers include genetic polymorphisms, RNA and protein expression (transcriptome and proteome), neurotransmitter levels (metabolome), additional measures of signaling cascades, oscillatory synchrony, neuronal circuits and neural pathways (connectome), along with other possible physiologic measures. All of these measures represent components of a continuum that extends from proximity to the genome to proximity to the clinical phenotype of depression, and there are many levels along this continuum at which useful IPs may be defined. Because of the highly integrative nature of brain systems and the complex neurobiology of depression, the most useful biomarkers are likely to be those with intermediate proximity both to the genome and the clinical phenotype of MDD. Translation of findings across the spectrum from genotype to phenotype promises to better characterize the complex disruptions in signaling and neuroplasticity that accompany MDD, and ultimately to lead to greater understanding of the causes of depressive illness. PMID:25733956

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase.

PubMed

Ang, J Sidney; Duffy, Supipi; Segovia, Romulo; Stirling, Peter C; Hieter, Philip

2016-11-01

Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype), or defects in genes that cause chromosome instability (CIN). To extend the catalog of genome instability genes, we systematically explored the effects of gene overexpression on mutation rate, using a forward-mutation screen in budding yeast. We screened ∼5100 plasmids, each overexpressing a unique single gene, and characterized the five strongest mutators, MPH1 (mutator phenotype 1), RRM3, UBP12, PIF1, and DNA2 We show that, for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the overexpression mutator phenotype is distinct from that of mph1Δ. Moreover, while four of our top hits encode DNA helicases, the overexpression of 48 other DNA helicases did not cause a mutator phenotype, suggesting this is not a general property of helicases. For Mph1 overexpression, helicase activity was not required for the mutator phenotype; in contrast Mph1 DEAH-box function was required for hypermutation. Mutagenesis by MPH1 overexpression was independent of translesion synthesis (TLS), but was suppressed by overexpression of RAD27, a conserved flap endonuclease. We propose that binding of DNA flap structures by excess Mph1 may block Rad27 action, creating a mutator phenotype that phenocopies rad27Δ. We believe this represents a novel mutator mode-of-action and opens up new prospects to understand how upregulation of DNA repair proteins may contribute to mutagenesis. Copyright © 2016 by the Genetics Society of America.

Temporal abstraction-based clinical phenotyping with Eureka!

PubMed

Post, Andrew R; Kurc, Tahsin; Willard, Richie; Rathod, Himanshu; Mansour, Michel; Pai, Akshatha Kalsanka; Torian, William M; Agravat, Sanjay; Sturm, Suzanne; Saltz, Joel H

2013-01-01

Temporal abstraction, a method for specifying and detecting temporal patterns in clinical databases, is very expressive and performs well, but it is difficult for clinical investigators and data analysts to understand. Such patterns are critical in phenotyping patients using their medical records in research and quality improvement. We have previously developed the Analytic Information Warehouse (AIW), which computes such phenotypes using temporal abstraction but requires software engineers to use. We have extended the AIW's web user interface, Eureka! Clinical Analytics, to support specifying phenotypes using an alternative model that we developed with clinical stakeholders. The software converts phenotypes from this model to that of temporal abstraction prior to data processing. The model can represent all phenotypes in a quality improvement project and a growing set of phenotypes in a multi-site research study. Phenotyping that is accessible to investigators and IT personnel may enable its broader adoption.

Exon-intron structure of the human neuronal nicotinic acetylcholine receptor {alpha}4 subunit (CHRNA4)

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

Steinlein, O.; Weiland, S.; Stoodt, J.

1996-03-01

The human neuronal nicotinic acetylcholine receptor {alpha}4 subunit gene (CHRNA4) is located in the candidate region for three different phenotypes: benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and low-voltage EEG. Recently, a missense mutation in transmembrane domain 2 of CHRNA4 was found to be associated with autosomal dominant nocturnal frontal lobe epilepsy in one extended pedigree. We have determined the genomic organization of CHRNA4, which consists of six exons distributed over approximately 17 kb of genomic DNA. The nucleotide sequence obtained from the genomic regions adjacent to the exon boundaries enabled us to develop a set ofmore » primer pairs for PCR amplification of the complete coding region. The sequence analysis provides the basis for a comprehensive mutation screening of CHRNA4 in the above-mentioned phenotypes and possibly in other types of idopathic epilepsies. 29 refs., 3 figs., 1 tab.« less

The strength of plants: theory and experimental methods to measure the mechanical properties of stems.

PubMed

Shah, Darshil U; Reynolds, Thomas P S; Ramage, Michael H

2017-07-20

From the stems of agricultural crops to the structural trunks of trees, studying the mechanical behaviour of plant stems is critical for both commerce and science. Plant scientists are also increasingly relying on mechanical test data for plant phenotyping. Yet there are neither standardized methods nor systematic reviews of current methods for the testing of herbaceous stems. We discuss the architecture of plant stems and highlight important micro- and macrostructural parameters that need to be controlled and accounted for when designing test methodologies, or that need to be understood in order to explain observed mechanical behaviour. Then, we critically evaluate various methods to test structural properties of stems, including flexural bending (two-, three-, and four-point bending) and axial loading (tensile, compressive, and buckling) tests. Recommendations are made on best practices. This review is relevant to fundamental studies exploring plant biomechanics, mechanical phenotyping of plants, and the determinants of mechanical properties in cell walls, as well as to application-focused studies, such as in agro-breeding and forest management projects, aiming to understand deformation processes of stem structures. The methods explored here can also be extended to other elongated, rod-shaped organs (e.g. petioles, midribs, and even roots). © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Structures of Rotavirus Reassortants Demonstrate Correlation of Altered Conformation of the VP4 Spike and Expression of Unexpected VP4-Associated Phenotypes

PubMed Central

Pesavento, Joseph B.; Billingsley, Angela M.; Roberts, Ed J.; Ramig, Robert F.; Prasad, B. V. Venkataram

2003-01-01

Numerous prior studies have indicated that viable rotavirus reassortants containing structural proteins of heterologous parental origin may express unexpected phenotypes, such as changes in infectivity and immunogenicity. To provide a structural basis for alterations in phenotypic expression, a three-dimensional structural analysis of these reassortants was conducted. The structures of the reassortants show that while VP4 generally maintains the parental structure when moved to a heterologous protein background, in certain reassortants, there are subtle alterations in the conformation of VP4. The alterations in VP4 conformation correlated with expression of unexpected VP4-associated phenotypes. Interactions between heterologous VP4 and VP7 in reassortants expressing unexpected phenotypes appeared to induce the conformational alterations seen in VP4. PMID:12584352

Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses

PubMed Central

Harvey, William T.; Benton, Donald J.; Gregory, Victoria; Hall, James P. J.; Daniels, Rodney S.; Bedford, Trevor; Haydon, Daniel T.; Hay, Alan J.; McCauley, John W.; Reeve, Richard

2016-01-01

Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens. PMID:27057693

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

Identifying Neurobiological Markers of the Broader Autism Phenotype

DTIC Science & Technology

2013-09-01

2014; proposed extended deadline: Jan 19, 2015). 15. SUBJECT TERMS Broader Autism Phenotype (BAP), Autism Spectrum Disorder (ASD), Social...difficulties in autism and the BAP. In this way, the current project not only changes how autistic traits are viewed; as falling along a spectrum ...than can be experienced by people with autism spectrum disorders . BODY The information below describes the research accomplishments

PCR on yeast colonies: an improved method for glyco-engineered Saccharomyces cerevisiae

PubMed Central

2013-01-01

Background Saccharomyces cerevisiae is extensively used in bio-industries. However, its genetic engineering to introduce new metabolism pathways can cause unexpected phenotypic alterations. For example, humanisation of the glycosylation pathways is a high priority pharmaceutical industry goal for production of therapeutic glycoproteins in yeast. Genomic modifications can lead to several described physiological changes: biomass yields decrease, temperature sensitivity or cell wall structure modifications. We have observed that deletion of several N-mannosyltransferases in Saccharomyces cerevisiae, results in strains that can no longer be analyzed by classical PCR on yeast colonies. Findings In order to validate our glyco-engineered Saccharomyces cerevisiae strains, we developed a new protocol to carry out PCR directly on genetically modified yeast colonies. A liquid culture phase, combined with the use of a Hot Start DNA polymerase, allows a 3-fold improvement of PCR efficiency. The results obtained are repeatable and independent of the targeted sequence; as such the protocol is well adapted for intensive screening applications. Conclusions The developed protocol enables by-passing of many of the difficulties associated with PCR caused by phenotypic modifications brought about by humanisation of the glycosylation in yeast and allows rapid validation of glyco-engineered Saccharomyces cerevisiae cells. It has the potential to be extended to other yeast strains presenting cell wall structure modifications. PMID:23688076

Phenotypic diversity, population structure and stress protein-based capacitoring in populations of Xeropicta derbentina, a heat-tolerant land snail species.

PubMed

Di Lellis, Maddalena A; Sereda, Sergej; Geißler, Anna; Picot, Adrien; Arnold, Petra; Lang, Stefanie; Troschinski, Sandra; Dieterich, Andreas; Hauffe, Torsten; Capowiez, Yvan; Mazzia, Christophe; Knigge, Thomas; Monsinjon, Tiphaine; Krais, Stefanie; Wilke, Thomas; Triebskorn, Rita; Köhler, Heinz-R

2014-11-01

The shell colour of many pulmonate land snail species is highly diverse. Besides a genetic basis, environmentally triggered epigenetic mechanisms including stress proteins as evolutionary capacitors are thought to influence such phenotypic diversity. In this study, we investigated the relationship of stress protein (Hsp70) levels with temperature stress tolerance, population structure and phenotypic diversity within and among different populations of a xerophilic Mediterranean snail species (Xeropicta derbentina). Hsp70 levels varied considerably among populations, and were significantly associated with shell colour diversity: individuals in populations exhibiting low diversity expressed higher Hsp70 levels both constitutively and under heat stress than those of phenotypically diverse populations. In contrast, population structure (cytochrome c oxidase subunit I gene) did not correlate with phenotypic diversity. However, genetic parameters (both within and among population differences) were able to explain variation in Hsp70 induction at elevated but non-pathologic temperatures. Our observation that (1) population structure had a high explanatory potential for Hsp70 induction and that (2) Hsp70 levels, in turn, correlated with phenotypic diversity while (3) population structure and phenotypic diversity failed to correlate provides empirical evidence for Hsp70 to act as a mediator between genotypic variation and phenotype and thus for chaperone-driven evolutionary capacitance in natural populations.

Patient-tailored prioritization for a pediatric care decision support system through machine learning.

PubMed

Klann, Jeffrey G; Anand, Vibha; Downs, Stephen M

2013-12-01

Over 8 years, we have developed an innovative computer decision support system that improves appropriate delivery of pediatric screening and care. This system employs a guidelines evaluation engine using data from the electronic health record (EHR) and input from patients and caregivers. Because guideline recommendations typically exceed the scope of one visit, the engine uses a static prioritization scheme to select recommendations. Here we extend an earlier idea to create patient-tailored prioritization. We used Bayesian structure learning to build networks of association among previously collected data from our decision support system. Using area under the receiver-operating characteristic curve (AUC) as a measure of discriminability (a sine qua non for expected value calculations needed for prioritization), we performed a structural analysis of variables with high AUC on a test set. Our source data included 177 variables for 29 402 patients. The method produced a network model containing 78 screening questions and anticipatory guidance (107 variables total). Average AUC was 0.65, which is sufficient for prioritization depending on factors such as population prevalence. Structure analysis of seven highly predictive variables reveals both face-validity (related nodes are connected) and non-intuitive relationships. We demonstrate the ability of a Bayesian structure learning method to 'phenotype the population' seen in our primary care pediatric clinics. The resulting network can be used to produce patient-tailored posterior probabilities that can be used to prioritize content based on the patient's current circumstances. This study demonstrates the feasibility of EHR-driven population phenotyping for patient-tailored prioritization of pediatric preventive care services.

An omnibus test for family-based association studies with multiple SNPs and multiple phenotypes.

PubMed

Lasky-Su, Jessica; Murphy, Amy; McQueen, Matthew B; Weiss, Scott; Lange, Christoph

2010-06-01

We propose an omnibus family-based association test (MFBAT) that can be applied to multiple markers and multiple phenotypes and that has only one degree of freedom. The proposed test statistic extends current FBAT methodology to incorporate multiple markers as well as multiple phenotypes. Using simulation studies, power estimates for the proposed methodology are compared with the standard methodologies. On the basis of these simulations, we find that MFBAT substantially outperforms other methods, including haplotypic approaches and doing multiple tests with single single-nucleotide polymorphisms (SNPs) and single phenotypes. The practical relevance of the approach is illustrated by an application to asthma in which SNP/phenotype combinations are identified and reach overall significance that would not have been identified using other approaches. This methodology is directly applicable to cases in which there are multiple SNPs, such as candidate gene studies, cases in which there are multiple phenotypes, such as expression data, and cases in which there are multiple phenotypes and genotypes, such as genome-wide association studies that incorporate expression profiles as phenotypes. This program is available in the PBAT analysis package.

Neutral lipid-storage disease with myopathy and extended phenotype with novel PNPLA2 mutation.

PubMed

Massa, Roberto; Pozzessere, Simone; Rastelli, Emanuele; Serra, Laura; Terracciano, Chiara; Gibellini, Manuela; Bozzali, Marco; Arca, Marcello

2016-04-01

Neutral lipid-storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multiorgan neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment. Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing. Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced gray matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A), resulting in a premature stop codon (p.Cys238*). Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment. © 2016 Wiley Periodicals, Inc.

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.

Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations.

PubMed

Gu, Shun; Tian, Yuanyuan; Chen, Xue; Zhao, Chen

2016-01-01

We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease-relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant's colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all Chinese patients carrying mutations in the EYS gene were also reviewed and summarized.

Studies on Manfred Eigen's model for the self-organization of information processing.

PubMed

Ebeling, W; Feistel, R

2018-05-01

In 1971, Manfred Eigen extended the principles of Darwinian evolution to chemical processes, from catalytic networks to the emergence of information processing at the molecular level, leading to the emergence of life. In this paper, we investigate some very general characteristics of this scenario, such as the valuation process of phenotypic traits in a high-dimensional fitness landscape, the effect of spatial compartmentation on the valuation, and the self-organized transition from structural to symbolic genetic information of replicating chain molecules. In the first part, we perform an analysis of typical dynamical properties of continuous dynamical models of evolutionary processes. In particular, we study the mapping of genotype to continuous phenotype spaces following the ideas of Wright and Conrad. We investigate typical features of a Schrödinger-like dynamics, the consequences of the high dimensionality, the leading role of saddle points, and Conrad's extra-dimensional bypass. In the last part, we discuss in brief the valuation of compartment models and the self-organized emergence of molecular symbols at the beginning of life.

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.

PubMed

Frankowski, Kevin J; Wang, Chen; Patnaik, Samarjit; Schoenen, Frank J; Southall, Noel; Li, Dandan; Teper, Yaroslav; Sun, Wei; Kandela, Irawati; Hu, Deqing; Dextras, Christopher; Knotts, Zachary; Bian, Yansong; Norton, John; Titus, Steve; Lewandowska, Marzena A; Wen, Yiping; Farley, Katherine I; Griner, Lesley Mathews; Sultan, Jamey; Meng, Zhaojing; Zhou, Ming; Vilimas, Tomas; Powers, Astin S; Kozlov, Serguei; Nagashima, Kunio; Quadri, Humair S; Fang, Min; Long, Charles; Khanolkar, Ojus; Chen, Warren; Kang, Jinsol; Huang, Helen; Chow, Eric; Goldberg, Esthermanya; Feldman, Coral; Xi, Romi; Kim, Hye Rim; Sahagian, Gary; Baserga, Susan J; Mazar, Andrew; Ferrer, Marc; Zheng, Wei; Shilatifard, Ali; Aubé, Jeffrey; Rudloff, Udo; Marugan, Juan Jose; Huang, Sui

2018-05-16

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Non a Priori Automatic Discovery of 3D Chemical Patterns: Application to Mutagenicity.

PubMed

Rabatel, Julien; Fannes, Thomas; Lepailleur, Alban; Le Goff, Jérémie; Crémilleux, Bruno; Ramon, Jan; Bureau, Ronan; Cuissart, Bertrand

2017-10-01

This article introduces a new type of structural fragment called a geometrical pattern. Such geometrical patterns are defined as molecular graphs that include a labelling of atoms together with constraints on interatomic distances. The discovery of geometrical patterns in a chemical dataset relies on the induction of multiple decision trees combined in random forests. Each computational step corresponds to a refinement of a preceding set of constraints, extending a previous geometrical pattern. This paper focuses on the mutagenicity of chemicals via the definition of structural alerts in relation with these geometrical patterns. It follows an experimental assessment of the main geometrical patterns to show how they can efficiently originate the definition of a chemical feature related to a chemical function or a chemical property. Geometrical patterns have provided a valuable and innovative approach to bring new pieces of information for discovering and assessing structural characteristics in relation to a particular biological phenotype. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.

PubMed

Gess, Burkhard; Auer-Grumbach, Michaela; Schirmacher, Anja; Strom, Tim; Zitzelsberger, Manuela; Rudnik-Schöneborn, Sabine; Röhr, Dominik; Halfter, Hartmut; Young, Peter; Senderek, Jan

2014-11-04

To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. © 2014 American Academy of Neurology.

Sexual and natural selection in the evolution of extended phenotypes: the use of green nesting material in starlings.

PubMed

Rubalcaba, J G; Polo, V; Maia, R; Rubenstein, D R; Veiga, J P

2016-08-01

Although sexual selection is typically considered the predominant force driving the evolution of ritualized sexual behaviours, natural selection may also play an important and often underappreciated role. The use of green aromatic plants among nesting birds has been interpreted as a component of extended phenotype that evolved either via natural selection due to potential sanitary functions or via sexual selection as a signal of male attractiveness. Here, we compared both hypotheses using comparative methods in starlings, a group where this behaviour is widespread. We found that the use of green plants was positively related to male-biased size dimorphism and that it was most likely to occur among cavity-nesting species. These results suggest that this behaviour is likely favoured by sexual selection, but also related to its sanitary use in response to higher parasite loads in cavities. We speculate that the use of green plants in starlings may be facilitated by cavity nesting and was subsequently co-opted as a sexual signal by males. Our results represent an example of how an extended phenotypic component of males becomes sexually selected by females. Thus, both natural selection and sexual selection are necessary to fully understand the evolution of ritualized behaviours involved in courtship. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

Simple Sugars to Complex Disease—Mucin-Type O-Glycans in Cancer

PubMed Central

Kudelka, Matthew R.; Ju, Tongzhong; Heimburg-Molinaro, Jamie; Cummings, Richard D.

2017-01-01

Mucin-type O-glycans are a class of glycans initiated with N-acetylgalactosamine (GalNAc) α-linked primarily to Ser/Thr residues within glycoproteins and often extended or branched by sugars or saccharides. Most secretory and membrane-bound proteins receive this modification, which is important in regulating many biological processes. Alterations in mucin-type O-glycans have been described across tumor types and include expression of relatively small-sized, truncated O-glycans and altered terminal structures, both of which are associated with patient prognosis. New discoveries in the identity and expression of tumor-associated O-glycans are providing new avenues for tumor detection and treatment. This chapter describes mucin-type O-glycan biosynthesis, altered mucin-type O-glycans in primary tumors, including mechanisms for structural changes and contributions to the tumor phenotype, and clinical approaches to detect and target altered O-glycans for cancer treatment and management. PMID:25727146

Adaptive phenotypic plasticity and local adaptation for temperature tolerance in freshwater zooplankton

PubMed Central

Yampolsky, Lev Y.; Schaer, Tobias M. M.; Ebert, Dieter

2014-01-01

Many organisms have geographical distributions extending from the tropics to near polar regions or can experience up to 30°C temperature variation within the lifespan of an individual. Two forms of evolutionary adaptation to such wide ranges in ambient temperatures are frequently discussed: local adaptation and phenotypic plasticity. The freshwater planktonic crustacean Daphnia magna, whose range extends from South Africa to near arctic sites, shows strong phenotypic and genotypic variation in response to temperature. In this study, we use D. magna clones from 22 populations (one clone per population) ranging from latitude 0° (Kenya) to 66° North (White Sea) to explore the contributions of phenotypic plasticity and local adaptation to high temperature tolerance. Temperature tolerance was studied as knockout time (time until immobilization, Timm) at 37°C in clones acclimatized to either 20°C or 28°C. Acclimatization to 28°C strongly increased Timm, testifying to adaptive phenotypic plasticity. At the same time, Timm significantly correlated with average high temperature at the clones’ sites of origin, suggesting local adaptation. As earlier studies have found that haemoglobin expression contributes to temperature tolerance, we also quantified haemoglobin concentration in experimental animals and found that both acclimatization temperature (AccT) and temperature at the site of origin are positively correlated with haemoglobin concentration. Furthermore, Daphnia from warmer climates upregulate haemoglobin much more strongly in response to AccT, suggesting local adaptation for plasticity in haemoglobin expression. Our results show that both local adaptation and phenotypic plasticity contribute to temperature tolerance, and elucidate a possible role of haemoglobin in mediating these effects that differs along a cold–warm gradient. PMID:24352948

A uniform method for the simultaneous blood group phenotyping of Fya , Fyb , Jka , Jkb , S, s̅, P1, k applying lateral-flow technique.

PubMed

Caesar, A; Meyer, S; Trost, N; Neuenschwander, K; Geisen, C; Frey, B M; Gassner, C; Schwind, P

2018-02-01

A lateral flow assay for simultaneous blood group typing of ABO, RhD, C, E, c, e, Cw and K with stable end-point and without centrifugation is in routine use since several years (MDmulticard ® ). The typing of extended phenotype parameters belonging to the Duffy, Kidd, MNSs blood group systems and others, however, has not yet been demonstrated for this technique. Reliable detection of Fy x , a weak Fy b phenotype with a pronounced quantitative reduction of the number of Fy b antigens on the erythrocyte surface, remains a weakness of current serological blood grouping techniques. The performance characteristics of the following reagents were evaluated in donor and patient samples in lateral flow technology (MDmulticard ® ): Anti-Fy a , -Fy b , -Jk a , -Jk b , -S, -s̅, -P1 and -k. The sensitivity to detect Fy x was in addition evaluated with Fy x positive samples, which had been preselected by MALDI-TOF MS-based genotyping. All results obtained with the MDmulticard ® were in full accordance with those of the CE-certified reference products for all the eight reagent formulations used: Anti-Fy a , -Fy b , -Jk a , -Jk b , -S, -s̅, -P1 and -k. Also, all Fy x phenotypes of the selected population of 93 positive samples, originally identified by MALDI-TOF MS-based genotyping, were reliably detected by the lateral flow assay. Extended phenotype blood group parameters, including the serologically challenging Fy x phenotype, can be determined simultaneously, rapidly and accurately using the lateral flow (MDmulticard ® ) technology, even in cases when IgG class antibodies are the only source of diagnostic antibodies. © 2017 International Society of Blood Transfusion.

Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia.

PubMed

Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

2014-09-01

Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.

Transitions in optimal adaptive strategies for populations in fluctuating environments

NASA Astrophysics Data System (ADS)

Mayer, Andreas; Mora, Thierry; Rivoire, Olivier; Walczak, Aleksandra M.

2017-09-01

Biological populations are subject to fluctuating environmental conditions. Different adaptive strategies can allow them to cope with these fluctuations: specialization to one particular environmental condition, adoption of a generalist phenotype that compromises between conditions, or population-wise diversification (bet hedging). Which strategy provides the largest selective advantage in the long run depends on the range of accessible phenotypes and the statistics of the environmental fluctuations. Here, we analyze this problem in a simple mathematical model of population growth. First, we review and extend a graphical method to identify the nature of the optimal strategy when the environmental fluctuations are uncorrelated. Temporal correlations in environmental fluctuations open up new strategies that rely on memory but are mathematically challenging to study: We present analytical results to address this challenge. We illustrate our general approach by analyzing optimal adaptive strategies in the presence of trade-offs that constrain the range of accessible phenotypes. Our results extend several previous studies and have applications to a variety of biological phenomena, from antibiotic resistance in bacteria to immune responses in vertebrates.

Quantifying male attractiveness.

PubMed Central

McNamara, John M; Houston, Alasdair I; Marques Dos Santos, Miguel; Kokko, Hanna; Brooks, Rob

2003-01-01

Genetic models of sexual selection are concerned with a dynamic process in which female preference and male trait values coevolve. We present a rigorous method for characterizing evolutionary endpoints of this process in phenotypic terms. In our phenotypic characterization the mate-choice strategy of female population members determines how attractive females should find each male, and a population is evolutionarily stable if population members are actually behaving in this way. This provides a justification of phenotypic explanations of sexual selection and the insights into sexual selection that they provide. Furthermore, the phenotypic approach also has enormous advantages over a genetic approach when computing evolutionarily stable mate-choice strategies, especially when strategies are allowed to be complex time-dependent preference rules. For simplicity and clarity our analysis deals with haploid mate-choice genetics and a male trait that is inherited phenotypically, for example by vertical cultural transmission. The method is, however, easily extendible to other cases. An example illustrates that the sexy son phenomenon can occur when there is phenotypic inheritance of the male trait. PMID:14561306

A case of paternity testing influenced by the silent allele of Rh erythrocyte groups.

PubMed

Ota, M; Yonemura, I; Fukushima, H; Hasekura, H; Ishimoto, G; Mizutani, Y; Yamada, T

1987-11-01

A paternity test is presented in which a father and his two children possessed an extremely rare amorphic gene R-29 (r,---). One of the children was determined to be illegitimate at the first trial as her Rh phenotype was R2R2(ccDEE) and the father's phenotype was R1R1(CCDee). At the Court of Appeal, however, the rare Rh gene r(---) was shown to be inherited from the father to the appellant child through extended tests including her brother whose phenotype was also R2R2(ccDEE). She was acknowledged to be legitimate.

A Brief Critique of the TATES Procedure.

PubMed

Aliev, Fazil; Salvatore, Jessica E; Agrawal, Arpana; Almasy, Laura; Chan, Grace; Edenberg, Howard J; Hesselbrock, Victor; Kuperman, Samuel; Meyers, Jacquelyn; Dick, Danielle M

2018-03-01

The Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes.

A multifamily study on the relationship between CYP2C19 genotype and s-mephenytoin oxidation phenotype.

PubMed

Brøsen, K; de Morais, S M; Meyer, U A; Goldstein, J A

1995-10-01

It has recently been shown that the most common mutation (named m1) in both Caucasian and Japanese poor metabolizers (PM) of S-mephenytoin is a single base pair mutation (G-->A) in exon 5 of the CYP2C19 gene. In Japanese, a second defective allele of CYP2C19 named m2 consists of a G-->A mutation in exon 4. In the present study, we have investigated the inheritance of the CYP2C19 wild type allele (wt) and the two defective alleles (m1 and m2) in families of 11 Danish PM probands. The study was carried out for two principal reasons. First, we wanted to confirm the autosomal recessive inheritance of the defective alleles, and second, we wanted to examine the specificity and sensitivity of the CYP2C19 genotyping test. Individuals were phenotyped by measuring the ratio of S/R mephenytoin excreted in the urine after administration of mephenytoin, and genotyping was carried out by a PCR-based DNA amplification procedure. The genotypes of nine of the 11 probands were consistent with their phenotypes. Eight were homozygous m1/m1, and one was heterozygous m1/m2. The genotypes of two putative PM probands (wt/m1) were not consistent with their phenotypes. On the basis of extended phenotyping (additional late urine collections (24-36 h) and acidification of urine), one of these could probably be reclassified as an extensive metabolizer (EM) while the other was considered to be a true PM. This suggests the presence of an additional unknown mutant allele in the latter. Seven of the 41 phenotyped relatives in the 11 families were phenotyped as PMs, and with the exception of the father of family 10, their genotypes (m1/m1) were consistent with their phenotypes. Extended phenotyping (acidification of urine) suggested that the father of family 10 in fact is an EM and hence that his genotype (wt/m1) is concordant with his phenotype. Thus, the specificity of genotyping tests for PM was 100%, while the sensitivity was 15/16 or 94%. Our study provides unequivocal evidence for autosomal recessive inheritance of the PM trait.

Clan-structured migration and phenotypic differentiation in the Jirels of Nepal.

PubMed

Williams-Blangero, S

1989-04-01

This paper examines the impact of clan-structured migration on the between-village differentiation of the Jirels, a tribal population of eastern Nepal. The Jirel population is geographically restricted to nine villages, all of which were sampled to some extent for this study. Data on five head measurements, stature, and digital ridge counts are utilized to illustrate the patterns of phenotypic variation. Multivariate statistical techniques are used to assess the extent to which clan membership and associated patterns of marital exchange influence the population structure of the Jirels. The phenotypic characteristics of randomly generated migrant sets are compared to those of the observed clan-structured sets, demonstrating the clan-related phenotypic nonrandomness of migrants. The results indicate that clan-structured migration may significantly influence the amount of between-village variation. Clan structure may be a significant factor in determining patterns of variation and should not be ignored in studies of microdifferentiation in tribal populations.

The macroevolutionary consequences of phenotypic integration: from development to deep time.

PubMed

Goswami, A; Smaers, J B; Soligo, C; Polly, P D

2014-08-19

Phenotypic integration is a pervasive characteristic of organisms. Numerous analyses have demonstrated that patterns of phenotypic integration are conserved across large clades, but that significant variation also exists. For example, heterochronic shifts related to different mammalian reproductive strategies are reflected in postcranial skeletal integration and in coordination of bone ossification. Phenotypic integration and modularity have been hypothesized to shape morphological evolution, and we extended simulations to confirm that trait integration can influence both the trajectory and magnitude of response to selection. We further demonstrate that phenotypic integration can produce both more and less disparate organisms than would be expected under random walk models by repartitioning variance in preferred directions. This effect can also be expected to favour homoplasy and convergent evolution. New empirical analyses of the carnivoran cranium show that rates of evolution, in contrast, are not strongly influenced by phenotypic integration and show little relationship to morphological disparity, suggesting that phenotypic integration may shape the direction of evolutionary change, but not necessarily the speed of it. Nonetheless, phenotypic integration is problematic for morphological clocks and should be incorporated more widely into models that seek to accurately reconstruct both trait and organismal evolution.

The macroevolutionary consequences of phenotypic integration: from development to deep time

PubMed Central

Goswami, A.; Smaers, J. B.; Soligo, C.; Polly, P. D.

2014-01-01

Phenotypic integration is a pervasive characteristic of organisms. Numerous analyses have demonstrated that patterns of phenotypic integration are conserved across large clades, but that significant variation also exists. For example, heterochronic shifts related to different mammalian reproductive strategies are reflected in postcranial skeletal integration and in coordination of bone ossification. Phenotypic integration and modularity have been hypothesized to shape morphological evolution, and we extended simulations to confirm that trait integration can influence both the trajectory and magnitude of response to selection. We further demonstrate that phenotypic integration can produce both more and less disparate organisms than would be expected under random walk models by repartitioning variance in preferred directions. This effect can also be expected to favour homoplasy and convergent evolution. New empirical analyses of the carnivoran cranium show that rates of evolution, in contrast, are not strongly influenced by phenotypic integration and show little relationship to morphological disparity, suggesting that phenotypic integration may shape the direction of evolutionary change, but not necessarily the speed of it. Nonetheless, phenotypic integration is problematic for morphological clocks and should be incorporated more widely into models that seek to accurately reconstruct both trait and organismal evolution. PMID:25002699

Multivariate modelling of endophenotypes associated with the metabolic syndrome in Chinese twins.

PubMed

Pang, Z; Zhang, D; Li, S; Duan, H; Hjelmborg, J; Kruse, T A; Kyvik, K O; Christensen, K; Tan, Q

2010-12-01

The common genetic and environmental effects on endophenotypes related to the metabolic syndrome have been investigated using bivariate and multivariate twin models. This paper extends the pairwise analysis approach by introducing independent and common pathway models to Chinese twin data. The aim was to explore the common genetic architecture in the development of these phenotypes in the Chinese population. Three multivariate models including the full saturated Cholesky decomposition model, the common factor independent pathway model and the common factor common pathway model were fitted to 695 pairs of Chinese twins representing six phenotypes including BMI, total cholesterol, total triacylglycerol, fasting glucose, HDL and LDL. Performances of the nested models were compared with that of the full Cholesky model. Cross-phenotype correlation coefficients gave clear indication of common genetic or environmental backgrounds in the phenotypes. Decomposition of phenotypic correlation by the Cholesky model revealed that the observed phenotypic correlation among lipid phenotypes had genetic and unique environmental backgrounds. Both pathway models suggest a common genetic architecture for lipid phenotypes, which is distinct from that of the non-lipid phenotypes. The declining performance with model restriction indicates biological heterogeneity in development among some of these phenotypes. Our multivariate analyses revealed common genetic and environmental backgrounds for the studied lipid phenotypes in Chinese twins. Model performance showed that physiologically distinct endophenotypes may follow different genetic regulations.

Understanding the Phenotypic Structure of Adult Retrospective ADHD Symptoms during Childhood in the United States

ERIC Educational Resources Information Center

Ranby, Krista W.; Boynton, Marcella H.; Kollins, Scott H.; McClernon, F. Joseph; Yang, Chongming; Fuemmeler, Bernard F.

2012-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder, and the phenotypic structure comprising inattentive and hyperactive-impulsive type symptoms has been the focus of a growing body of recent research. Methodological studies are needed to better characterize phenotypes to advance research as well as clinical…

Infantile onset progressive cerebellar atrophy and anterior horn cell degeneration--a late onset variant of PCH-1?

PubMed

Lev, Dorit; Michelson-Kerman, Marina; Vinkler, Chana; Blumkin, Lubov; Shalev, Stavit A; Lerman-Sagie, Tally

2008-03-01

Despite major recent advances in our understanding of developmental cerebellar disorders, classification and delineation of these disorders remains difficult. The term pontocerebellar hypoplasia is used when there is a structural defect, originating in utero of both pons and cerebellar hemispheres. The term olivopontocerebellar atrophy is used when the disorder starts later in life and the process is a primary degeneration of cerebellar neurons. Pontocerebellar hypoplasia type 1 is associated with spinal anterior horn cell degeneration, congenital contractures, microcephaly, polyhydramnion and respiratory insufficiency leading to early death. However, anterior horn cell degeneration has also been described in cases with later onset pontocerebellar atrophy and recently the spectrum has even been further extended to include the association of anterior horn cell degeneration and cerebellar atrophy without pontine involvement. We describe two siblings from a consanguineous Moslem Arabic family who presented with progressive degeneration of both the cerebellum and the anterior horn cells. The patients presented after 1 year of age with a slow neurodegenerative course that included both cognitive and motor functions. There is considerable phenotypic variability; the sister shows a much milder course. Both children are still alive at 6 and 9 years. The sister could still crawl and speak two word sentences at the age of 3 years while the brother was bedridden and only uttered guttural sounds at the same age. Our cases further extend the phenotype of the cerebellar syndromes with anterior horn cell involvement to include a childhood onset and protracted course and further prove that this neurodegenerative disorder may start in utero or later in life.

Arabidopsis Chloroplast Mini-Ribonuclease III Participates in rRNA Maturation and Intron Recycling

PubMed Central

Hotto, Amber M.; Castandet, Benoît; Gilet, Laetitia; Higdon, Andrea; Condon, Ciarán; Stern, David B.

2015-01-01

RNase III proteins recognize double-stranded RNA structures and catalyze endoribonucleolytic cleavages that often regulate gene expression. Here, we characterize the functions of RNC3 and RNC4, two Arabidopsis thaliana chloroplast Mini-RNase III-like enzymes sharing 75% amino acid sequence identity. Whereas rnc3 and rnc4 null mutants have no visible phenotype, rnc3/rnc4 (rnc3/4) double mutants are slightly smaller and chlorotic compared with the wild type. In Bacillus subtilis, the RNase Mini-III is integral to 23S rRNA maturation. In Arabidopsis, we observed imprecise maturation of 23S rRNA in the rnc3/4 double mutant, suggesting that exoribonucleases generated staggered ends in the absence of specific Mini-III-catalyzed cleavages. A similar phenotype was found at the 3′ end of the 16S rRNA, and the primary 4.5S rRNA transcript contained 3′ extensions, suggesting that Mini-III catalyzes several processing events of the polycistronic rRNA precursor. The rnc3/4 mutant showed overaccumulation of a noncoding RNA complementary to the 4.5S-5S rRNA intergenic region, and its presence correlated with that of the extended 4.5S rRNA precursor. Finally, we found rnc3/4-specific intron degradation intermediates that are probable substrates for Mini-III and show that B. subtilis Mini-III is also involved in intron regulation. Overall, this study extends our knowledge of the key role of Mini-III in intron and noncoding RNA regulation and provides important insight into plastid rRNA maturation. PMID:25724636

Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome.

PubMed

Kaminen-Ahola, Nina; Ahola, Arttu; Flatscher-Bader, Traute; Wilkins, Sarah J; Anderson, Greg J; Whitelaw, Emma; Chong, Suyinn

2010-10-01

Growth restriction, craniofacial dysmorphology, and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal or postnatal, but the underlying mechanisms remain unknown.We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome (e.g., craniofacial changes and growth restriction in adolescent mice). In this study, we characterize in detail the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and by extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of nonfostered, ethanol-exposed and control mice at postnatal day 28.We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This finding suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiologic result of ethanol exposure in utero. We also find that, despite some catch-up growth after 5 weeks of age, the effect extends into adulthood, which is consistent with longitudinal studies in humans.Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis, and lipid metabolism. © 2010 Wiley-Liss, Inc.

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

Genotypic and epidemiologic characterization of extended-spectrum cephalosporin resistant Salmonella enterica from US beef feedlots.

PubMed

Mollenkopf, D F; Mathys, D A; Dargatz, D A; Erdman, M M; Habing, G G; Daniels, J B; Wittum, T E

2017-10-01

In the US, nontyphoidal Salmonellae are a common foodborne zoonotic pathogen causing gastroenteritis. Invasive Salmonella infections caused by extended-spectrum cephalosporin resistant (ESCR) phenotypes are more likely to result in treatment failure and adverse health outcomes, especially in severe pediatric Salmonella infections where the extended-spectrum β-lactams are the therapy of choice. To examine the genetic and epidemiologic characteristics of ESCR Salmonellae which may enter the food chain, we characterized 44 ceftiofur-resistant Salmonella isolates from the National Animal Health Monitoring System (NAHMS) 2011 beef cattle feedlot health and management study. As part of the NAHMS Feedlot 2011 study, 5050 individual fecal samples from 68 large (1000+ head capacity) feedlots were cultured for Salmonella spp. The resulting 460 positive samples yielded 571 Salmonella isolates with 44 (8%) expressing an AmpC β-lactamase phenotype. These phenotypic bla CMY-2 Salmonella isolates represented 8 serotypes, most commonly S. Newport (n=14, 32%), S. Typhimurium (n=13, 30%), and S. Reading (n=5, 11%), followed by S. Dublin, S. Infantis, S. Montevideo, S. Rough O:i;v:1;7, and S. Uganda. Carriage of the bla CMY-2 gene was confirmed for all isolates expressing an AmpC β-lactamase phenotype by PCR. Additionally, all 44 isolates were shown to carry the bla CMY-2 gene on a large IncA/C plasmid, a gene/plasmid combination which has been previously reported in multiple species. Other plasmids, including IncN, FIC, and FIIA, were also detected in some isolates. Cattle fed chlortetracycline were less likely to be positive for a bla CMY-2 Salmonella isolate in their enteric flora compared to those not receiving chlortetracycline during the feeding period. Carriage of bla CMY-2 was more prevalent in Salmonella isolates originating from lighter weight cattle, cattle fed tylosin and dairy breeds. Our characterization of the NAHMS Feedlot 2011 study Salmonella isolates with ESCR phenotype shows that while other cephalosporin resistance mechanisms have been reported in US cattle, specific serotypes harboring bla CMY-2 on IncA/C plasmids may be the dominant resistance genotype. Copyright © 2017 Elsevier B.V. All rights reserved.

Human sexual conflict from molecules to culture.

PubMed

Gorelik, Gregory; Shackelford, Todd K

2011-12-15

Coevolutionary arms races between males and females have equipped both sexes with mutually manipulative and defensive adaptations. These adaptations function to benefit individual reproductive interests at the cost of the reproductive interests of opposite-sex mates, and arise from evolutionary dynamics such as parental investment (unequal reproductive costs between the sexes) and sexual selection (unequal access to opposite-sex mates). Individuals use these adaptations to hijack others' reproductive systems, psychological states, and behaviors--essentially using other individuals as extended phenotypes of themselves. Such extended phenotypic manipulation of sexual rivals and opposite-sex mates is enacted by humans with the aid of hormones, pheromones, neurotransmitters, emotions, language, mind-altering substances, social institutions, technologies, and ideologies. Furthermore, sexual conflict may be experienced at an individual level when maternal genes and paternal genes are in conflict within an organism. Sexual conflict may be physically and emotionally destructive, but may also be exciting and constructive for relationships. By extending the biological concept of sexual conflict into social and cultural domains, scholars may successfully bridge many of the interdisciplinary gaps that separate the sciences from the humanities.

Biodiversity and the Species Concept-Lineages are not Enough.

PubMed

Freudenstein, John V; Broe, Michael B; Folk, Ryan A; Sinn, Brandon T

2017-07-01

The nature and definition of species continue to be matters of debate. Current views of species often focus on their nature as lineages-maximal reproductive communities through time. Whereas many authors point to the Evolutionary Species Concept as optimal, in its original form it stressed the ecological role of species as well as their history as lineages, but most recent authors have ignored the role aspect of the concept, making it difficult to apply unambiguously in a time-extended way. This trend has been exacerbated by the application of methods and concepts emphasizing the notion of monophyly, originally applied only at higher levels, to the level of individuals, as well as by the current emphasis on molecular data. Hence, some current authors recognize units that are no more than probable exclusive lineages as species. We argue that biodiversity is inherently a phenotypic concept and that role, as manifested in the organismal extended phenotype, is a necessary component of the species concept. Viewing species as historically connected populations with unique role brings together the temporal and phenotypic natures of species, providing a clear way to view species both in a time-limited and time-extended way. Doing so alleviates perceived issues with "paraphyletic species" and returns the focus of species to units that are most relevant for biodiversity. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A unified genetic association test robust to latent population structure for a count phenotype.

PubMed

Song, Minsun

2018-06-04

Confounding caused by latent population structure in genome-wide association studies has been a big concern despite the success of genome-wide association studies at identifying genetic variants associated with complex diseases. In particular, because of the growing interest in association mapping using count phenotype data, it would be interesting to develop a testing framework for genetic associations that is immune to population structure when phenotype data consist of count measurements. Here, I propose a solution for testing associations between single nucleotide polymorphisms and a count phenotype in the presence of an arbitrary population structure. I consider a classical range of models for count phenotype data. Under these models, a unified test for genetic associations that protects against confounding was derived. An algorithm was developed to efficiently estimate the parameters that are required to fit the proposed model. I illustrate the proposed approach using simulation studies and an empirical study. Both simulated and real-data examples suggest that the proposed method successfully corrects population structure. Copyright © 2018 John Wiley & Sons, Ltd.

Wild yeast harbor a variety of distinct amyloid structures with strong prion-inducing capabilities

PubMed Central

Westergard, Laura; True, Heather L.

2014-01-01

Summary Variation in amyloid structures profoundly influences a wide array of pathological phenotypes in mammalian protein conformation disorders and dominantly inherited phenotypes in yeast. Here, we describe, for the first time, naturally occurring, self-propagating, structural variants of a prion protein isolated from wild strains of the yeast Saccharomyces cerevisiae. Variants of the [RNQ+] prion propagating in a variety of wild yeast differ biochemically, in their intracellular distributions, and in their ability to promote formation of the [PSI+] prion. [PSI+] is an epigenetic regulator of cellular phenotype and adaptability. Strikingly, we find that most natural [RNQ+] variants induced [PSI+] at high frequencies and the majority of [PSI+] variants elicited strong cellular phenotypes. We hypothesize that the presence of an efficient [RNQ+] template primes the cell for [PSI+] formation in order to induce [PSI+] in conditions where it would be advantageous. These studies utilize naturally occurring structural variants to expand our understanding of the consequences of diverse prion conformations on cellular phenotypes. PMID:24673812

Geometric Morphometrics on Gene Expression Patterns Within Phenotypes: A Case Example on Limb Development

PubMed Central

Martínez-Abadías, Neus; Mateu, Roger; Niksic, Martina; Russo, Lucia; Sharpe, James

2016-01-01

How the genotype translates into the phenotype through development is critical to fully understand the evolution of phenotypes. We propose a novel approach to directly assess how changes in gene expression patterns are associated with changes in morphology using the limb as a case example. Our method combines molecular biology techniques, such as whole-mount in situ hybridization, with image and shape analysis, extending the use of Geometric Morphometrics to the analysis of nonanatomical shapes, such as gene expression domains. Elliptical Fourier and Procrustes-based semilandmark analyses were used to analyze the variation and covariation patterns of the limb bud shape with the expression patterns of two relevant genes for limb morphogenesis, Hoxa11 and Hoxa13. We devised a multiple thresholding method to semiautomatically segment gene domains at several expression levels in large samples of limb buds from C57Bl6 mouse embryos between 10 and 12 postfertilization days. Besides providing an accurate phenotyping tool to quantify the spatiotemporal dynamics of gene expression patterns within developing structures, our morphometric analyses revealed high, non-random, and gene-specific variation undergoing canalization during limb development. Our results demonstrate that Hoxa11 and Hoxa13, despite being paralogs with analogous functions in limb patterning, show clearly distinct dynamic patterns, both in shape and size, and are associated differently with the limb bud shape. The correspondence between our results and already well-established molecular processes underlying limb development confirms that this morphometric approach is a powerful tool to extract features of development regulating morphogenesis. Such multilevel analyses are promising in systems where not so much molecular information is available and will advance our understanding of the genotype–phenotype map. In systematics, this knowledge will increase our ability to infer how evolution modified a common developmental pattern to generate a wide diversity of morphologies, as in the vertebrate limb. PMID:26377442

The use of imputed sibling genotypes in sibship-based association analysis: on modeling alternatives, power and model misspecification.

PubMed

Minică, Camelia C; Dolan, Conor V; Hottenga, Jouke-Jan; Willemsen, Gonneke; Vink, Jacqueline M; Boomsma, Dorret I

2013-05-01

When phenotypic, but no genotypic data are available for relatives of participants in genetic association studies, previous research has shown that family-based imputed genotypes can boost the statistical power when included in such studies. Here, using simulations, we compared the performance of two statistical approaches suitable to model imputed genotype data: the mixture approach, which involves the full distribution of the imputed genotypes and the dosage approach, where the mean of the conditional distribution features as the imputed genotype. Simulations were run by varying sibship size, size of the phenotypic correlations among siblings, imputation accuracy and minor allele frequency of the causal SNP. Furthermore, as imputing sibling data and extending the model to include sibships of size two or greater requires modeling the familial covariance matrix, we inquired whether model misspecification affects power. Finally, the results obtained via simulations were empirically verified in two datasets with continuous phenotype data (height) and with a dichotomous phenotype (smoking initiation). Across the settings considered, the mixture and the dosage approach are equally powerful and both produce unbiased parameter estimates. In addition, the likelihood-ratio test in the linear mixed model appears to be robust to the considered misspecification in the background covariance structure, given low to moderate phenotypic correlations among siblings. Empirical results show that the inclusion in association analysis of imputed sibling genotypes does not always result in larger test statistic. The actual test statistic may drop in value due to small effect sizes. That is, if the power benefit is small, that the change in distribution of the test statistic under the alternative is relatively small, the probability is greater of obtaining a smaller test statistic. As the genetic effects are typically hypothesized to be small, in practice, the decision on whether family-based imputation could be used as a means to increase power should be informed by prior power calculations and by the consideration of the background correlation.

Evaluation of Semantic Web Technologies for Storing Computable Definitions of Electronic Health Records Phenotyping Algorithms.

PubMed

Papež, Václav; Denaxas, Spiros; Hemingway, Harry

2017-01-01

Electronic Health Records are electronic data generated during or as a byproduct of routine patient care. Structured, semi-structured and unstructured EHR offer researchers unprecedented phenotypic breadth and depth and have the potential to accelerate the development of precision medicine approaches at scale. A main EHR use-case is defining phenotyping algorithms that identify disease status, onset and severity. Phenotyping algorithms utilize diagnoses, prescriptions, laboratory tests, symptoms and other elements in order to identify patients with or without a specific trait. No common standardized, structured, computable format exists for storing phenotyping algorithms. The majority of algorithms are stored as human-readable descriptive text documents making their translation to code challenging due to their inherent complexity and hinders their sharing and re-use across the community. In this paper, we evaluate the two key Semantic Web Technologies, the Web Ontology Language and the Resource Description Framework, for enabling computable representations of EHR-driven phenotyping algorithms.

Identity Crisis

ERIC Educational Resources Information Center

Meraw, Leonard J.

2012-01-01

The article presents a simple and highly engaging activity for students involving DNA fingerprints, DNA bands, genotypes, phenotypes, and DNA morphology. The science of DNA fingerprinting, currently done by electrophoresis, extends to all living organisms containing DNA. (Contains 4 figures.)

Reversion of mtDNA depletion in a patient with TK2 deficiency.

PubMed

Vilà, M R; Segovia-Silvestre, T; Gámez, J; Marina, A; Naini, A B; Meseguer, A; Lombès, A; Bonilla, E; DiMauro, S; Hirano, M; Andreu, A L

2003-04-08

Mutations in the thymidine kinase 2 (TK2) gene cause a myopathic form of the mitochondrial DNA depletion syndrome (MDS). Here, the authors report the unusual clinical, biochemical, and molecular findings in a 14-year-old patient in whom pathogenic mutations were identified in the TK2 gene. This report extends the phenotypic expression of primary TK2 deficiency and suggests that factors other than TK2 may modify expression of the clinical phenotype in patients with MDS syndrome.

Detecting Genetic Interactions for Quantitative Traits Using m-Spacing Entropy Measure

PubMed Central

Yee, Jaeyong; Kwon, Min-Seok; Park, Taesung; Park, Mira

2015-01-01

A number of statistical methods for detecting gene-gene interactions have been developed in genetic association studies with binary traits. However, many phenotype measures are intrinsically quantitative and categorizing continuous traits may not always be straightforward and meaningful. Association of gene-gene interactions with an observed distribution of such phenotypes needs to be investigated directly without categorization. Information gain based on entropy measure has previously been successful in identifying genetic associations with binary traits. We extend the usefulness of this information gain by proposing a nonparametric evaluation method of conditional entropy of a quantitative phenotype associated with a given genotype. Hence, the information gain can be obtained for any phenotype distribution. Because any functional form, such as Gaussian, is not assumed for the entire distribution of a trait or a given genotype, this method is expected to be robust enough to be applied to any phenotypic association data. Here, we show its use to successfully identify the main effect, as well as the genetic interactions, associated with a quantitative trait. PMID:26339620

Phenotypic and genotypic data integration and exploration through a web-service architecture.

PubMed

Nuzzo, Angelo; Riva, Alberto; Bellazzi, Riccardo

2009-10-15

Linking genotypic and phenotypic information is one of the greatest challenges of current genetics research. The definition of an Information Technology infrastructure to support this kind of studies, and in particular studies aimed at the analysis of complex traits, which require the definition of multifaceted phenotypes and the integration genotypic information to discover the most prevalent diseases, is a paradigmatic goal of Biomedical Informatics. This paper describes the use of Information Technology methods and tools to develop a system for the management, inspection and integration of phenotypic and genotypic data. We present the design and architecture of the Phenotype Miner, a software system able to flexibly manage phenotypic information, and its extended functionalities to retrieve genotype information from external repositories and to relate it to phenotypic data. For this purpose we developed a module to allow customized data upload by the user and a SOAP-based communications layer to retrieve data from existing biomedical knowledge management tools. In this paper we also demonstrate the system functionality by an example application of the system in which we analyze two related genomic datasets. In this paper we show how a comprehensive, integrated and automated workbench for genotype and phenotype integration can facilitate and improve the hypothesis generation process underlying modern genetic studies.

Contemporary and historical evolutionary processes interact to shape patterns of within-lake phenotypic divergences in polyphenic pumpkinseed sunfish, Lepomis gibbosus.

PubMed

Weese, Dylan J; Ferguson, Moira M; Robinson, Beren W

2012-03-01

Historical and contemporary evolutionary processes can both contribute to patterns of phenotypic variation among populations of a species. Recent studies are revealing how interactions between historical and contemporary processes better explain observed patterns of phenotypic divergence than either process alone. Here, we investigate the roles of evolutionary history and adaptation to current environmental conditions in structuring phenotypic variation among polyphenic populations of sunfish inhabiting 12 postglacial lakes in eastern North America. The pumpkinseed sunfish polyphenism includes sympatric ecomorphs specialized for littoral or pelagic lake habitats. First, we use population genetic methods to test the evolutionary independence of within-lake phenotypic divergences of ecomorphs and to describe patterns of genetic structure among lake populations that clustered into three geographical groupings. We then used multivariate analysis of covariance (MANCOVA) to partition body shape variation (quantified with geometric morphometrics) among the effects of evolutionary history (reflecting phenotypic variation among genetic clusters), the shared phenotypic response of all populations to alternate habitats within lakes (reflecting adaptation to contemporary conditions), and unique phenotypic responses to habitats within lakes nested within genetic clusters. All effects had a significant influence on body form, but the effects of history and the interaction between history and contemporary habitat were larger than contemporary processes in structuring phenotypic variation. This highlights how divergence can be better understood against a known backdrop of evolutionary history.

Correlation of RNA secondary structure and attenuation of Sabin vaccine strains of poliovirus in tissue culture.

PubMed

Macadam, A J; Ferguson, G; Burlison, J; Stone, D; Skuce, R; Almond, J W; Minor, P D

1992-08-01

Part of the 5' noncoding regions of all three Sabin vaccine strains of poliovirus contains determinants of attenuation that are shown here to influence the ability of these strains to grow at elevated temperatures in BGM cells. The predicted RNA secondary structure of this region (nt 464-542 in P3/Sabin) suggests that both phenotypes are due to perturbation of base-paired stems. Ts phenotypes of site-directed mutants with defined changes in this region correlated well with predicted secondary structure stabilities. Reversal of base-pair orientation had little effect whereas stem disruption led to marked increases in temperature sensitivity. Phenotypic revertants of such viruses displayed mutations on either side of the stem. Mutations destabilizing stems led to intermediate phenotypes. These results provided evidence for the biological significance of the predicted RNA secondary structure.

Physiological characterisation of the efflux pump system of antibiotic-susceptible and multidrug-resistant Enterobacter aerogenes.

PubMed

Martins, A; Spengler, G; Martins, M; Rodrigues, L; Viveiros, M; Davin-Regli, A; Chevalier, J; Couto, I; Pagès, J M; Amaral, L

2010-10-01

Enterobacter aerogenes predominates amongst Enterobacteriaceae species that are increasingly reported as producers of extended-spectrum beta-lactamases. Although this mechanism of resistance to beta-lactams is important, other mechanisms bestowing a multidrug-resistant (MDR) phenotype in this species are now well documented. Amongst these mechanisms is the overexpression of efflux pumps that extrude structurally unrelated antibiotics prior to their reaching their targets. Interestingly, although knowledge of the genetic background behind efflux pumps is rapidly advancing, few studies assess the physiological nature of the overall efflux pump system of this, or for that matter any other, bacterium. The study reported here evaluates physiologically the efflux pump system of an E. aerogenes ATCC reference as well as two strains whose MDR phenotypes are mediated by overexpressed efflux pumps. The activities of the efflux pumps in these strains are modulated by pH and glucose, although the effects of the latter are essentially restricted to pH 8, suggesting the presence of two general efflux pump systems, i.e. proton-motive force-dependent and ABC transporter types, respectively. Copyright 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice

PubMed Central

Coughlan, Karen S.; Halang, Luise; Woods, Ina

2016-01-01

ABSTRACT Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43A315T mice. Similar to our recent results in SOD1G93A mice, TDP-43A315T mice fed a standard pellet diet showed increased 5′ adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43A315T mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43A315T model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. PMID:27491077

A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice.

PubMed

Coughlan, Karen S; Halang, Luise; Woods, Ina; Prehn, Jochen H M

2016-09-01

Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice. Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43(A315T) mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. © 2016. Published by The Company of Biologists Ltd.

Cosmetics as a feature of the extended human phenotype: modulation of the perception of biologically important facial signals.

PubMed

Etcoff, Nancy L; Stock, Shannon; Haley, Lauren E; Vickery, Sarah A; House, David M

2011-01-01

Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time. Here, we investigate one tool, the use of color cosmetics. In two studies, we asked viewers to rate the same female faces with or without color cosmetics, and we varied the style of makeup from minimal (natural), to moderate (professional), to dramatic (glamorous). Each look provided increasing luminance contrast between the facial features and surrounding skin. Faces were shown for 250 ms or for unlimited inspection time, and subjects rated them for attractiveness, competence, likeability and trustworthiness. At 250 ms, cosmetics had significant positive effects on all outcomes. Length of inspection time did not change the effect for competence or attractiveness. However, with longer inspection time, the effect of cosmetics on likability and trust varied by specific makeup looks, indicating that cosmetics could impact automatic and deliberative judgments differently. The results suggest that cosmetics can create supernormal facial stimuli, and that one way they may do so is by exaggerating cues to sexual dimorphism. Our results provide evidence that judgments of facial trustworthiness and attractiveness are at least partially separable, that beauty has a significant positive effect on judgment of competence, a universal dimension of social cognition, but has a more nuanced effect on the other universal dimension of social warmth, and that the extended phenotype significantly influences perception of biologically important signals at first glance and at longer inspection.

Cosmetics as a Feature of the Extended Human Phenotype: Modulation of the Perception of Biologically Important Facial Signals

PubMed Central

Etcoff, Nancy L.; Stock, Shannon; Haley, Lauren E.; Vickery, Sarah A.; House, David M.

2011-01-01

Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time. Here, we investigate one tool, the use of color cosmetics. In two studies, we asked viewers to rate the same female faces with or without color cosmetics, and we varied the style of makeup from minimal (natural), to moderate (professional), to dramatic (glamorous). Each look provided increasing luminance contrast between the facial features and surrounding skin. Faces were shown for 250 ms or for unlimited inspection time, and subjects rated them for attractiveness, competence, likeability and trustworthiness. At 250 ms, cosmetics had significant positive effects on all outcomes. Length of inspection time did not change the effect for competence or attractiveness. However, with longer inspection time, the effect of cosmetics on likability and trust varied by specific makeup looks, indicating that cosmetics could impact automatic and deliberative judgments differently. The results suggest that cosmetics can create supernormal facial stimuli, and that one way they may do so is by exaggerating cues to sexual dimorphism. Our results provide evidence that judgments of facial trustworthiness and attractiveness are at least partially separable, that beauty has a significant positive effect on judgment of competence, a universal dimension of social cognition, but has a more nuanced effect on the other universal dimension of social warmth, and that the extended phenotype significantly influences perception of biologically important signals at first glance and at longer inspection. PMID:21991328

Characterisation of North American Brucella isolates from marine mammals.

PubMed

Whatmore, Adrian M; Dawson, Claire; Muchowski, Jakub; Perrett, Lorraine L; Stubberfield, Emma; Koylass, Mark; Foster, Geoffrey; Davison, Nicholas J; Quance, Christine; Sidor, Inga F; Field, Cara L; St Leger, Judy

2017-01-01

Extension of known ecological niches of Brucella has included the description of two novel species from marine mammals. Brucella pinnipedialis is associated predominantly with seals, while two major Brucella ceti clades, most commonly associated with porpoises or dolphins respectively, have been identified. To date there has been limited characterisation of Brucella isolates obtained from marine mammals outside Northern European waters, including North American waters. To address this gap, and extend knowledge of the global population structure and host associations of these Brucella species, 61 isolates from marine mammals inhabiting North American waters were subject to molecular and phenotypic characterisation enabling comparison with existing European isolates. The majority of isolates represent genotypes previously described in Europe although novel genotypes were identified in both B. ceti clades. Harp seals were found to carry B. pinnipedialis genotypes previously confined to hooded seals among a diverse repertoire of sequence types (STs) associated with this species. For the first time Brucella isolates were characterised from beluga whales and found to represent a number of distinct B. pinnipedialis genotypes. In addition the known host range of ST27 was extended with the identification of this ST from California sea lion samples. Finally the performance of the frequently used diagnostic tool Bruce-ladder, in differentiating B. ceti and B. pinnipedialis, was critically assessed based on improved knowledge of the global population structure of Brucella associated with marine mammals.

Characterisation of North American Brucella isolates from marine mammals

PubMed Central

Dawson, Claire; Muchowski, Jakub; Perrett, Lorraine L.; Stubberfield, Emma; Koylass, Mark; Foster, Geoffrey; Davison, Nicholas J.; Quance, Christine; Sidor, Inga F.; Field, Cara L.; St. Leger, Judy

2017-01-01

Extension of known ecological niches of Brucella has included the description of two novel species from marine mammals. Brucella pinnipedialis is associated predominantly with seals, while two major Brucella ceti clades, most commonly associated with porpoises or dolphins respectively, have been identified. To date there has been limited characterisation of Brucella isolates obtained from marine mammals outside Northern European waters, including North American waters. To address this gap, and extend knowledge of the global population structure and host associations of these Brucella species, 61 isolates from marine mammals inhabiting North American waters were subject to molecular and phenotypic characterisation enabling comparison with existing European isolates. The majority of isolates represent genotypes previously described in Europe although novel genotypes were identified in both B. ceti clades. Harp seals were found to carry B. pinnipedialis genotypes previously confined to hooded seals among a diverse repertoire of sequence types (STs) associated with this species. For the first time Brucella isolates were characterised from beluga whales and found to represent a number of distinct B. pinnipedialis genotypes. In addition the known host range of ST27 was extended with the identification of this ST from California sea lion samples. Finally the performance of the frequently used diagnostic tool Bruce-ladder, in differentiating B. ceti and B. pinnipedialis, was critically assessed based on improved knowledge of the global population structure of Brucella associated with marine mammals. PMID:28934239

Systems biology of the structural proteome.

PubMed

Brunk, Elizabeth; Mih, Nathan; Monk, Jonathan; Zhang, Zhen; O'Brien, Edward J; Bliven, Spencer E; Chen, Ke; Chang, Roger L; Bourne, Philip E; Palsson, Bernhard O

2016-03-11

The success of genome-scale models (GEMs) can be attributed to the high-quality, bottom-up reconstructions of metabolic, protein synthesis, and transcriptional regulatory networks on an organism-specific basis. Such reconstructions are biochemically, genetically, and genomically structured knowledge bases that can be converted into a mathematical format to enable a myriad of computational biological studies. In recent years, genome-scale reconstructions have been extended to include protein structural information, which has opened up new vistas in systems biology research and empowered applications in structural systems biology and systems pharmacology. Here, we present the generation, application, and dissemination of genome-scale models with protein structures (GEM-PRO) for Escherichia coli and Thermotoga maritima. We show the utility of integrating molecular scale analyses with systems biology approaches by discussing several comparative analyses on the temperature dependence of growth, the distribution of protein fold families, substrate specificity, and characteristic features of whole cell proteomes. Finally, to aid in the grand challenge of big data to knowledge, we provide several explicit tutorials of how protein-related information can be linked to genome-scale models in a public GitHub repository ( https://github.com/SBRG/GEMPro/tree/master/GEMPro_recon/). Translating genome-scale, protein-related information to structured data in the format of a GEM provides a direct mapping of gene to gene-product to protein structure to biochemical reaction to network states to phenotypic function. Integration of molecular-level details of individual proteins, such as their physical, chemical, and structural properties, further expands the description of biochemical network-level properties, and can ultimately influence how to model and predict whole cell phenotypes as well as perform comparative systems biology approaches to study differences between organisms. GEM-PRO offers insight into the physical embodiment of an organism's genotype, and its use in this comparative framework enables exploration of adaptive strategies for these organisms, opening the door to many new lines of research. With these provided tools, tutorials, and background, the reader will be in a position to run GEM-PRO for their own purposes.

Machine-learning phenotypic classification of bicuspid aortopathy.

PubMed

Wojnarski, Charles M; Roselli, Eric E; Idrees, Jay J; Zhu, Yuanjia; Carnes, Theresa A; Lowry, Ashley M; Collier, Patrick H; Griffin, Brian; Ehrlinger, John; Blackstone, Eugene H; Svensson, Lars G; Lytle, Bruce W

2018-02-01

Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize their association with valve morphology and patient characteristics. We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis. Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right-noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy. Three distinct phenotypes of bicuspid valve-associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Prediction of gene-phenotype associations in humans, mice, and plants using phenologs.

PubMed

Woods, John O; Singh-Blom, Ulf Martin; Laurent, Jon M; McGary, Kriston L; Marcotte, Edward M

2013-06-21

Phenotypes and diseases may be related to seemingly dissimilar phenotypes in other species by means of the orthology of underlying genes. Such "orthologous phenotypes," or "phenologs," are examples of deep homology, and may be used to predict additional candidate disease genes. In this work, we develop an unsupervised algorithm for ranking phenolog-based candidate disease genes through the integration of predictions from the k nearest neighbor phenologs, comparing classifiers and weighting functions by cross-validation. We also improve upon the original method by extending the theory to paralogous phenotypes. Our algorithm makes use of additional phenotype data--from chicken, zebrafish, and E. coli, as well as new datasets for C. elegans--establishing that several types of annotations may be treated as phenotypes. We demonstrate the use of our algorithm to predict novel candidate genes for human atrial fibrillation (such as HRH2, ATP4A, ATP4B, and HOPX) and epilepsy (e.g., PAX6 and NKX2-1). We suggest gene candidates for pharmacologically-induced seizures in mouse, solely based on orthologous phenotypes from E. coli. We also explore the prediction of plant gene-phenotype associations, as for the Arabidopsis response to vernalization phenotype. We are able to rank gene predictions for a significant portion of the diseases in the Online Mendelian Inheritance in Man database. Additionally, our method suggests candidate genes for mammalian seizures based only on bacterial phenotypes and gene orthology. We demonstrate that phenotype information may come from diverse sources, including drug sensitivities, gene ontology biological processes, and in situ hybridization annotations. Finally, we offer testable candidates for a variety of human diseases, plant traits, and other classes of phenotypes across a wide array of species.

Genetic identification of the central nucleus and other components of the central extended amygdala in chicken during development

PubMed Central

Vicario, Alba; Abellán, Antonio; Desfilis, Ester; Medina, Loreta

2014-01-01

In mammals, the central extended amygdala shows a highly complex organization, and is essential for animal survival due to its implication in fear responses. However, many aspects of its evolution are still unknown, and this structure is especially poorly understood in birds. The aim of this study was to define the central extended amygdala in chicken, by means of a battery of region-specific transcription factors (Pax6, Islet1, Nkx2.1) and phenotypic markers that characterize these different subdivisions in mammals. Our results allowed the identification of at least six distinct subdivisions in the lateral part of the avian central extended amygdala: (1) capsular central subdivision; (2) a group of intercalated-like cell patches; (3) oval central nucleus; (4) peri-intrapeduncular (peri-INP) island field; (5) perioval zone; and (6) a rostral part of the subpallial extended amygdala. In addition, we identified three subdivisions of the laterodorsal bed nucleus of the stria terminalis (BSTLd) belonging to the medial region of the chicken central extended amygdala complex. Based on their genetic profile, cellular composition and apparent embryonic origin of the cells, we discuss the similarity of these different subdivisions of chicken with different parts of the mouse central amygdala and surrounding cell masses, including the intercalated amygdalar masses and the sublenticular part of the central extended amygdala. Most of the subdivisions include various subpopulations of cells that apparently originate in the dorsal striatal, ventral striatal, pallidal, and preoptic embryonic domains, reaching their final location by either radial or tangential migrations. Similarly to mammals, the central amygdala and BSTLd of chicken project to the hypothalamus, and include different neurons expressing proenkephalin, corticotropin-releasing factor, somatostatin or tyrosine hydroxylase, which may be involved in the control of different aspects of fear/anxiety-related behavior. PMID:25309337

Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations

PubMed Central

Gu, Shun; Tian, Yuanyuan; Chen, Xue

2016-01-01

Purpose We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Methods Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease–relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Results Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant’s colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Conclusions Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all Chinese patients carrying mutations in the EYS gene were also reviewed and summarized. PMID:27375351

The evolutionary time machine: forecasting how populations can adapt to changing environments using dormant propagules

PubMed Central

Orsini, Luisa; Schwenk, Klaus; De Meester, Luc; Colbourne, John K.; Pfrender, Michael E.; Weider, Lawrence J.

2013-01-01

Evolutionary changes are determined by a complex assortment of ecological, demographic and adaptive histories. Predicting how evolution will shape the genetic structures of populations coping with current (and future) environmental challenges has principally relied on investigations through space, in lieu of time, because long-term phenotypic and molecular data are scarce. Yet, dormant propagules in sediments, soils and permafrost are convenient natural archives of population-histories from which to trace adaptive trajectories along extended time periods. DNA sequence data obtained from these natural archives, combined with pioneering methods for analyzing both ecological and population genomic time-series data, are likely to provide predictive models to forecast evolutionary responses of natural populations to environmental changes resulting from natural and anthropogenic stressors, including climate change. PMID:23395434

Phenotypic Characterization of Multidrug-resistant Escherichia Coli with Special Reference to Extended-spectrum-beta-lactamases and Metallo-beta-lactamases in a Tertiary Care Center.

PubMed

Shrestha, B; Shrestha, S; Mishra, S K; Kattel, H P; Tada, T; Ohara, H; Kirikae, T; Rijal, B P; Sherchand, J B; Pokhrel, B M

2015-01-01

The increasing reports on extended-spectrum-beta-lactamase and metallo-beta-lactamase producing Escherichia coli have addressed a potential threat to global health since it is found to be highly resistance to most of the currently available antibiotics including carbapenems. The present study was aimed to determine the antibiogram of extended-spectrum-beta-lactamase and metallo-beta-lactamase producing MDR E. coli isolates from various clinical samples. This was a cross-sectional study conducted over a period of seven months from December 2013 to July 2014 at bacteriology laboratory of Tribhuvan University Teaching Hospital. A total of 250 clinical specimens (urine, pus, sputum, blood, body fluid, bile, tissue and central venous pressure line tip) were processed from inpatients, with multidrug-resistant Escherichia coli infections. Standard microbiological techniques were used for isolation and identification of the isolates. The presence of extended-spectrum-beta-lactamase was detected by phenotypic confirmatory test recommended by Clinical and Laboratory Standards Institute and imipenem (IMP) /EDTA combined disc method was performed to detect metallo-beta-lactamase mediated resistance mechanism. We found high level of beta lactamase mediated resistance mechanism as part of multidrug resistance. Among 250 MDR isolates, 60% isolates were extended-spectrum-beta-lactamase producers and 17.2% isolates were metallo-beta-lactamase producers. Co-existence of extended-spectrum-beta-lactamase and metallo-beta-lactamase identified in 6.8% isolates. Beta-lactamase mediated resistance mechanisms are accounting very high in the multidrug resistant isolates of E. coli. Therefore, early detection of beta lactamase mediated resistant strains and their current antibiotic susceptibility pattern is necessary to avoid treatment failure and prevent the spread of MDR.

Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila.

PubMed

Tsuda, Manabu; Ootaka, Ryousuke; Ohkura, Chiaki; Kishita, Yoshihito; Seong, Ki-Hyeon; Matsuo, Takashi; Aigaki, Toshiro

2010-08-04

Overexpression of thioredoxin (TRX) confers oxidative stress resistance and extends lifespan in mammals and insects. However, less is known about phenotypes associated with loss of TRX. We investigated loss-of-function phenotypes of Trx-2 in Drosophila, and found that the mutant flies are hyper-susceptible to paraquat, a free radical generator, but not to hydrogen peroxide. They contain a high amount of protein carbonyl, which dramatically increases with age. Trx-2 mutants express high levels of anti-oxidant genes, such as superoxide dismutase, catalase, and glutathione synthetase. This is the first demonstration of biochemical and physiological consequences caused by loss of Trx-2 in Drosophila. Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Maximum entropy modeling of metabolic networks by constraining growth-rate moments predicts coexistence of phenotypes

NASA Astrophysics Data System (ADS)

De Martino, Daniele

2017-12-01

In this work maximum entropy distributions in the space of steady states of metabolic networks are considered upon constraining the first and second moments of the growth rate. Coexistence of fast and slow phenotypes, with bimodal flux distributions, emerges upon considering control on the average growth (optimization) and its fluctuations (heterogeneity). This is applied to the carbon catabolic core of Escherichia coli where it quantifies the metabolic activity of slow growing phenotypes and it provides a quantitative map with metabolic fluxes, opening the possibility to detect coexistence from flux data. A preliminary analysis on data for E. coli cultures in standard conditions shows degeneracy for the inferred parameters that extend in the coexistence region.

Method for Phenotypic Detection of Extended-Spectrum Beta-Lactamases in Enterobacter Species in the Routine Clinical Setting ▿

PubMed Central

Stuart, James Cohen; Diederen, Bram; al Naiemi, Nashwan; Fluit, Ad; Arents, Niek; Thijsen, Steven; Vlaminckx, Bart; Mouton, Johan W.; Leverstein-van Hall, Maurine

2011-01-01

In 271 Enterobacter blood culture isolates from 12 hospitals, extended-spectrum beta-lactamase (ESBL) prevalence varied between 0% and 30% per hospital. High prevalence was associated with dissemination, indicating the potential relevance of infection control measures. Screening with cefepime or Vitek 2, followed by a cefepime/cefepime-clavulanate Etest, was an accurate strategy for ESBL detection in Enterobacter isolates (positive predictive value, 100%; negative predictive value, 99%). PMID:21562100

Phenotype- and Genotype-Specific Structural Alterations in Spasmodic Dysphonia

PubMed Central

Bianchi, Serena; Battistella, Giovanni; Huddleston, Hailey; Scharf, Rebecca; Fleysher, Lazar; Rumbach, Anna F.; Frucht, Steven J.; Blitzer, Andrew; Ozelius, Laurie J.; Simonyan, Kristina

2017-01-01

Background Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. Methods Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). Results Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. Conclusions Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. PMID:28186656

Enhancing GTEx by bridging the gaps between genotype, gene expression, and disease.

PubMed

2017-12-01

Genetic variants have been associated with myriad molecular phenotypes that provide new insight into the range of mechanisms underlying genetic traits and diseases. Identifying any particular genetic variant's cascade of effects, from molecule to individual, requires assaying multiple layers of molecular complexity. We introduce the Enhancing GTEx (eGTEx) project that extends the GTEx project to combine gene expression with additional intermediate molecular measurements on the same tissues to provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health.

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer.

PubMed

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-05-30

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity.

Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis

PubMed Central

Huang, Bin; Jolly, Mohit Kumar; Lu, Mingyang; Tsarfaty, Ilan; Ben-Jacob, Eshel; Onuchic, Jose’ N

2015-01-01

Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms —Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) – have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT). PMID:26627083

Discordant introgression in a rapidly expanding hybrid swarm

USGS Publications Warehouse

Ward, Jessica L.; Blum, Mike J.; Walters, David M.; Porter, Brady A.; Burkhead, Noel; Freeman, Byron

2012-01-01

The erosion of species boundaries can involve rapid evolutionary change. Consequently, many aspects of the process remain poorly understood, including the formation, expansion, and evolution of hybrid swarms. Biological invasions involving hybridization present exceptional opportunities to study the erosion of species boundaries because timelines of interactions and outcomes are frequently well known. Here, we examined clinal variation across codominant and maternally inherited genetic markers as well as phenotypic traits to characterize the expansion and evolution of a hybrid swarm between native Cyprinella venusta and invasive Cyprinella lutrensis minnows. Discordant introgression of phenotype, microsatellite multilocus genotype, and mtDNA haplotype indicates that the observable expansion of the C. venusta x C. lutrensis hybrid swarm is a false invasion front. Both parental and hybrid individuals closely resembling C. lutrensis are numerically dominant in the expansion wake, indicating that the non-native parental phenotype may be selectively favored. These findings show that cryptic introgression can extend beyond the phenotypic boundaries of hybrid swarms and that hybrid swarms likely expand more rapidly than can be documented from phenotypic variation alone. Similarly, dominance of a single parental phenotype following an introduction event may lead to instances of species erosion being mistaken for species displacement without hybridization.

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

PubMed Central

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-01-01

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

Figurative language processing in atypical populations: the ASD perspective

PubMed Central

Vulchanova, Mila; Saldaña, David; Chahboun, Sobh; Vulchanov, Valentin

2015-01-01

This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation. PMID:25741261

Figurative language processing in atypical populations: the ASD perspective.

PubMed

Vulchanova, Mila; Saldaña, David; Chahboun, Sobh; Vulchanov, Valentin

2015-01-01

This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation.

Structural and functional role of bases 32 and 33 in the anticodon loop of yeast mitochondrial tRNAIle

PubMed Central

Montanari, Arianna; De Luca, Cristina; Di Micco, Patrizio; Morea, Veronica; Frontali, Laura; Francisci, Silvia

2011-01-01

Previous work has demonstrated the usefulness of the yeast model to investigate the molecular mechanisms underlying defects due to base substitutions in mitochondrial tRNA genes, and to identify suppressing molecules endowed with potential clinical relevance. The present paper extends these investigations to two human equivalent yeast mutations located at positions 32 and 33 in the anticodon loop of tRNAIle. Notwithstanding the proximity of the two T>C base substitutions, the effects of these mutations have been found to be quite different in yeast, as they are in human. The T32C substitution has a very severe effect in yeast, consisting in a complete inhibition of growth on nonfermentable substrates. Conversely, respiratory defects caused by the T33C mutation could only be observed in a defined genetic context. Analyses of available sequences and selected tRNA three-dimensional structures were performed to provide explanations for the different behavior of these adjacent mutations. Examination of the effects of previously identified suppressors demonstrated that overexpression of the TUF1 gene did not rescue the defective phenotypes determined by either mutation, possibly as a consequence of the lack of interactions between EF-Tu and the tRNA anticodon arm in known structures. On the contrary, both the cognate IleRS and the noncognate LeuRS and ValRS are endowed with suppressing activities toward both mutations. This allows us to extend to the tRNAIle mutants the cross-suppression activity of aminoacyl-tRNA synthetases previously demonstrated for tRNALeu and tRNAVal mutants. PMID:21914842

Distribution of genotype network sizes in sequence-to-structure genotype-phenotype maps.

PubMed

Manrubia, Susanna; Cuesta, José A

2017-04-01

An essential quantity to ensure evolvability of populations is the navigability of the genotype space. Navigability, understood as the ease with which alternative phenotypes are reached, relies on the existence of sufficiently large and mutually attainable genotype networks. The size of genotype networks (e.g. the number of RNA sequences folding into a particular secondary structure or the number of DNA sequences coding for the same protein structure) is astronomically large in all functional molecules investigated: an exhaustive experimental or computational study of all RNA folds or all protein structures becomes impossible even for moderately long sequences. Here, we analytically derive the distribution of genotype network sizes for a hierarchy of models which successively incorporate features of increasingly realistic sequence-to-structure genotype-phenotype maps. The main feature of these models relies on the characterization of each phenotype through a prototypical sequence whose sites admit a variable fraction of letters of the alphabet. Our models interpolate between two limit distributions: a power-law distribution, when the ordering of sites in the prototypical sequence is strongly constrained, and a lognormal distribution, as suggested for RNA, when different orderings of the same set of sites yield different phenotypes. Our main result is the qualitative and quantitative identification of those features of sequence-to-structure maps that lead to different distributions of genotype network sizes. © 2017 The Author(s).

Adaptive potential of genomic structural variation in human and mammalian evolution.

PubMed

Radke, David W; Lee, Charles

2015-09-01

Because phenotypic innovations must be genetically heritable for biological evolution to proceed, it is natural to consider new mutation events as well as standing genetic variation as sources for their birth. Previous research has identified a number of single-nucleotide polymorphisms that underlie a subset of adaptive traits in organisms. However, another well-known class of variation, genomic structural variation, could have even greater potential to produce adaptive phenotypes, due to the variety of possible types of alterations (deletions, insertions, duplications, among others) at different genomic positions and with variable lengths. It is from these dramatic genomic alterations, and selection on their phenotypic consequences, that adaptations leading to biological diversification could be derived. In this review, using studies in humans and other mammals, we highlight examples of how phenotypic variation from structural variants might become adaptive in populations and potentially enable biological diversification. Phenotypic change arising from structural variants will be described according to their immediate effect on organismal metabolic processes, immunological response and physical features. Study of population dynamics of segregating structural variation can therefore provide a window into understanding current and historical biological diversification. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Chemical Fluxes in Cellular Steady States Measured by Fluorescence Correlation Spectroscopy

NASA Astrophysics Data System (ADS)

Qian, Hong; Elson, Elliot L.

Genetically, identical cells adopt phenotypes that have different structures, functions, and metabolic properties. In multi-cellular organisms, for example, tissue-specific phenotypes distinguish muscle cells, liver cells, fibroblasts, and blood cells that differ in biochemical functions, geometric forms, and interactions with extracellular environments. Tissue-specific cells usually have different metabolic functions such as synthesis of distinct spectra of secreted proteins, e.g., by liver or pancreatic cells, or of structural proteins, e.g., muscle vs. epithelial cells. But more importantly, a phenotype should include a dynamic aspect: different phenotypes can have distinctly different dynamic functions such as contraction of muscle cells and locomotion of leukocytes. The phenotypes of differentiated tissue cells are typically stable, but they can respond to changes in external conditions, e.g., as in the hypertrophy of muscle cells in response to extra load [1] or the phenotypic shift of fibroblasts to myofibroblasts as part of the wound healing response [2]. Cells pass through sequences of phenotypes during development and also undergo malignant phenotypic transformations as occur in cancer and heart disease.

Mutational robustness accelerates the origin of novel RNA phenotypes through phenotypic plasticity.

PubMed

Wagner, Andreas

2014-02-18

Novel phenotypes can originate either through mutations in existing genotypes or through phenotypic plasticity, the ability of one genotype to form multiple phenotypes. From molecules to organisms, plasticity is a ubiquitous feature of life, and a potential source of exaptations, adaptive traits that originated for nonadaptive reasons. Another ubiquitous feature is robustness to mutations, although it is unknown whether such robustness helps or hinders the origin of new phenotypes through plasticity. RNA is ideal to address this question, because it shows extensive plasticity in its secondary structure phenotypes, a consequence of their continual folding and unfolding, and these phenotypes have important biological functions. Moreover, RNA is to some extent robust to mutations. This robustness structures RNA genotype space into myriad connected networks of genotypes with the same phenotype, and it influences the dynamics of evolving populations on a genotype network. In this study I show that both effects help accelerate the exploration of novel phenotypes through plasticity. My observations are based on many RNA molecules sampled at random from RNA sequence space, and on 30 biological RNA molecules. They are thus not only a generic feature of RNA sequence space but are relevant for the molecular evolution of biological RNA. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Long-term culture-induced phenotypic difference and efficient cryopreservation of small intestinal organoids by treatment timing of Rho kinase inhibitor.

PubMed

Han, Sung-Hoon; Shim, Sehwan; Kim, Min-Jung; Shin, Hye-Yun; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Lee, Seung Bum; Park, Sunhoo

2017-02-14

To investigate a suitable long-term culture system and optimal cryopreservation of intestinal organoid to improve organoid-based therapy by acquiring large numbers of cells. Crypts were isolated from jejunum of C57BL/6 mouse. Two hundred crypts were cultured in organoid medium with either epidermal growth factor/Noggin/R-spondin1 (ENR) or ENR/CHIR99021/VPA (ENR-CV). For subculture, organoids cultured on day 7 were passaged using enzyme-free cell dissociation buffer (STEMCELL Technologies). The passage was performed once per week until indicated passage. For cryopreservation, undissociated and dissociated organoids were resuspended in freezing medium with or without Rho kinase inhibitor subjected to different treatment times. The characteristics of intestinal organoids upon extended passage and freeze-thaw were analyzed using EdU staining, methyl thiazolyl tetrazolium assay, qPCR and time-lapse live cell imaging. We established a three-dimensional culture system for murine small intestinal organoids using ENR and ENR-CV media. Both conditions yielded organoids with a crypt-villus architecture exhibiting Lgr5 + cells and differentiated intestinal epithelial cells as shown by morphological and biochemical analysis. However, during extended passage (more than 3 mo), a comparative analysis revealed that continuous passaging under ENR-CV conditions, but not ENR conditions induced phenotypic changes as observed by morphological transition, reduced numbers of Lgr5 + cells and inconsistent expression of markers for differentiated intestinal epithelial cell types. We also found that recovery of long-term cryopreserved organoids was significantly affected by the organoid state, i.e ., whether dissociation was applied, and the timing of treatment with the Rho-kinase inhibitor Y-27632. Furthermore, the retention of typical morphological characteristics of intestinal organoids such as the crypt-villus structure from freeze-thawed cells was observed by live cell imaging. The maintenance of the characteristics of intestinal organoids upon extended passage is mediated by ENR condition, but not ENR-CV condition. Identified long-term cryopreservation may contribute to the establishment of standardized cryopreservation protocols for intestinal organoids for use in clinical applications.

The role of social and ecological processes in structuring animal populations: a case study from automated tracking of wild birds

PubMed Central

Farine, Damien R.; Firth, Josh A.; Aplin, Lucy M.; Crates, Ross A.; Culina, Antica; Garroway, Colin J.; Hinde, Camilla A.; Kidd, Lindall R.; Milligan, Nicole D.; Psorakis, Ioannis; Radersma, Reinder; Verhelst, Brecht; Voelkl, Bernhard; Sheldon, Ben C.

2015-01-01

Both social and ecological factors influence population process and structure, with resultant consequences for phenotypic selection on individuals. Understanding the scale and relative contribution of these two factors is thus a central aim in evolutionary ecology. In this study, we develop a framework using null models to identify the social and spatial patterns that contribute to phenotypic structure in a wild population of songbirds. We used automated technologies to track 1053 individuals that formed 73 737 groups from which we inferred a social network. Our framework identified that both social and spatial drivers contributed to assortment in the network. In particular, groups had a more even sex ratio than expected and exhibited a consistent age structure that suggested local association preferences, such as preferential attachment or avoidance. By contrast, recent immigrants were spatially partitioned from locally born individuals, suggesting differential dispersal strategies by phenotype. Our results highlight how different scales of social decision-making, ranging from post-natal dispersal settlement to fission–fusion dynamics, can interact to drive phenotypic structure in animal populations. PMID:26064644

Phenotype- and genotype-specific structural alterations in spasmodic dysphonia.

PubMed

Bianchi, Serena; Battistella, Giovanni; Huddleston, Hailey; Scharf, Rebecca; Fleysher, Lazar; Rumbach, Anna F; Frucht, Steven J; Blitzer, Andrew; Ozelius, Laurie J; Simonyan, Kristina

2017-04-01

Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Defining the Relationship Between Phenotypic and Genotypic Resistance Profiles of Multidrug-Resistant Enterobacterial Clinical Isolates.

PubMed

Galal, Lamis; Abdel Aziz, Neveen A; Hassan, Walaa M

2018-05-11

Fluoroquinolones and aminoglycosides offer effective therapy for extended-spectrum beta-lactamase (ESBL)-producing enterobacterial infections, but their usefulness is threatened by increasing resistant strains. This study was conducted to demonstrate the phenotypic outcomes of the coexistence of genetic determinants mediating resistance to extended-spectrum cephalosporins and quinolones in enterobacterial isolates collected from patients with health-care-associated infections in Egypt. ESBL phenotype was determined using double-disk synergy test (DDST). The PCR technique was used to detect the presence of the genes mediating quinolone resistance (qnr and aac(6')-Ib-cr) and coexistence with ESBL genes. We also examined the association between the genetic makeup of the isolates and their resistance profiles including effect on MIC results. Phenotypically ESBLs were detected in 60-82% of the enterobacterial isolates. ESBL, qnr and aac(6')-Ib-cr genes were detected with the following percentages in Citrobacter isolates (69%, 69%, and 43%, respectively), E.coli isolates (65%, 70%, and 45%, respectively), Enterobacter isolates (56%, 67%, and 33%, respectively), and finally Klebsiella isolates (42%, 66%, and 25%, respectively). The coexistence of these multiresistant genetic elements significantly increased the MIC values of the tested antibiotics from different classes. We suggest using blaTEM, blaCTX-M-15, qnr, and aac(6')-Ib-cr genes for better and faster prediction of suitable antibiotic therapy with effective doses against ESBL-producing isolates harboring plasmid-mediated quinolone resistance (PMQR) determinants. Amikacin, meropenem, gentamicin, and imipenem seem to be better choices of treatment for such life-threatening infections, because of their remaining highest activity.

A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.

PubMed

Bruserud, Øyvind; Oftedal, Bergithe E; Landegren, Nils; Erichsen, Martina M; Bratland, Eirik; Lima, Kari; Jørgensen, Anders P; Myhre, Anne G; Svartberg, Johan; Fougner, Kristian J; Bakke, Åsne; Nedrebø, Bjørn G; Mella, Bjarne; Breivik, Lars; Viken, Marte K; Knappskog, Per M; Marthinussen, Mihaela C; Løvås, Kristian; Kämpe, Olle; Wolff, Anette B; Husebye, Eystein S

2016-08-01

Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). All known Norwegian patients with APS1. Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1

PubMed Central

Bruserud, Øyvind; Oftedal, Bergithe E.; Landegren, Nils; Erichsen, Martina M.; Bratland, Eirik; Lima, Kari; Jørgensen, Anders P.; Myhre, Anne G.; Svartberg, Johan; Fougner, Kristian J.; Bakke, Åsne; Nedrebø, Bjørn G.; Mella, Bjarne; Breivik, Lars; Viken, Marte K.; Knappskog, Per M.; Marthinussen, Mihaela C.; Løvås, Kristian; Kämpe, Olle; Wolff, Anette B.

2016-01-01

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996–2016). Patients: All known Norwegian patients with APS1. Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center. PMID:27253668

Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice

PubMed Central

Kwon, Deborah Y.; Motley, William W.; Fischbeck, Kenneth H.; Burnett, Barrington G.

2011-01-01

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced levels of the survival motor neuron (SMN) protein. Here we show that the proteasome inhibitor, bortezomib, increases SMN in cultured cells and in peripheral tissues of SMA model mice. Bortezomib-treated animals had improved motor function, which was associated with reduced spinal cord and muscle pathology and improved neuromuscular junction size, but no change in survival. Combining bortezomib with the histone deacetylase inhibitor trichostatin A (TSA) resulted in a synergistic increase in SMN protein levels in mouse tissue and extended survival of SMA mice more than TSA alone. Our results demonstrate that a combined regimen of drugs that decrease SMN protein degradation and increase SMN gene transcription synergistically increases SMN levels and improves the lifespan of SMA model mice. Moreover, this study indicates that while increasing SMN levels in the central nervous system may help extend survival, peripheral tissues can also be targeted to improve the SMA disease phenotype. PMID:21693563

Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancer in vivo

NASA Astrophysics Data System (ADS)

Lobikin, Maria; Chernet, Brook; Lobo, Daniel; Levin, Michael

2012-12-01

Cancer may result from localized failure of instructive cues that normally orchestrate cell behaviors toward the patterning needs of the organism. Steady-state gradients of transmembrane voltage (Vmem) in non-neural cells are instructive, epigenetic signals that regulate pattern formation during embryogenesis and morphostatic repair. Here, we review molecular data on the role of bioelectric cues in cancer and present new findings in the Xenopus laevis model on how the microenvironment's biophysical properties contribute to cancer in vivo. First, we investigated the melanoma-like phenotype arising from serotonergic signaling by ‘instructor’ cells—a cell population that is able to induce a metastatic phenotype in normal melanocytes. We show that when these instructor cells are depolarized, blood vessel patterning is disrupted in addition to the metastatic phenotype induced in melanocytes. Surprisingly, very few instructor cells need to be depolarized for the hyperpigmentation phenotype to occur; we present a model of antagonistic signaling by serotonin receptors that explains the unusual all-or-none nature of this effect. In addition to the body-wide depolarization-induced metastatic phenotype, we investigated the bioelectrical properties of tumor-like structures induced by canonical oncogenes and cancer-causing compounds. Exposure to carcinogen 4-nitroquinoline 1-oxide (4NQO) induces localized tumors, but has a broad (and variable) effect on the bioelectric properties of the whole body. Tumors induced by oncogenes show aberrantly high sodium content, representing a non-invasive diagnostic modality. Importantly, depolarized transmembrane potential is not only a marker of cancer but is functionally instructive: susceptibility to oncogene-induced tumorigenesis is significantly reduced by forced prior expression of hyperpolarizing ion channels. Importantly, the same effect can be achieved by pharmacological manipulation of endogenous chloride channels, suggesting a strategy for cancer suppression that does not require gene therapy. Together, these data extend our understanding of the recently demonstrated role of transmembrane potential in tumor formation and metastatic cell behavior. Vmem is an important non-genetic biophysical aspect of the microenvironment that regulates the balance between normally patterned growth and carcinogenesis.

PlantCV v2: Image analysis software for high-throughput plant phenotyping

PubMed Central

Abbasi, Arash; Berry, Jeffrey C.; Callen, Steven T.; Chavez, Leonardo; Doust, Andrew N.; Feldman, Max J.; Gilbert, Kerrigan B.; Hodge, John G.; Hoyer, J. Steen; Lin, Andy; Liu, Suxing; Lizárraga, César; Lorence, Argelia; Miller, Michael; Platon, Eric; Tessman, Monica; Sax, Tony

2017-01-01

Systems for collecting image data in conjunction with computer vision techniques are a powerful tool for increasing the temporal resolution at which plant phenotypes can be measured non-destructively. Computational tools that are flexible and extendable are needed to address the diversity of plant phenotyping problems. We previously described the Plant Computer Vision (PlantCV) software package, which is an image processing toolkit for plant phenotyping analysis. The goal of the PlantCV project is to develop a set of modular, reusable, and repurposable tools for plant image analysis that are open-source and community-developed. Here we present the details and rationale for major developments in the second major release of PlantCV. In addition to overall improvements in the organization of the PlantCV project, new functionality includes a set of new image processing and normalization tools, support for analyzing images that include multiple plants, leaf segmentation, landmark identification tools for morphometrics, and modules for machine learning. PMID:29209576

PlantCV v2: Image analysis software for high-throughput plant phenotyping.

PubMed

Gehan, Malia A; Fahlgren, Noah; Abbasi, Arash; Berry, Jeffrey C; Callen, Steven T; Chavez, Leonardo; Doust, Andrew N; Feldman, Max J; Gilbert, Kerrigan B; Hodge, John G; Hoyer, J Steen; Lin, Andy; Liu, Suxing; Lizárraga, César; Lorence, Argelia; Miller, Michael; Platon, Eric; Tessman, Monica; Sax, Tony

2017-01-01

Systems for collecting image data in conjunction with computer vision techniques are a powerful tool for increasing the temporal resolution at which plant phenotypes can be measured non-destructively. Computational tools that are flexible and extendable are needed to address the diversity of plant phenotyping problems. We previously described the Plant Computer Vision (PlantCV) software package, which is an image processing toolkit for plant phenotyping analysis. The goal of the PlantCV project is to develop a set of modular, reusable, and repurposable tools for plant image analysis that are open-source and community-developed. Here we present the details and rationale for major developments in the second major release of PlantCV. In addition to overall improvements in the organization of the PlantCV project, new functionality includes a set of new image processing and normalization tools, support for analyzing images that include multiple plants, leaf segmentation, landmark identification tools for morphometrics, and modules for machine learning.

PlantCV v2: Image analysis software for high-throughput plant phenotyping

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

Gehan, Malia A.; Fahlgren, Noah; Abbasi, Arash

Systems for collecting image data in conjunction with computer vision techniques are a powerful tool for increasing the temporal resolution at which plant phenotypes can be measured non-destructively. Computational tools that are flexible and extendable are needed to address the diversity of plant phenotyping problems. We previously described the Plant Computer Vision (PlantCV) software package, which is an image processing toolkit for plant phenotyping analysis. The goal of the PlantCV project is to develop a set of modular, reusable, and repurposable tools for plant image analysis that are open-source and community-developed. Here in this paper we present the details andmore » rationale for major developments in the second major release of PlantCV. In addition to overall improvements in the organization of the PlantCV project, new functionality includes a set of new image processing and normalization tools, support for analyzing images that include multiple plants, leaf segmentation, landmark identification tools for morphometrics, and modules for machine learning.« less

A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype-phenotype correlation.

PubMed

M'Dimegh, Saoussen; Aquaviva-Bourdain, Cécile; Omezzine, Asma; M'Barek, Ibtihel; Souche, Geneviéve; Zellama, Dorsaf; Abidi, Kamel; Achour, Abdelattif; Gargah, Tahar; Abroug, Saoussen; Bouslama, Ali

2016-09-01

Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron-exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.Gln137Hisfs*19 mutation detected in our study extend the spectrum of known AGXT gene mutations in Tunisia.

An evaluation of the NQF Quality Data Model for representing Electronic Health Record driven phenotyping algorithms.

PubMed

Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Peissig, Peggy L; Denny, Joshua C; Kho, Abel N; Miller, Aaron; Pathak, Jyotishman

2012-01-01

The development of Electronic Health Record (EHR)-based phenotype selection algorithms is a non-trivial and highly iterative process involving domain experts and informaticians. To make it easier to port algorithms across institutions, it is desirable to represent them using an unambiguous formal specification language. For this purpose we evaluated the recently developed National Quality Forum (NQF) information model designed for EHR-based quality measures: the Quality Data Model (QDM). We selected 9 phenotyping algorithms that had been previously developed as part of the eMERGE consortium and translated them into QDM format. Our study concluded that the QDM contains several core elements that make it a promising format for EHR-driven phenotyping algorithms for clinical research. However, we also found areas in which the QDM could be usefully extended, such as representing information extracted from clinical text, and the ability to handle algorithms that do not consist of Boolean combinations of criteria.

PlantCV v2: Image analysis software for high-throughput plant phenotyping

DOE PAGES

Gehan, Malia A.; Fahlgren, Noah; Abbasi, Arash; ...

2017-12-01

Systems for collecting image data in conjunction with computer vision techniques are a powerful tool for increasing the temporal resolution at which plant phenotypes can be measured non-destructively. Computational tools that are flexible and extendable are needed to address the diversity of plant phenotyping problems. We previously described the Plant Computer Vision (PlantCV) software package, which is an image processing toolkit for plant phenotyping analysis. The goal of the PlantCV project is to develop a set of modular, reusable, and repurposable tools for plant image analysis that are open-source and community-developed. Here in this paper we present the details andmore » rationale for major developments in the second major release of PlantCV. In addition to overall improvements in the organization of the PlantCV project, new functionality includes a set of new image processing and normalization tools, support for analyzing images that include multiple plants, leaf segmentation, landmark identification tools for morphometrics, and modules for machine learning.« less

Palisade endings are present in canine extraocular muscles and have a cholinergic phenotype.

PubMed

Rungaldier, Stefanie; Pomikal, Christine; Streicher, Johannes; Blumer, Roland

2009-11-20

Classical proprioceptors, like Golgi tendon organs and muscle spindles are absent in the extraocular muscles (EOMs) of most mammals. Instead, a nerve end organ was detected in the EOMs of each species including sheep, cat, rabbit, rat, monkey, and human examined so far: the palisade ending. Until now no clear evidence appeared that palisade endings are also present in canine EOMs. Here, we analyzed dog EOMs by confocal laser scanning microscopy, 3D reconstruction, and transmission electron microscopy. In EOM wholemount preparations stained with antibodies against neurofilament and synaptophysin we could demonstrate typical palisade endings. Nerve fibers coming from the muscle extend into the tendon. There, the nerve fibers turn 180 degrees and return to branch into preterminal axons which establish nerve terminals around a single muscle fiber tip. Fine structural analysis revealed that each palisade ending in dog EOMs establish nerve terminals on the tendon. In some palisade endings we found nerve terminals contacting the muscle fiber as well. Such neuromuscular contacts have a basal lamina in the synaptic cleft. By using an antibody against choline acetyltransferase (ChAT) we proved that canine palisade endings are ChAT-immunoreactive. This study shows that palisade endings are present in canine EOMs. In line with prior findings in cat and monkey, palisade endings in dog have a cholinergic phenotype.

ABO blood group phenotype frequency estimation using molecular phenotyping in rhesus and cynomolgus macaques.

PubMed

Kanthaswamy, S; Ng, J; Oldt, R F; Valdivia, L; Houghton, P; Smith, D G

2017-11-01

A much larger sample (N = 2369) was used to evaluate a previously reported distribution of the A, AB and B blood group phenotypes in rhesus and cynomolgus macaques from six different regional populations. These samples, acquired from 15 different breeding and research facilities in the United States, were analyzed using a real-time quantitative polymerase chain reaction (qPCR) assay that targets single nucleotide polymorphisms (SNPs) responsible for the macaque A, B and AB phenotypes. The frequency distributions of blood group phenotypes of the two species differ significantly from each other and significant regional differentiation within the geographic ranges of each species was also observed. The B blood group phenotype was prevalent in rhesus macaques, especially those from India, while the frequencies of the A, B and AB phenotypes varied significantly among cynomolgus macaques from different geographic regions. The Mauritian cynomolgus macaques, despite having originated in Indonesia, showed significant (P ≪ .01) divergence from the Indonesian animals at the ABO blood group locus. Most Mauritian animals belonged to the B blood group while the Indonesian animals were mostly A. The close similarity in blood group frequency distributions between the Chinese rhesus and Indochinese cynomolgus macaques demonstrates that the introgression between these two species extends beyond the zone of intergradation in Indochina. This study underscores the importance of ABO blood group phenotyping of the domestic supply of macaques and their biospecimens. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of the Clinical and Laboratory Standards Institute phenotypic confirmatory test to detect the presence of extended-spectrum β-lactamases from 4005 Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae and Proteus mirabilis isolates.

PubMed

Morrissey, Ian; Bouchillon, Samuel K; Hackel, Meredith; Biedenbach, Douglas J; Hawser, Stephen; Hoban, Daryl; Badal, Robert E

2014-04-01

A subset of Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae and Proteus mirabilis isolates collected for the Study for Monitoring Antimicrobial Resistance Trends that were positive for the Clinical and Laboratory Standards Institute (CLSI) extended-spectrum β-lactamase (ESBL) phenotypic confirmatory test (n = 3245) or had an ertapenem MIC of ≥0.5 µg ml(-1) (n = 293), or both (n = 467), were analysed for ESBL genes. Most ESBL phenotype E. coli or K. pneumoniae possessed an ESBL gene (95.8 and 88.4 %, respectively), and this was 93.1 % if carbapenem-non-susceptible K. pneumoniae were removed. This rate was lower for P. mirabilis (73.4 %) and K. oxytoca (62.5 %). Virtually all ESBL-positive isolates (99.5 %) were cefotaxime non-susceptible [CLSI or European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints)]. Fewer isolates (82 %) were ceftazidime non-susceptible (CLSI breakpoints). In addition, 21.1 % of E. coli, 25 % of K. oxytoca and 78.7 % of P. mirabilis isolates were ceftazidime susceptible but ESBL positive. This suggests that CLSI breakpoints for ceftazidime are too high to detect ESBLs. The lower EUCAST breakpoints detected ESBLs in E. coli and K. oxytoca better, but 59.6 % of ESBL-positive isolates of P. mirabilis were ceftazidime susceptible. For isolates with ertapenem MICs ≥0.5 µg ml(-1), more accurate ESBL phenotype analysis was observed for E. coli and K. pneumoniae (sensitivity >95 % for both, specificity 94.4 and 54.1 %, respectively). If carbapenemase-positive K. pneumoniae were excluded, the specificity increased to 78 %. The positive predictive values for the ESBL phenotypic test with E. coli and K. pneumoniae were 97.6 and 81.8 %, respectively, and negative predictive values were 75.9 and 95.2 %, respectively. We therefore suggest that it would be prudent to confirm phenotypic ESBL-positive P. mirabilis, K. pneumoniae and K. oxytoca with molecular analysis.

Genome-wide Association Study Identifies Loci for the Polled Phenotype in Yak

PubMed Central

Wu, Xiaoyun; Wang, Kun; Ding, Xuezhi; Wang, Mingcheng; Chu, Min; Xie, Xiuyue; Qiu, Qiang; Yan, Ping

2016-01-01

The absence of horns, known as the polled phenotype, is an economically important trait in modern yak husbandry, but the genomic structure and genetic basis of this phenotype have yet to be discovered. Here, we conducted a genome-wide association study with a panel of 10 horned and 10 polled yaks using whole genome sequencing. We mapped the POLLED locus to a 200-kb interval, which comprises three protein-coding genes. Further characterization of the candidate region showed recent artificial selection signals resulting from the breeding process. We suggest that expressional variations rather than structural variations in protein probably contribute to the polled phenotype. Our results not only represent the first and important step in establishing the genomic structure of the polled region in yak, but also add to our understanding of the polled trait in bovid species. PMID:27389700

Structure of the Autism Symptom Phenotype: A Proposed Multidimensional Model

ERIC Educational Resources Information Center

Georgiades, Stelios; Szatmari, Peter; Zwaigenbaum, Lonnie; Duku, Eric; Bryson, Susan; Roberts, Wendy; Goldberg, Jeremy; Mahoney, William

2007-01-01

Background: The main objective of this study was to develop a comprehensive, empirical model that would allow the reorganization of the structure of the pervasive developmental disorder symptom phenotype through factor analysis into more homogeneous dimensions. Method: The sample consisted of 209 children with pervasive developmental disorder…

Potentials and capabilities of the Extracellular Vesicle (EV) Array.

PubMed

Jørgensen, Malene Møller; Bæk, Rikke; Varming, Kim

2015-01-01

Extracellular vesicles (EVs) and exosomes are difficult to enrich or purify from biofluids, hence quantification and phenotyping of these are tedious and inaccurate. The multiplexed, highly sensitive and high-throughput platform of the EV Array presented by Jørgensen et al., (J Extracell Vesicles, 2013; 2: 10) has been refined regarding the capabilities of the method for characterization and molecular profiling of EV surface markers. Here, we present an extended microarray platform to detect and phenotype plasma-derived EVs (optimized for exosomes) for up to 60 antigens without any enrichment or purification prior to analysis.

Copy number variation signature to predict human ancestry

PubMed Central

2012-01-01

Background Copy number variations (CNVs) are genomic structural variants that are found in healthy populations and have been observed to be associated with disease susceptibility. Existing methods for CNV detection are often performed on a sample-by-sample basis, which is not ideal for large datasets where common CNVs must be estimated by comparing the frequency of CNVs in the individual samples. Here we describe a simple and novel approach to locate genome-wide CNVs common to a specific population, using human ancestry as the phenotype. Results We utilized our previously published Genome Alteration Detection Analysis (GADA) algorithm to identify common ancestry CNVs (caCNVs) and built a caCNV model to predict population structure. We identified a 73 caCNV signature using a training set of 225 healthy individuals from European, Asian, and African ancestry. The signature was validated on an independent test set of 300 individuals with similar ancestral background. The error rate in predicting ancestry in this test set was 2% using the 73 caCNV signature. Among the caCNVs identified, several were previously confirmed experimentally to vary by ancestry. Our signature also contains a caCNV region with a single microRNA (MIR270), which represents the first reported variation of microRNA by ancestry. Conclusions We developed a new methodology to identify common CNVs and demonstrated its performance by building a caCNV signature to predict human ancestry with high accuracy. The utility of our approach could be extended to large case–control studies to identify CNV signatures for other phenotypes such as disease susceptibility and drug response. PMID:23270563

Structural and Functional Phenotyping of the Failing Heart: Is the Left Ventricular Ejection Fraction Obsolete?

PubMed

Bristow, Michael R; Kao, David P; Breathett, Khadijah K; Altman, Natasha L; Gorcsan, John; Gill, Edward A; Lowes, Brian D; Gilbert, Edward M; Quaife, Robert A; Mann, Douglas L

2017-11-01

Diagnosis, prognosis, treatment, and development of new therapies for diseases or syndromes depend on a reliable means of identifying phenotypes associated with distinct predictive probabilities for these various objectives. Left ventricular ejection fraction (LVEF) provides the current basis for combined functional and structural phenotyping in heart failure by classifying patients as those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF). Recently the utility of LVEF as the major phenotypic determinant of heart failure has been challenged based on its load dependency and measurement variability. We review the history of the development and adoption of LVEF as a critical measurement of LV function and structure and demonstrate that, in chronic heart failure, load dependency is not an important practical issue, and we provide hemodynamic and molecular biomarker evidence that LVEF is superior or equal to more unwieldy methods of identifying phenotypes of ventricular remodeling. We conclude that, because it reliably measures both left ventricular function and structure, LVEF remains the best current method of assessing pathologic remodeling in heart failure in both individual clinical and multicenter group settings. Because of the present and future importance of left ventricular phenotyping in heart failure, LVEF should be measured by using the most accurate technology and methodologic refinements available, and improved characterization methods should continue to be sought. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology

PubMed Central

Shackman, Alexander J.; Fox, Andrew S.; Oler, Jonathan A.; Shelton, Steven E.; Oakes, Terrence R.; Davidson, Richard J.; Kalin, Ned H.

2016-01-01

Children with an anxious temperament (AT) are prone to heightened shyness and behavioral inhibition (BI). When chronic and extreme, this anxious, inhibited phenotype is an important early-life risk factor for the development of anxiety disorders, depression, and co-morbid substance abuse. Individuals with extreme AT often show persistent distress in the absence of immediate threat and this contextually inappropriate anxiety predicts future symptom development. Despite its clear clinical relevance, the neural circuitry governing the maladaptive persistence of anxiety remains unknown. Here, we used a well-established nonhuman primate model of childhood temperament and high-resolution 18fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to understand the neural systems governing persistent anxiety and clarify their relevance to early-life phenotypic risk. We focused on BI, a core component of anxious temperament, because it affords the moment-by-moment temporal resolution needed to assess contextually appropriate and inappropriate anxiety. From a pool of 109 peri-adolescent rhesus monkeys, we formed groups characterized by high or low levels of BI, as indexed by freezing in response to an unfamiliar human intruder’s profile. The High-BI group showed consistently elevated signs of anxiety and wariness across more than 2 years of assessments. At the time of brain imaging, 1.5 years after initial phenotyping, the High-BI group showed persistently elevated freezing during a 30-min ‘recovery’ period following an encounter with the intruder — more than an order of magnitude greater than the Low-BI group — and this was associated with increased metabolism in the bed nucleus of the stria terminalis, a key component of the central extended amygdala. These observations provide a neurobiological framework for understanding the early phenotypic risk to develop anxiety-related psychopathology, for accelerating the development of improved interventions, and for understanding the origins of childhood temperament. PMID:27573879

An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

PubMed

Mugzach, Omri; Peleg, Mor; Bagley, Steven C; Guter, Stephen J; Cook, Edwin H; Altman, Russ B

2015-08-01

Our goal is to create an ontology that will allow data integration and reasoning with subject data to classify subjects, and based on this classification, to infer new knowledge on Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders (NDD). We take a first step toward this goal by extending an existing autism ontology to allow automatic inference of ASD phenotypes and Diagnostic & Statistical Manual of Mental Disorders (DSM) criteria based on subjects' Autism Diagnostic Interview-Revised (ADI-R) assessment data. Knowledge regarding diagnostic instruments, ASD phenotypes and risk factors was added to augment an existing autism ontology via Ontology Web Language class definitions and semantic web rules. We developed a custom Protégé plugin for enumerating combinatorial OWL axioms to support the many-to-many relations of ADI-R items to diagnostic categories in the DSM. We utilized a reasoner to infer whether 2642 subjects, whose data was obtained from the Simons Foundation Autism Research Initiative, meet DSM-IV-TR (DSM-IV) and DSM-5 diagnostic criteria based on their ADI-R data. We extended the ontology by adding 443 classes and 632 rules that represent phenotypes, along with their synonyms, environmental risk factors, and frequency of comorbidities. Applying the rules on the data set showed that the method produced accurate results: the true positive and true negative rates for inferring autistic disorder diagnosis according to DSM-IV criteria were 1 and 0.065, respectively; the true positive rate for inferring ASD based on DSM-5 criteria was 0.94. The ontology allows automatic inference of subjects' disease phenotypes and diagnosis with high accuracy. The ontology may benefit future studies by serving as a knowledge base for ASD. In addition, by adding knowledge of related NDDs, commonalities and differences in manifestations and risk factors could be automatically inferred, contributing to the understanding of ASD pathophysiology. Copyright © 2015 Elsevier Inc. All rights reserved.

Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

PubMed Central

Hopkinson, Mark; Poulet, Blandine; Pollard, Andrea S.; Shefelbine, Sandra J.; Chang, Yu-Mei; Francis-West, Philippa; Bou-Gharios, George; Pitsillides, Andrew A.

2016-01-01

Tissue inhibitor of metalloproteinases-3 (TIMP-3) regulates extracellular matrix via its inhibition of matrix metalloproteinases and membrane-bound sheddases. Timp-3 is expressed at multiple sites of extensive tissue remodelling. This extends to bone where its role, however, remains largely unresolved. In this study, we have used Micro-CT to assess bone mass and architecture, histological and histochemical evaluation to characterise the skeletal phenotype of Timp-3 KO mice and have complemented this by also examining similar indices in mice harbouring a Timp-3 transgene driven via a Col-2a-driven promoter to specifically target overexpression to chondrocytes. Our data show that Timp-3 deficiency compromises tibial bone mass and structure in both cortical and trabecular compartments, with corresponding increases in osteoclasts. Transgenic overexpression also generates defects in tibial structure predominantly in the cortical bone along the entire shaft without significant increases in osteoclasts. These alterations in cortical mass significantly compromise predicted tibial load-bearing resistance to torsion in both genotypes. Neither Timp-3 KO nor transgenic mouse growth plates are significantly affected. The impact of Timp-3 deficiency and of transgenic overexpression extends to produce modification in craniofacial bones of both endochondral and intramembranous origins. These data indicate that the levels of Timp-3 are crucial in the attainment of functionally-appropriate bone mass and architecture and that this arises from chondrogenic and osteogenic lineages. PMID:27519049

Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

PubMed

Cohen, Mark; Appleby, Brian; Safar, Jiri G

2016-01-01

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

Packaging and structural phenotype of brome mosaic virus capsid protein with altered N-terminal {beta}-hexamer structure

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

Wispelaere, Melissanne de; Chaturvedi, Sonali; Wilkens, Stephan

2011-10-10

The first 45 amino acid region of brome mosaic virus (BMV) capsid protein (CP) contains RNA binding and structural domains that are implicated in the assembly of infectious virions. One such important structural domain encompassing amino acids {sup 28}QPVIV{sup 32}, highly conserved between BMV and cowpea chlorotic mottle virus (CCMV), exhibits a {beta}-hexamer structure. In this study we report that alteration of the {beta}-hexamer structure by mutating {sup 28}QPVIV{sup 32} to {sup 28}AAAAA{sup 32} had no effect either on symptom phenotype, local and systemic movement in Chenopodium quinoa and RNA profile of in vivo assembled virions. However, sensitivity to RNasemore » and assembly phenotypes distinguished virions assembled with CP subunits having {beta}-hexamer from those of wild type. A comparison of 3-D models obtained by cryo electron microscopy revealed overall similar structural features for wild type and mutant virions, with small but significant differences near the 3-fold axes of symmetry.« less

Microbial community analysis of field-grown soybeans with different nodulation phenotypes.

PubMed

Ikeda, Seishi; Rallos, Lynn Esther E; Okubo, Takashi; Eda, Shima; Inaba, Shoko; Mitsui, Hisayuki; Minamisawa, Kiwamu

2008-09-01

Microorganisms associated with the stems and roots of nonnodulated (Nod(-)), wild-type nodulated (Nod(+)), and hypernodulated (Nod(++)) soybeans [Glycine max (L.) Merril] were analyzed by ribosomal intergenic transcribed spacer analysis (RISA) and automated RISA (ARISA). RISA of stem samples detected no bands specific to the nodulation phenotype, whereas RISA of root samples revealed differential bands for the nodulation phenotypes. Pseudomonas fluorescens was exclusively associated with Nod(+) soybean roots. Fusarium solani was stably associated with nodulated (Nod(+) and Nod(++)) roots and less abundant in Nod(-) soybeans, whereas the abundance of basidiomycetes was just the opposite. The phylogenetic analyses suggested that these basidiomycetous fungi might represent a root-associated group in the Auriculariales. Principal-component analysis of the ARISA results showed that there was no clear relationship between nodulation phenotype and bacterial community structure in the stem. In contrast, both the bacterial and fungal community structures in the roots were related to nodulation phenotype. The principal-component analysis further suggested that bacterial community structure in roots could be classified into three groups according to the nodulation phenotype (Nod(-), Nod(+), or Nod(++)). The analysis of root samples indicated that the microbial community in Nod(-) soybeans was more similar to that in Nod(++) soybeans than to that in Nod(+) soybeans.

Decomposing phenotype descriptions for the human skeletal phenome.

PubMed

Groza, Tudor; Hunter, Jane; Zankl, Andreas

2013-01-01

Over the course of the last few years there has been a significant amount of research performed on ontology-based formalization of phenotype descriptions. The intrinsic value and knowledge captured within such descriptions can only be expressed by taking advantage of their inner structure that implicitly combines qualities and anatomical entities. We present a meta-model (the Phenotype Fragment Ontology) and a processing pipeline that enable together the automatic decomposition and conceptualization of phenotype descriptions for the human skeletal phenome. We use this approach to showcase the usefulness of the generic concept of phenotype decomposition by performing an experimental study on all skeletal phenotype concepts defined in the Human Phenotype Ontology.

Topological Structure of the Space of Phenotypes: The Case of RNA Neutral Networks

PubMed Central

Aguirre, Jacobo; Buldú, Javier M.; Stich, Michael; Manrubia, Susanna C.

2011-01-01

The evolution and adaptation of molecular populations is constrained by the diversity accessible through mutational processes. RNA is a paradigmatic example of biopolymer where genotype (sequence) and phenotype (approximated by the secondary structure fold) are identified in a single molecule. The extreme redundancy of the genotype-phenotype map leads to large ensembles of RNA sequences that fold into the same secondary structure and can be connected through single-point mutations. These ensembles define neutral networks of phenotypes in sequence space. Here we analyze the topological properties of neutral networks formed by 12-nucleotides RNA sequences, obtained through the exhaustive folding of sequence space. A total of 412 sequences fragments into 645 subnetworks that correspond to 57 different secondary structures. The topological analysis reveals that each subnetwork is far from being random: it has a degree distribution with a well-defined average and a small dispersion, a high clustering coefficient, and an average shortest path between nodes close to its minimum possible value, i.e. the Hamming distance between sequences. RNA neutral networks are assortative due to the correlation in the composition of neighboring sequences, a feature that together with the symmetries inherent to the folding process explains the existence of communities. Several topological relationships can be analytically derived attending to structural restrictions and generic properties of the folding process. The average degree of these phenotypic networks grows logarithmically with their size, such that abundant phenotypes have the additional advantage of being more robust to mutations. This property prevents fragmentation of neutral networks and thus enhances the navigability of sequence space. In summary, RNA neutral networks show unique topological properties, unknown to other networks previously described. PMID:22028856

Endocrinology of human female sexuality, mating, and reproductive behavior.

PubMed

Motta-Mena, Natalie V; Puts, David A

2017-05-01

Hormones orchestrate and coordinate human female sexual development, sexuality, and reproduction in relation to three types of phenotypic changes: life history transitions such as puberty and childbirth, responses to contextual factors such as caloric intake and stress, and cyclical patterns such as the ovulatory cycle. Here, we review the endocrinology underlying women's reproductive phenotypes, including sexual orientation and gender identity, mate preferences, competition for mates, sex drive, and maternal behavior. We highlight distinctive aspects of women's sexuality such as the possession of sexual ornaments, relatively cryptic fertile windows, extended sexual behavior across the ovulatory cycle, and a period of midlife reproductive senescence-and we focus on how hormonal mechanisms were shaped by selection to produce adaptive outcomes. We conclude with suggestions for future research to elucidate how hormonal mechanisms subserve women's reproductive phenotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Changing practice: red blood cell typing by molecular methods for patients with sickle cell disease.

PubMed

Casas, Jessica; Friedman, David F; Jackson, Tannoa; Vege, Sunitha; Westhoff, Connie M; Chou, Stella T

2015-06-01

Extended red blood cell (RBC) antigen matching is recommended to limit alloimmunization in patients with sickle cell disease (SCD). DNA-based testing to predict blood group phenotypes has enhanced availability of antigen-negative donor units and improved typing of transfused patients, but replacement of routine serologic typing for non-ABO antigens with molecular typing for patients has not been reported. This study compared the historical RBC antigen phenotypes obtained by hemagglutination methods with genotype predictions in 494 patients with SCD. For discrepant results, repeat serologic testing was performed and/or investigated by gene sequencing for silent or variant alleles. Seventy-one typing discrepancies were identified among 6360 antigen comparisons (1.1%). New specimens for repeat serologic testing were obtained for 66 discrepancies and retyping agreed with the genotype in 64 cases. One repeat Jk(b-) serologic phenotype, predicted Jk(b+) by genotype, was found by direct sequencing of JK to be a silenced allele, and one N typing discrepancy remains under investigation. Fifteen false-negative serologic results were associated with alleles encoding weak antigens or single-dose Fy(b) expression. DNA-based RBC typing provided improved accuracy and expanded information on RBC antigens compared to hemagglutination methods, leading to its implementation as the primary method for extended RBC typing for patients with SCD at our institution. © 2015 AABB.

A combined disc method with resazurin agar plate assay for early phenotypic screening of KPC, MBL and OXA-48 carbapenemases among Enterobacteriaceae.

PubMed

Teethaisong, Y; Eumkeb, G; Nakouti, I; Evans, K; Hobbs, G

2016-08-01

To validate a combined disc method along with resazurin chromogenic agar for early screening and differentiation of Klebsiella pneumoniae carbapenemase, metallo-β-lactamase and OXA-48 carbapenemase-producing Enterobacteriaceae. The combined disc test comprising of meropenem alone and with EDTA, phenylboronic acid or both EDTA and phenylboronic acid, and temocillin alone were evaluated with the resazurin chromogenic agar plate assay against a total of 86 molecularly confirmed Enterobacteriaceae clinical isolates (11 metallo-β-lactamases, eight Kl. pneumoniae carbapenemases, 11 OXA-48, 32 AmpC and 15 extended-spectrum-β-lactamase producers and nine co-producers of extended-spectrum-β-lactamase and AmpC). The inhibition zone diameters were measured and interpreted at 7 h for the presence of carbapenemase. All carbapenemase producers were phenotypically distinguished by this assay with 100% sensitivity and specificity. This early phenotypic method is very simple, inexpensive, and reliable in the detection and differentiation of carbapenemase-producing Enterobacteriaceae. It could be exploited in any microbiological laboratory for diagnosis of these recalcitrant bacteria. This assay poses excellent performance in discrimination of Kl. pneumoniae carbapenemase, metallo-β-lactamase and OXA-48 carbapenemases within 7 h, which is much faster than conventional disc diffusion methods. The rapid detection could help clinicians screen patients, control infection and provide epidemiological surveillance. © 2016 The Society for Applied Microbiology.

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

Correlates across the Structural, Functional, and Molecular Phenotypes of Fragile X Syndrome

ERIC Educational Resources Information Center

Beckel-Mitchener, Andrea; Greenough, William T.

2004-01-01

Fragile X syndrome (FXS) is characterized by a pattern of morphological, functional, and molecular characteristics with, in at least some cases, apparent relationships among phenotypic features at different levels. Gross morphology differences in the sizes of some human brain regions are accompanied by fine structural alterations in the shapes and…

Continuation-like semantics for modeling structural process anomalies

PubMed Central

2012-01-01

Background Biomedical ontologies usually encode knowledge that applies always or at least most of the time, that is in normal circumstances. But for some applications like phenotype ontologies it is becoming increasingly important to represent information about aberrations from a norm. These aberrations may be modifications of physiological structures, but also modifications of biological processes. Methods To facilitate precise definitions of process-related phenotypes, such as delayed eruption of the primary teeth or disrupted ocular pursuit movements, I introduce a modeling approach that draws inspiration from the use of continuations in the analysis of programming languages and apply a similar idea to ontological modeling. This approach characterises processes by describing their outcome up to a certain point and the way they will continue in the canonical case. Definitions of process types are then given in terms of their continuations and anomalous phenotypes are defined by their differences to the canonical definitions. Results The resulting model is capable of accurately representing structural process anomalies. It allows distinguishing between different anomaly kinds (delays, interruptions), gives identity criteria for interrupted processes, and explains why normal and anomalous process instances can be subsumed under a common type, thus establishing the connection between canonical and anomalous process-related phenotypes. Conclusion This paper shows how to to give semantically rich definitions of process-related phenotypes. These allow to expand the application areas of phenotype ontologies beyond literature annotation and establishment of genotype-phenotype associations to the detection of anomalies in suitably encoded datasets. PMID:23046705

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.

Cleft palate and ADULT phenotype in a patient with a novel TP63 mutation suggests lumping of EEC/LM/ADULT syndromes into a unique entity: ELA syndrome.

PubMed

Prontera, Paolo; Garelli, Emanuela; Isidori, Ilenia; Mencarelli, Amedea; Carando, Adriana; Silengo, Margherita Cirillo; Donti, Emilio

2011-11-01

Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare condition belonging to the group of ectodermal dysplasias caused by TP63 mutations. Its clinical phenotype is similar to ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) and limb-mammary syndrome (LMS), and differs from these disorders mainly by the absence of cleft lip and/or palate. We report on a 39-year-old patient who was found to be heterozygous for a c.401G > T (p.Gly134Val) de novo mutation of TP63. This patient had the ADULT phenotype associated with cleft palate. Our findings, rather than extend the clinical spectrum of ADULT syndrome, suggest that cleft palate can no longer be considered an element for differential diagnosis for ADULT, EEC, and LMS. Our data, added to other reports on overlapping phenotypes, support the combining of these three phenotypes into a unique entity that we propose to call "ELA syndrome," which is an acronym of ectrodactyly-ectodermal dysplasia-cleft lip and palate, limb-mammary, and ADULT syndromes. Copyright © 2011 Wiley Periodicals, Inc.

New insights into genotype–phenotype correlation for GLI3 mutations

PubMed Central

Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent- Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

2015-01-01

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues. PMID:24736735

New insights into genotype-phenotype correlation for GLI3 mutations.

PubMed

Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent-Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

2015-01-01

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

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.

An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance.

PubMed

Gordon, Derek; Londono, Douglas; Patel, Payal; Kim, Wonkuk; Finch, Stephen J; Heiman, Gary A

2016-01-01

Our motivation here is to calculate the power of 3 statistical tests used when there are genetic traits that operate under a pleiotropic mode of inheritance and when qualitative phenotypes are defined by use of thresholds for the multiple quantitative phenotypes. Specifically, we formulate a multivariate function that provides the probability that an individual has a vector of specific quantitative trait values conditional on having a risk locus genotype, and we apply thresholds to define qualitative phenotypes (affected, unaffected) and compute penetrances and conditional genotype frequencies based on the multivariate function. We extend the analytic power and minimum-sample-size-necessary (MSSN) formulas for 2 categorical data-based tests (genotype, linear trend test [LTT]) of genetic association to the pleiotropic model. We further compare the MSSN of the genotype test and the LTT with that of a multivariate ANOVA (Pillai). We approximate the MSSN for statistics by linear models using a factorial design and ANOVA. With ANOVA decomposition, we determine which factors most significantly change the power/MSSN for all statistics. Finally, we determine which test statistics have the smallest MSSN. In this work, MSSN calculations are for 2 traits (bivariate distributions) only (for illustrative purposes). We note that the calculations may be extended to address any number of traits. Our key findings are that the genotype test usually has lower MSSN requirements than the LTT. More inclusive thresholds (top/bottom 25% vs. top/bottom 10%) have higher sample size requirements. The Pillai test has a much larger MSSN than both the genotype test and the LTT, as a result of sample selection. With these formulas, researchers can specify how many subjects they must collect to localize genes for pleiotropic phenotypes. © 2017 S. Karger AG, Basel.

Phenotypes, antioxidant responses, and gene expression changes accompanying a sugar-only diet in Bactrocera dorsalis (Hendel) (Diptera: Tephritidae).

PubMed

Chen, Er-Hu; Hou, Qiu-Li; Wei, Dan-Dan; Jiang, Hong-Bo; Wang, Jin-Jun

2017-08-17

Diet composition (yeast:carbohydrate ratio) is an important determinant of growth, development, and reproduction. Recent studies have shown that decreased yeast intake elicits numerous transcriptomic changes and enhances somatic maintenance and lifespan, which in turn reduces reproduction in various insects. However, our understanding of the responses leading to a decrease in yeast ratio to 0% is limited. In the present study, we investigated the effects of a sugar-only diet (SD) on the gene expression patterns of the oriental fruit fly, Bactrocera dorsalis (Hendel), one of the most economically important pests in the family Tephritidae. RNA sequencing analyses showed that flies reared on an SD induced significant changes in the expression levels of genes associated with specific metabolic as well as cell growth and death pathways. Moreover, the observed upregulated genes in energy production and downregulated genes associated with reproduction suggested that SD affects somatic maintenance and reproduction in B. dorsalis. As expected, we observed that SD altered B. dorsalis phenotypes by significantly increasing stress (starvation and desiccation) resistance, decreasing reproduction, but did not extend lifespan compared to those that received a normal diet (ND) regime. In addition, administration of an SD resulted in a reduction in antioxidant enzyme activities and an increase in MDA concentrations, thereby suggesting that antioxidants cannot keep up with the increase in oxidative damage induced by SD regime. The application of an SD diet induces changes in phenotypes, antioxidant responses, and gene expressions in B. dorsalis. Previous studies have associated extended lifespan with reduced fecundity. The current study did not observe a prolongation of lifespan in B. dorsalis, which instead incurred oxidative damage. The findings of the present study improve our understanding of the molecular, biochemical, and phenotypic response of B. dorsalis to an SD diet.

Extending RosBREED in the Pacific Northwest for strawberry processing traits: year 1

USDA-ARS?s Scientific Manuscript database

In an effort to implement marker-assisted breeding in Rosaceae, many traits need to be characterized in diverse germplasm. The USDA-NIFA Specialty Crop Research Initiative-funded RosBREED project includes breeding programs of four Rosaceae crops (apple, peach, cherry, and strawberry). Phenotyping ea...

Fine Mapping of Bone Structure and Strength QTLs in Heterogeneous Stock Rat

PubMed Central

Alam, Imranul; Koller, Daniel L.; Cañete, Toni; Blázquez, Gloria; Mont-Cardona, Carme; López-Aumatell, Regina; Martínez-Membrives, Esther; Díaz-Morán, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Stridh, Pernilla; Diez, Margarita; Olsson, Tomas; Johannesson, Martina; Baud, Amelie; Econs, Michael J.; Foroud, Tatiana

2015-01-01

We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3 × 10−6). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis. PMID:26297441

Adaptation to local ultraviolet radiation conditions among neighbouring Daphnia populations

PubMed Central

Miner, Brooks E.; Kerr, Benjamin

2011-01-01

Understanding the historical processes that generated current patterns of phenotypic diversity in nature is particularly challenging in subdivided populations. Populations often exhibit heritable genetic differences that correlate with environmental variables, but the non-independence among neighbouring populations complicates statistical inference of adaptation. To understand the relative influence of adaptive and non-adaptive processes in generating phenotypes requires joint evaluation of genetic and phenotypic divergence in an integrated and statistically appropriate analysis. We investigated phenotypic divergence, population-genetic structure and potential fitness trade-offs in populations of Daphnia melanica inhabiting neighbouring subalpine ponds of widely differing transparency to ultraviolet radiation (UVR). Using a combination of experimental, population-genetic and statistical techniques, we separated the effects of shared population ancestry and environmental variables in predicting phenotypic divergence among populations. We found that native water transparency significantly predicted divergence in phenotypes among populations even after accounting for significant population structure. This result demonstrates that environmental factors such as UVR can at least partially account for phenotypic divergence. However, a lack of evidence for a hypothesized trade-off between UVR tolerance and growth rates in the absence of UVR prevents us from ruling out the possibility that non-adaptive processes are partially responsible for phenotypic differentiation in this system. PMID:20943691

The design and function of birds' nests

PubMed Central

Mainwaring, Mark C; Hartley, Ian R; Lambrechts, Marcel M; Deeming, D Charles

2014-01-01

All birds construct nests in which to lay eggs and/or raise offspring. Traditionally, it was thought that natural selection and the requirement to minimize the risk of predation determined the design of completed nests. However, it is becoming increasingly apparent that sexual selection also influences nest design. This is an important development as while species such as bowerbirds build structures that are extended phenotypic signals whose sole purpose is to attract a mate, nests contain eggs and/or offspring, thereby suggesting a direct trade-off between the conflicting requirements of natural and sexual selection. Nest design also varies adaptively in order to both minimize the detrimental effects of parasites and to create a suitable microclimate for parents and developing offspring in relation to predictable variation in environmental conditions. Our understanding of the design and function of birds' nests has increased considerably in recent years, and the evidence suggests that nests have four nonmutually exclusive functions. Consequently, we conclude that the design of birds' nests is far more sophisticated than previously realized and that nests are multifunctional structures that have important fitness consequences for the builder/s. PMID:25505520

Desiderata for computable representations of electronic health records-driven phenotype algorithms

PubMed Central

Mo, Huan; Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Jiang, Guoqian; Kiefer, Richard; Zhu, Qian; Xu, Jie; Montague, Enid; Carrell, David S; Lingren, Todd; Mentch, Frank D; Ni, Yizhao; Wehbe, Firas H; Peissig, Peggy L; Tromp, Gerard; Larson, Eric B; Chute, Christopher G; Pathak, Jyotishman; Speltz, Peter; Kho, Abel N; Jarvik, Gail P; Bejan, Cosmin A; Williams, Marc S; Borthwick, Kenneth; Kitchner, Terrie E; Roden, Dan M; Harris, Paul A

2015-01-01

Background Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM). Methods A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms. Results We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility. Conclusion A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages. PMID:26342218

Generation and characterization of human smooth muscle cell lines derived from atherosclerotic plaque.

PubMed

Bonin, L R; Madden, K; Shera, K; Ihle, J; Matthews, C; Aziz, S; Perez-Reyes, N; McDougall, J K; Conroy, S C

1999-03-01

The study of atherogenesis in humans has been restricted by the limited availability and brief in vitro life span of plaque smooth muscle cells (SMCs). We describe plaque SMC lines with extended life spans generated by the expression of the human papillomavirus (HPV)-16 E6 and E7 genes, which has been shown to extend the life span of normal adult human aortic SMCs. Resulting cell lines (pdSMC1A and 2) demonstrated at least 10-fold increases in life span; pdSMC1A became immortal. The SMC identity of both pdSMC lines was confirmed by SM22 mRNA expression. pdSMC2 were generally diploid but with various structural and numerical alterations; pdSMC1A demonstrated several chromosomal abnormalities, most commonly -Y, +7, -13, anomalies previously reported in both primary pdSMCs and atherosclerotic tissue. Confluent pdSMC2 appeared grossly similar to HPV-16 E6/E7-expressing normal adult aortic SMCs (AASMCs), exhibiting typical SMC morphology/growth patterns; pdSMC1A displayed irregular cell shape/organization with numerous mitotic figures. Dedifferentiation to a synthetic/proliferative phenotype has been hypothesized as a critical step in atherogenesis, because rat neonatal SMCs and adult intimal SMCs exhibit similar gene expression patterns. To confirm that our pdSMC lines likewise express this apparent plaque phenotype, osteopontin, platelet-derived growth factor B, and elastin mRNA levels were determined in pdSMC1A, pdSMC2, and AASMCs. However, no significant increases in osteopontin or platelet-derived growth factor B expression levels were observed in either pdSMC compared with AASMCs. pdSMC2 alone expressed high levels of elastin mRNA. Lower levels of SM22 mRNA in pdSMC1A suggested greater dedifferentiation and/or additional population doublings in pdSMC1A relative to pdSMC2. Both pdSMC lines (particularly 1A) demonstrated high message levels for matrix Gla protein, previously reported to be highly expressed by human neointimal SMCs in vitro. These results describe 2 novel plaque cell lines exhibiting various features of plaque SMC biology; pdSMC2 may represent an earlier plaque SMC phenotype, whereas pdSMC1A may be representative of cells comprising an advanced atherosclerotic lesion.

Whole genome prediction and heritability of childhood asthma phenotypes.

PubMed

McGeachie, Michael J; Clemmer, George L; Croteau-Chonka, Damien C; Castaldi, Peter J; Cho, Michael H; Sordillo, Joanne E; Lasky-Su, Jessica A; Raby, Benjamin A; Tantisira, Kelan G; Weiss, Scott T

2016-12-01

While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma-related phenotypes. We applied several WGP methods to a well-phenotyped cohort of 832 children with mild-to-moderate asthma from CAMP. We assessed narrow-sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre- and post-bronchodilator forced expiratory volume in 1 sec (FEV 1 ), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort. We found that longitudinal lung function phenotypes demonstrated significant narrow-sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4-8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts. Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP-prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma-related heritable traits.

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

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.

Cancer heterogeneity and multilayer spatial evolutionary games.

PubMed

Świerniak, Andrzej; Krześlak, Michał

2016-10-13

Evolutionary game theory (EGT) has been widely used to simulate tumour processes. In almost all studies on EGT models analysis is limited to two or three phenotypes. Our model contains four main phenotypes. Moreover, in a standard approach only heterogeneity of populations is studied, while cancer cells remain homogeneous. A multilayer approach proposed in this paper enables to study heterogeneity of single cells. In the extended model presented in this paper we consider four strategies (phenotypes) that can arise by mutations. We propose multilayer spatial evolutionary games (MSEG) played on multiple 2D lattices corresponding to the possible phenotypes. It enables simulation and investigation of heterogeneity on the player-level in addition to the population-level. Moreover, it allows to model interactions between arbitrary many phenotypes resulting from the mixture of basic traits. Different equilibrium points and scenarios (monomorphic and polymorphic populations) have been achieved depending on model parameters and the type of played game. However, there is a possibility of stable quadromorphic population in MSEG games for the same set of parameters like for the mean-field game. The model assumes an existence of four possible phenotypes (strategies) in the population of cells that make up tumour. Various parameters and relations between cells lead to complex analysis of this model and give diverse results. One of them is a possibility of stable coexistence of different tumour cells within the population, representing almost arbitrary mixture of the basic phenotypes. This article was reviewed by Tomasz Lipniacki, Urszula Ledzewicz and Jacek Banasiak.

Morphological and Genetic Analysis of Four Color Morphs of Bean Leaf Beetle.

PubMed

Tiroesele, Bamphitlhi; Skoda, Steven R; Hunt, Thomas E; Lee, Donald J; Ullah, Muhammad Irfan; Molina-Ochoa, Jaime; Foster, John E

2018-03-01

Bean leaf beetle (BLB), Cerotoma trifurcata (Forster; Coleoptera: Chrysomelidae), exhibits considerable color variation but little is known about the underlying genetic structure and gene flow among color phenotypes. Genetic and morphological variation among four color phenotypes-green with spots (G+S), green without spots (G-S), red with spots (R+S) and red without spots (R-S)-were analyzed using amplified fragment length polymorphisms (AFLP) and morphometrics, respectively. AFLP generated 175 markers that showed ≥80% polymorphism. Analysis of molecular variance (AMOVA) indicated that genetic variation was greatest within phenotypes (82.6-84.0%); gene flow among the four phenotypes was relatively high (Nm = 3.82). The dendrogram and STRUCTURE analysis indicated some population divergence of G-S from the other phenotypes. Morphological parameters were similar among phenotypes except that R+S showed significant differences in weight and body-length. Canonical variables 1 and 2, based on average morphometric characters, accounted for 98% of the total variation; some divergence was indicated between G+S and R+S from each other and from the G-S/R-S BLB color morphs. The pattern of genetic variation indicated potential divergence of G-S and G+S from each other and from R-S and R+S. Although these results indicate that the four different color morphs are not genetically or reproductively isolated, there is some genetic differentiation/structure and morphological dissimilarity suggesting weak/incomplete isolation.

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.

Using The Corngrass1 Gene To Enhance The Biofuel Properties Of Crop Plants

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

Hake, Sarah; Chuck, George

2015-10-29

The development of novel plant germplasm is vital to addressing our increasing bioenergy demands. The major hurdle to digesting plant biomass is the complex structure of the cell walls, the substrate of fermentation. Plant cell walls are inaccessible matrices of macromolecules that are polymerized with lignin, making fermentation difficult. Overcoming this hurdle is a major goal toward developing usable bioenergy crop plants. Our project seeks to enhance the biofuel properties of perennial grass species using the Corngrass1 (Cg1) gene and its targets. Dominant maize Cg1 mutants produce increased biomass by continuously initiating extra axillary meristems and leaves. We cloned Cg1more » and showed that its phenotype is caused by over expression of a unique miR156 microRNA gene that negatively regulates SPL transcription factors. We transferred the Cg1 phenotype to other plants by expressing the gene behind constitutive promoters in four different species, including the monocots, Brachypodium and switchgrass, and dicots, Arabidopsis and poplar. All transformants displayed a similar range of phenotypes, including increased biomass from extended leaf production, and increased vegetative branching. Field grown switchgrass transformants showed that overall lignin content was reduced, the ratio of glucans to xylans was increased, and surprisingly, that starch levels were greatly increased. The goals of this project are to control the tissue and temporal expression of Cg1 by using different promoters to drive its expression, elucidate the function of the SPL targets of Cg1 by generating gain and loss of function alleles, and isolate downstream targets of select SPL genes using deep sequencing and chromatin immunoprecipitation. We believe it is possible to control biomass accumulation, cell wall properties, and sugar levels through manipulation of either the Cg1 gene and/or its SPL targets.« less

NF1 Microdeletion Syndrome: Refined FISH Characterization of Sporadic and Familial Deletions with Locus-Specific Probes

PubMed Central

Riva, Paola; Corrado, Lucia; Natacci, Federica; Castorina, Pierangela; Wu, Bai-Li; Schneider, Gretchen H.; Clementi, Maurizio; Tenconi, Romano; Korf, Bruce R.; Larizza, Lidia

2000-01-01

Summary Two familial and seven sporadic patients with neurofibromatosis 1—who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene—were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the ∼0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes—BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS—were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8–3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions. PMID:10631140

Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes

PubMed Central

Islam, Rakibul; Jackson, Catherine; Eidet, Jon R.; Messelt, Edward B.; Corraya, Rima Maria; Lyberg, Torstein; Griffith, May; Dartt, Darlene A.; Utheim, Tor P.

2015-01-01

Purpose/Aims To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). Materials and Methods Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4°C increments from 4°C to 37°C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. Results Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12°C and 16°C storage groups (85%±13% and 68%±10%, respectively). Expression of ABCG2, Bmi1, C/EBPδ, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4°C and 20°C, compared to the non-stored control. Glucose, pH and pO2 in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12°C, 16°C, and 20°C. Conclusion We conclude that storage temperatures of 12°C and 16°C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology. PMID:26052937

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

PubMed Central

Arbogast, Thomas; Iacono, Giovanni; Chevalier, Claire; Afinowi, Nurudeen O.; Houbaert, Xander; Laliberte, Christine; Birling, Marie-Christine; Linda, Katrin; Meziane, Hamid; Selloum, Mohammed; Sorg, Tania; Koolen, David A.; Stunnenberg, Henk G.; Kopanitsa, Maksym; Humeau, Yann; De Vries, Bert B. A.

2017-01-01

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches. PMID:28704368

Spallanzani's mouse: a model of restoration and regeneration.

PubMed

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

Platelet dysfunction associated with the novel Trp29Cys thromboxane A₂ receptor variant.

PubMed

Mumford, A D; Nisar, S; Darnige, L; Jones, M L; Bachelot-Loza, C; Gandrille, S; Zinzindohoue, F; Fischer, A-M; Mundell, S J; Gaussem, P

2013-03-01

Genetic variations that affect the structure of the thromboxane A2 receptor (TP receptor) provide insights into the function of this key platelet and vascular receptor, but are very rare in unselected populations. To determine the functional consequences of the TP receptor Trp29Cys (W29C) substitution. We performed a detailed phenotypic analysis of an index case (P1) with reduced platelet aggregation and secretion responses to TP receptor pathway activators, and a heterozygous TP receptor W29C substitution. An analysis of the variant W29C TP receptor expressed in heterologous cells was performed. Total TP receptor expression in platelets from P1 was similar to that of controls, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist [(3) H]SQ29548. HEK293 cells transfected with W29C TP receptor cDNA showed similar total TP receptor expression to wild-type (WT) controls. However, the TP receptor agonist U46619 was less potent at inducing rises in cytosolic free Ca(2+) in HEK293 cells expressing the W29C TP receptor than in WT controls, indicating reduced receptor function. Immunofluorescence microscopy and cell surface ELISA showed intracellular retention and reduced cell surface expression of the W29C TP receptor in HEK293 cells. Consistent with the platelet phenotype, both maximum binding and the affinity of binding of [(3) H]SQ29548 to the W29C TP receptor were reduced compared to WT controls. These findings extend the phenotypic description of the very rare disorder TP receptor deficiency, and show that the W29C substitution reduces TP receptor function by reducing surface receptor expression and by disrupting ligand binding. © 2012 International Society on Thrombosis and Haemostasis.

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.

PubMed

Sanders, Anna A W M; de Vrieze, Erik; Alazami, Anas M; Alzahrani, Fatema; Malarkey, Erik B; Sorusch, Nasrin; Tebbe, Lars; Kuhns, Stefanie; van Dam, Teunis J P; Alhashem, Amal; Tabarki, Brahim; Lu, Qianhao; Lambacher, Nils J; Kennedy, Julie E; Bowie, Rachel V; Hetterschijt, Lisette; van Beersum, Sylvia; van Reeuwijk, Jeroen; Boldt, Karsten; Kremer, Hannie; Kesterson, Robert A; Monies, Dorota; Abouelhoda, Mohamed; Roepman, Ronald; Huynen, Martijn H; Ueffing, Marius; Russell, Rob B; Wolfrum, Uwe; Yoder, Bradley K; van Wijk, Erwin; Alkuraya, Fowzan S; Blacque, Oliver E

2015-12-29

Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation.

The complexity of silk under the spotlight of synthetic biology.

PubMed

Vollrath, Fritz

2016-08-15

For centuries silkworm filaments have been the focus of R&D innovation centred on textile manufacture with high added value. Most recently, silk research has focused on more fundamental issues concerning bio-polymer structure-property-function relationships. This essay outlines the complexity and fundamentals of silk spinning, and presents arguments for establishing this substance as an interesting and important subject at the interface of systems biology (discovery) and synthetic biology (translation). It is argued that silk is a generic class of materials where each type of silk presents a different embodiment of emergent properties that combine genetically determined (anticipatory) and environmentally responsive components. In spiders' webs the various silks have evolved to form the interactive components of an intricate fabric that provides an extended phenotype to the spider's body morphology. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Vascular Neural Network phenotypic transformation after traumatic injury: potential role in long-term sequelae

PubMed Central

Badaut, J.; Bix, G.J.

2014-01-01

The classical neurovascular unit (NVU), composed primarily of endothelium, astrocytes and neurons, could be expanded to include smooth muscle and perivascular nerves present in both the up and down stream feeding blood vessels (arteries and veins). The extended NVU, which can be defined as the vascular neural network (VNN), may represent a new physiological unit to consider for therapeutic development in stroke, traumatic brain injury, and other brain disorders [1]. This review is focused on traumatic brain injury and resultant post-traumatic changes in cerebral blood-flow, smooth muscle cells, matrix, BBB structures and function and the association of these changes with cognitive outcomes as described in clinical and experimental reports. We suggest that studies characterizing TBI outcomes should increase their focus on changes to the VNN as this may yield meaningful therapeutic targets to resolve post-traumatic dysfunction. PMID:24323723

An Epigenetic Gateway to Brain Tumor Cell Identity

PubMed Central

Mack, Stephen C.; Hubert, Christopher G.; Miller, Tyler E.; Taylor, Michael D.; Rich, Jeremy N.

2017-01-01

Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic, and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks, and disruption of chromatin structure. In this review, we describe the convergence of genetic, metabolic, and micro-environmental factors upon mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state, and neoplastic transformation, in addition to the potential to exploit these alterations as novel therapeutic strategies for the treatment of brain cancer. PMID:26713744

Parenclitic networks: uncovering new functions in biological data

PubMed Central

Zanin, Massimiliano; Alcazar, Joaquín Medina; Carbajosa, Jesus Vicente; Paez, Marcela Gomez; Papo, David; Sousa, Pedro; Menasalvas, Ernestina; Boccaletti, Stefano

2014-01-01

We introduce a novel method to represent time independent, scalar data sets as complex networks. We apply our method to investigate gene expression in the response to osmotic stress of Arabidopsis thaliana. In the proposed network representation, the most important genes for the plant response turn out to be the nodes with highest centrality in appropriately reconstructed networks. We also performed a target experiment, in which the predicted genes were artificially induced one by one, and the growth of the corresponding phenotypes compared to that of the wild-type. The joint application of the network reconstruction method and of the in vivo experiments allowed identifying 15 previously unknown key genes, and provided models of their mutual relationships. This novel representation extends the use of graph theory to data sets hitherto considered outside of the realm of its application, vastly simplifying the characterization of their underlying structure. PMID:24870931

Intergenerational neural mediators of early-life anxious temperament.

PubMed

Fox, Andrew S; Oler, Jonathan A; Shackman, Alexander J; Shelton, Steven E; Raveendran, Muthuswamy; McKay, D Reese; Converse, Alexander K; Alexander, Andrew; Davidson, Richard J; Blangero, John; Rogers, Jeffrey; Kalin, Ned H

2015-07-21

Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism-not brain structure-that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.

Smoothness within ruggedness: the role of neutrality in adaptation.

PubMed Central

Huynen, M A; Stadler, P F; Fontana, W

1996-01-01

RNA secondary structure folding algorithms predict the existence of connected networks of RNA sequences with identical structure. On such networks, evolving populations split into subpopulations, which diffuse independently in sequence space. This demands a distinction between two mutation thresholds: one at which genotypic information is lost and one at which phenotypic information is lost. In between, diffusion enables the search of vast areas in genotype space while still preserving the dominant phenotype. By this dynamic the success of phenotypic adaptation becomes much less sensitive to the initial conditions in genotype space. Images Fig. 2 PMID:8552647

SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey.

PubMed

Yucesan, E; Ugur Iseri, Sibel A; Bilgic, B; Gormez, Z; Bakir Gungor, B; Sarac, A; Ozdemir, O; Sagiroglu, M; Gurvit, H; Hanagasi, H; Ozbek, U

2017-12-01

SYNE1 related autosomal recessive cerebellar ataxia type 1 (ARCA1) is a late-onset cerebellar ataxia with slow progression originally demonstrated in French-Canadian populations of Quebec, Canada. Nevertheless, recent studies on SYNE1 ataxia have conveyed the condition from a geographically limited pure cerebellar recessive ataxia to a complex multisystem phenotype that is relatively common on the global scale. To determine the underlying genetic cause of the ataxia phenotype in a consanguineous family from Turkey presenting with very slow progressive cerebellar symptoms including dysarthria, dysmetria, and gait ataxia, we performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in two affected siblings. We identified a homozygous variant in SYNE1 (NM_033071.3: c.13086delC; p.His4362GlnfsX2) in all four affected siblings. This variant presented herein has originally been associated with only pure ataxia in a single case. We thus present segregation and phenotypic manifestations of this variant in four affected family members and further extend the pure ataxia phenotype with upper motor neuron involvement and peripheral neuropathy. Our findings in turn established a precise molecular diagnosis in this family, demonstrating the use of WES combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.

Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

PubMed Central

Pierson, Tyler Mark; Simeonov, Dimitre R; Sincan, Murat; Adams, David A; Markello, Thomas; Golas, Gretchen; Fuentes-Fajardo, Karin; Hansen, Nancy F; Cherukuri, Praveen F; Cruz, Pedro; Blackstone, Craig; Tifft, Cynthia; Boerkoel, Cornelius F; Gahl, William A

2012-01-01

Fatty acid hydroxylase-associated neurodegeneration due to fatty acid 2-hydroxylase deficiency presents with a wide range of phenotypes including spastic paraplegia, leukodystrophy, and/or brain iron deposition. All previously described families with this disorder were consanguineous, with homozygous mutations in the probands. We describe a 10-year-old male, from a non-consanguineous family, with progressive spastic paraplegia, dystonia, ataxia, and cognitive decline associated with a sural axonal neuropathy. The use of high-throughput sequencing techniques combined with SNP array analyses revealed a novel paternally derived missense mutation and an overlapping novel maternally derived ∼28-kb genomic deletion in FA2H. This patient provides further insight into the consistent features of this disorder and expands our understanding of its phenotypic presentation. The presence of a sural nerve axonal neuropathy had not been previously associated with this disorder and so may extend the phenotype. PMID:22146942

Genetic dyslexia risk variant is related to neural connectivity patterns underlying phonological awareness in children.

PubMed

Skeide, Michael A; Kirsten, Holger; Kraft, Indra; Schaadt, Gesa; Müller, Bent; Neef, Nicole; Brauer, Jens; Wilcke, Arndt; Emmrich, Frank; Boltze, Johannes; Friederici, Angela D

2015-09-01

Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia. Copyright © 2015 Elsevier Inc. All rights reserved.

Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.

PubMed

Cavill, Rachel; Kamburov, Atanas; Ellis, James K; Athersuch, Toby J; Blagrove, Marcus S C; Herwig, Ralf; Ebbels, Timothy M D; Keun, Hector C

2011-03-01

Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.

Comparative multi-goal tradeoffs in systems engineering of microbial metabolism

PubMed Central

2012-01-01

Background Metabolic engineering design methodology has evolved from using pathway-centric, random and empirical-based methods to using systems-wide, rational and integrated computational and experimental approaches. Persistent during these advances has been the desire to develop design strategies that address multiple simultaneous engineering goals, such as maximizing productivity, while minimizing raw material costs. Results Here, we use constraint-based modeling to systematically design multiple combinations of medium compositions and gene-deletion strains for three microorganisms (Escherichia coli, Saccharomyces cerevisiae, and Shewanella oneidensis) and six industrially important byproducts (acetate, D-lactate, hydrogen, ethanol, formate, and succinate). We evaluated over 435 million simulated conditions and 36 engineering metabolic traits, including product rates, costs, yields and purity. Conclusions The resulting metabolic phenotypes can be classified into dominant clusters (meta-phenotypes) for each organism. These meta-phenotypes illustrate global phenotypic variation and sensitivities, trade-offs associated with multiple engineering goals, and fundamental differences in organism-specific capabilities. Given the increasing number of sequenced genomes and corresponding stoichiometric models, we envisage that the proposed strategy could be extended to address a growing range of biological questions and engineering applications. PMID:23009214

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.

A novel zebrafish mutant with wavy-notochord: an effective biological index for monitoring the copper pollution of water from natural resources.

PubMed

Chen, Yau-Hung; Lin, Ji-Sheng

2011-02-01

We identified a novel zebrafish mutant that has wavy-notochord phenotypes, such as severely twisted notochord and posterior malformations, but has normal melanocytes. Histological evidences showed that proliferating vacuolar cells extended their growth to the muscle region, and consequently caused the wavy-notochord phenotypes. Interestingly, those malformations can be greatly reversed by exposure with copper, suggesting that copper plays an important role on wavy-notochord phenotypes. In addition, after long-term copper exposure, the surviving larvae derived from wavy-notochord mutants displayed bone malformations, such as twisted axial skeleton and osteophyte. These phenotypic changes and molecular evidences of wavy-notochord mutants are highly similar to those embryos whose lysyl oxidases activities have been inactivated. Taken together, we propose that (i) the putative mutated genes of this wavy-notochord mutant might be highly associated with the lysyl oxidase genes in zebrafish; and (ii) this fish model is an effective tool for monitoring copper pollution of water from natural resources. Copyright © 2009 Wiley Periodicals, Inc.

Vinobot and Vinoculer: Two Robotic Platforms for High-Throughput Field Phenotyping

PubMed Central

Shafiekhani, Ali; Kadam, Suhas; Fritschi, Felix B.; DeSouza, Guilherme N.

2017-01-01

In this paper, a new robotic architecture for plant phenotyping is being introduced. The architecture consists of two robotic platforms: an autonomous ground vehicle (Vinobot) and a mobile observation tower (Vinoculer). The ground vehicle collects data from individual plants, while the observation tower oversees an entire field, identifying specific plants for further inspection by the Vinobot. The advantage of this architecture is threefold: first, it allows the system to inspect large areas of a field at any time, during the day and night, while identifying specific regions affected by biotic and/or abiotic stresses; second, it provides high-throughput plant phenotyping in the field by either comprehensive or selective acquisition of accurate and detailed data from groups or individual plants; and third, it eliminates the need for expensive and cumbersome aerial vehicles or similarly expensive and confined field platforms. As the preliminary results from our algorithms for data collection and 3D image processing, as well as the data analysis and comparison with phenotype data collected by hand demonstrate, the proposed architecture is cost effective, reliable, versatile, and extendable. PMID:28124976

Quantitative genetic methods depending on the nature of the phenotypic trait.

PubMed

de Villemereuil, Pierre

2018-01-24

A consequence of the assumptions of the infinitesimal model, one of the most important theoretical foundations of quantitative genetics, is that phenotypic traits are predicted to be most often normally distributed (so-called Gaussian traits). But phenotypic traits, especially those interesting for evolutionary biology, might be shaped according to very diverse distributions. Here, I show how quantitative genetics tools have been extended to account for a wider diversity of phenotypic traits using first the threshold model and then more recently using generalized linear mixed models. I explore the assumptions behind these models and how they can be used to study the genetics of non-Gaussian complex traits. I also comment on three recent methodological advances in quantitative genetics that widen our ability to study new kinds of traits: the use of "modular" hierarchical modeling (e.g., to study survival in the context of capture-recapture approaches for wild populations); the use of aster models to study a set of traits with conditional relationships (e.g., life-history traits); and, finally, the study of high-dimensional traits, such as gene expression. © 2018 New York Academy of Sciences.

An Adaptive Association Test for Multiple Phenotypes with GWAS Summary Statistics.

PubMed

Kim, Junghi; Bai, Yun; Pan, Wei

2015-12-01

We study the problem of testing for single marker-multiple phenotype associations based on genome-wide association study (GWAS) summary statistics without access to individual-level genotype and phenotype data. For most published GWASs, because obtaining summary data is substantially easier than accessing individual-level phenotype and genotype data, while often multiple correlated traits have been collected, the problem studied here has become increasingly important. We propose a powerful adaptive test and compare its performance with some existing tests. We illustrate its applications to analyses of a meta-analyzed GWAS dataset with three blood lipid traits and another with sex-stratified anthropometric traits, and further demonstrate its potential power gain over some existing methods through realistic simulation studies. We start from the situation with only one set of (possibly meta-analyzed) genome-wide summary statistics, then extend the method to meta-analysis of multiple sets of genome-wide summary statistics, each from one GWAS. We expect the proposed test to be useful in practice as more powerful than or complementary to existing methods. © 2015 WILEY PERIODICALS, INC.

Validation of electronic medical record-based phenotyping algorithms: results and lessons learned from the eMERGE network.

PubMed

Newton, Katherine M; Peissig, Peggy L; Kho, Abel Ngo; Bielinski, Suzette J; Berg, Richard L; Choudhary, Vidhu; Basford, Melissa; Chute, Christopher G; Kullo, Iftikhar J; Li, Rongling; Pacheco, Jennifer A; Rasmussen, Luke V; Spangler, Leslie; Denny, Joshua C

2013-06-01

Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats. To present lessons learned about validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies. The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University. By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results. Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.

Desiderata for computable representations of electronic health records-driven phenotype algorithms.

PubMed

Mo, Huan; Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Jiang, Guoqian; Kiefer, Richard; Zhu, Qian; Xu, Jie; Montague, Enid; Carrell, David S; Lingren, Todd; Mentch, Frank D; Ni, Yizhao; Wehbe, Firas H; Peissig, Peggy L; Tromp, Gerard; Larson, Eric B; Chute, Christopher G; Pathak, Jyotishman; Denny, Joshua C; Speltz, Peter; Kho, Abel N; Jarvik, Gail P; Bejan, Cosmin A; Williams, Marc S; Borthwick, Kenneth; Kitchner, Terrie E; Roden, Dan M; Harris, Paul A

2015-11-01

Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM). A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms. We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility. A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Extending the ‘cross-disorder’ relevance of executive functions to dimensional neuropsychiatric traits in youth

PubMed Central

McGrath, Lauren M.; Braaten, Ellen B.; Doty, Nathan D.; Willoughby, Brian L.; Wilson, H. Kent; O’Donnell, Ellen H.; Colvin, Mary K.; Ditmars, Hillary L.; Blais, Jessica E.; Hill, Erin N.; Metzger, Aaron; Perlis, Roy H.; Willcutt, Erik G.; Smoller, Jordan W.; Waldman, Irwin D.; Faraone, Stephen V.; Seidman, Larry J.; Doyle, Alysa E.

2016-01-01

Background Evidence that different neuropsychiatric conditions share genetic liability has increased interest in phenotypes with ‘cross-disorder’ relevance, as they may contribute to revised models of psychopathology. Cognition is a promising construct for study; yet, evidence that the same cognitive functions are impaired across different forms of psychopathology comes primarily from separate studies of individual categorical diagnoses versus controls. Given growing support for dimensional models that cut across traditional diagnostic boundaries, we aimed to determine, within a single cohort, whether performance on measures of executive functions (EFs) predicted dimensions of different psychopathological conditions known to share genetic liability. Methods Data are from 393 participants, ages 8 to 17, consecutively enrolled in the Longitudinal Study of Genetic Influences on Cognition (LOGIC). This project is conducting deep phenotyping and genomic analyses in youth referred for neuropsychiatric evaluation. Using structural equation modeling, we examined whether EFs predicted variation in core dimensions of autism spectrum disorder, bipolar illness and schizophrenia, including social responsiveness, mania/emotion regulation, and positive symptoms of psychosis, respectively. Results We modeled three cognitive factors (working memory, shifting, and executive processing speed) that loaded on a second-order EF factor. The EF factor predicted variation in our three target traits but not in a negative control (somatization). Moreover, this EF factor was primarily associated with the overlapping (rather than unique) variance across the three outcome measures, suggesting it related to a general increase in psychopathology symptoms across those dimensions. Conclusions Findings extend support for the relevance of cognition to neuropsychiatric conditions that share underlying genetic risk. They suggest that higher-order cognition, including EFs, relate to the dimensional spectrum of each of these disorders and not just the clinical diagnoses. Moreover, results have implications for bottom-up models linking genes, cognition, and a general psychopathology liability. PMID:26411927

Genome-wide copy number variation analysis in extended families and unrelated individuals characterized for musical aptitude and creativity in music.

PubMed

Ukkola-Vuoti, Liisa; Kanduri, Chakravarthi; Oikkonen, Jaana; Buck, Gemma; Blancher, Christine; Raijas, Pirre; Karma, Kai; Lähdesmäki, Harri; Järvelä, Irma

2013-01-01

Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire.Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-α gene cluster (Pcdha 1-9) was found co-segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study.

Genome-Wide Copy Number Variation Analysis in Extended Families and Unrelated Individuals Characterized for Musical Aptitude and Creativity in Music

PubMed Central

Oikkonen, Jaana; Buck, Gemma; Blancher, Christine; Raijas, Pirre; Karma, Kai; Lähdesmäki, Harri; Järvelä, Irma

2013-01-01

Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-α gene cluster (Pcdha 1-9) was found co-segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study. PMID:23460800

Transcriptomic analysis of swarm motility phenotype of Salmonella enterica serovar Typhimurium mutant defective in periplasmic glucan synthesis

USDA-ARS?s Scientific Manuscript database

Movement of food-borne pathogens on moist surfaces enables them to migrate towards more favorable niches and facilitate their survival for extended periods of time. Salmonella enterica serovar Typhimurium mutants defective in OPG synthesis are unable to exhibit motility on moist surfaces (swarming) ...

Think laterally: horizontal gene transfer from symbiotic microbes may extend the phenotype of marine sessile hosts

PubMed Central

Degnan, Sandie M.

2014-01-01

Since the origin of the animal kingdom, marine animals have lived in association with viruses, prokaryotes and unicellular eukaryotes, often as symbionts. This long and continuous interaction has provided ample opportunity not only for the evolution of intimate interactions such as sharing of metabolic pathways, but also for horizontal gene transfer (HGT) of non-metazoan genes into metazoan genomes. The number of demonstrated cases of inter-kingdom HGT is currently small, such that it is not yet widely appreciated as a significant player in animal evolution. Sessile marine invertebrates that vertically inherit bacterial symbionts, that have no dedicated germ line, or that bud or excise pluripotent somatic cells during their life history may be particularly receptive to HGT from their symbionts. Closer scrutiny of the growing number of genomes being accrued for these animals may thus reveal HGT as a regular source of novel variation that can function to extend the host phenotype metabolically, morphologically, or even behaviorally. Taxonomic identification of symbionts will help to address the intriguing question of whether past HGT events may constrain contemporary symbioses. PMID:25477875

Resistance to Extended-Spectrum β-Lactamases in Salmonella from a Broiler Supply Chain

PubMed Central

Gelinski, Jane Mary Lafayette Neves; Bombassaro, Amanda; Baratto, César Milton; Vicente, Vânia Aparecida

2014-01-01

The prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae varies worldwide, however, the incidence of ESBL-producing environmental Salmonella isolates is increasing. Salmonella is still one of the most important pathogens that occur in the poultry supply chain. Therefore, this study analyzed the susceptibility of Salmonella isolates collected from a poultry supply chain to β-lactam antibiotics, and examined the phenotypes of the isolates based on enzyme-inducible AmpC β-lactamase analysis. All analysis of the putative positive isolates in the current study confirmed that 27.02% (77/285 analysis) of all ESBL tests realized with the isolates produced a profile of resistance consistent with β-lactamase production. All isolates of S. Minnesota serotype had ESBL phenotype. Aztreonam resistance was the least common amongst the Salmonella isolates, followed by ceftazidime. The presence of inducible chromosomal ESBL was detected in 14 different isolates of the 19 serotypes investigated. These results are very indicatives of the presence of ESBL genes in Salmonella isolates from a broiler supply chain, reaffirming the growing global problem of ESBL resistance. PMID:25402566

Construction of a series of congenic mice with recombinant chromosome 1 regions surrounding the genetic loci for resistance to intracellular parasites (Ity, Lsh, and Bcg), DNA repair responses (Rep-1), and the cytoskeletal protein villin (Vil).

PubMed

Mock, B A; Holiday, D L; Cerretti, D P; Darnell, S C; O'Brien, A D; Potter, M

1994-01-01

The interval of mouse chromosome 1 extending from Idh-1 to Pep-3 harbors the natural resistance gene Ity/Lsh/Bcg; it controls the outcome of infection with Salmonella typhimurium, Leishmania donovani, and several Mycobacterium species. This region also contains a DNA repair gene, Rep-1, which determines the rapidity with which double-strand breaks in chromatin are repaired. BALB/cAnPt and DBA/2N mice differ in their phenotypic expression of these genes. To generate appropriate strains of mice for the study of these genes, a series of 10 C.D2 congenic strains recombinant across a 28-centimorgan interval of mouse chromosome 1 extending from Idh-1 to Pep-3 were derived from crosses of the C.D2-Idh-1 Pep-3 congenic strain back to BALB/cAn. Analyses of these recombinant strains will allow the correlation of biological-immunological phenotypes with defined genetic regions.

Construction of a series of congenic mice with recombinant chromosome 1 regions surrounding the genetic loci for resistance to intracellular parasites (Ity, Lsh, and Bcg), DNA repair responses (Rep-1), and the cytoskeletal protein villin (Vil).

PubMed Central

Mock, B A; Holiday, D L; Cerretti, D P; Darnell, S C; O'Brien, A D; Potter, M

1994-01-01

The interval of mouse chromosome 1 extending from Idh-1 to Pep-3 harbors the natural resistance gene Ity/Lsh/Bcg; it controls the outcome of infection with Salmonella typhimurium, Leishmania donovani, and several Mycobacterium species. This region also contains a DNA repair gene, Rep-1, which determines the rapidity with which double-strand breaks in chromatin are repaired. BALB/cAnPt and DBA/2N mice differ in their phenotypic expression of these genes. To generate appropriate strains of mice for the study of these genes, a series of 10 C.D2 congenic strains recombinant across a 28-centimorgan interval of mouse chromosome 1 extending from Idh-1 to Pep-3 were derived from crosses of the C.D2-Idh-1 Pep-3 congenic strain back to BALB/cAn. Analyses of these recombinant strains will allow the correlation of biological-immunological phenotypes with defined genetic regions. PMID:8262646

Dimensional Structure of the Autism Phenotype: Relations between Early Development and Current Presentation

ERIC Educational Resources Information Center

Kamp-Becker, Inge; Ghahreman, Mardjan; Smidt, Judith; Remschmidt, Helmut

2009-01-01

The dimensional structure of higher functioning autism phenotype was investigated by factor analysis. The goal of this study was to identify the degree to which early symptoms of autism (measured using the ADI-R) could be predictive of the current symptoms of autism as identified using the ADOS, the adaptive behavior scales, IQ scores and theory…

Tag-mediated cooperation with non-deterministic genotype-phenotype mapping

NASA Astrophysics Data System (ADS)

Zhang, Hong; Chen, Shu

2016-01-01

Tag-mediated cooperation provides a helpful framework for resolving evolutionary social dilemmas. However, most of the previous studies have not taken into account genotype-phenotype distinction in tags, which may play an important role in the process of evolution. To take this into consideration, we introduce non-deterministic genotype-phenotype mapping into a tag-based model with spatial prisoner's dilemma. By our definition, the similarity between genotypic tags does not directly imply the similarity between phenotypic tags. We find that the non-deterministic mapping from genotypic tag to phenotypic tag has non-trivial effects on tag-mediated cooperation. Although we observe that high levels of cooperation can be established under a wide variety of conditions especially when the decisiveness is moderate, the uncertainty in the determination of phenotypic tags may have a detrimental effect on the tag mechanism by disturbing the homophilic interaction structure which can explain the promotion of cooperation in tag systems. Furthermore, the non-deterministic mapping may undermine the robustness of the tag mechanism with respect to various factors such as the structure of the tag space and the tag flexibility. This observation warns us about the danger of applying the classical tag-based models to the analysis of empirical phenomena if genotype-phenotype distinction is significant in real world. Non-deterministic genotype-phenotype mapping thus provides a new perspective to the understanding of tag-mediated cooperation.

The flora phenotype ontology (FLOPO): tool for integrating morphological traits and phenotypes of vascular plants.

PubMed

Hoehndorf, Robert; Alshahrani, Mona; Gkoutos, Georgios V; Gosline, George; Groom, Quentin; Hamann, Thomas; Kattge, Jens; de Oliveira, Sylvia Mota; Schmidt, Marco; Sierra, Soraya; Smets, Erik; Vos, Rutger A; Weiland, Claus

2016-11-14

The systematic analysis of a large number of comparable plant trait data can support investigations into phylogenetics and ecological adaptation, with broad applications in evolutionary biology, agriculture, conservation, and the functioning of ecosystems. Floras, i.e., books collecting the information on all known plant species found within a region, are a potentially rich source of such plant trait data. Floras describe plant traits with a focus on morphology and other traits relevant for species identification in addition to other characteristics of plant species, such as ecological affinities, distribution, economic value, health applications, traditional uses, and so on. However, a key limitation in systematically analyzing information in Floras is the lack of a standardized vocabulary for the described traits as well as the difficulties in extracting structured information from free text. We have developed the Flora Phenotype Ontology (FLOPO), an ontology for describing traits of plant species found in Floras. We used the Plant Ontology (PO) and the Phenotype And Trait Ontology (PATO) to extract entity-quality relationships from digitized taxon descriptions in Floras, and used a formal ontological approach based on phenotype description patterns and automated reasoning to generate the FLOPO. The resulting ontology consists of 25,407 classes and is based on the PO and PATO. The classified ontology closely follows the structure of Plant Ontology in that the primary axis of classification is the observed plant anatomical structure, and more specific traits are then classified based on parthood and subclass relations between anatomical structures as well as subclass relations between phenotypic qualities. The FLOPO is primarily intended as a framework based on which plant traits can be integrated computationally across all species and higher taxa of flowering plants. Importantly, it is not intended to replace established vocabularies or ontologies, but rather serve as an overarching framework based on which different application- and domain-specific ontologies, thesauri and vocabularies of phenotypes observed in flowering plants can be integrated.

Phenotypic integration in an extended phenotype: among-individual variation in nest-building traits of the alfalfa leafcutting bee (Megachile rotundata).

PubMed

Royauté, Raphaël; Wilson, Elisabeth S; Helm, Bryan R; Mallinger, Rachel E; Prasifka, Jarrad; Greenlee, Kendra J; Bowsher, Julia H

2018-03-02

Structures such as nests and burrows are an essential component of many organisms' life-cycle and require a complex sequence of behaviours. Because behaviours can vary consistently among individuals and be correlated with one another, we hypothesized that these structures would (1) show evidence of among-individual variation, (2) be organized into distinct functional modules and (3) show evidence of trade-offs among functional modules due to limits on energy budgets. We tested these hypotheses using the alfalfa leafcutting bee, Megachile rotundata, a solitary bee and important crop pollinator. Megachile rotundata constructs complex nests by gathering leaf materials to form a linear series of cells in pre-existing cavities. In this study, we examined variation in the following nest construction traits: reproduction (number of cells per nest and nest length), nest protection (cap length and number of leaves per cap), cell construction (cell size and number of leaves per cell) and cell provisioning (cell mass) from 60 nests. We found a general decline in investment in cell construction and provisioning with each new cell built. In addition, we found evidence for both repeatability and plasticity in cell provisioning with little evidence for trade-offs among traits. Instead, most traits were positively, albeit weakly, correlated (r ~ 0.15), and traits were loosely organized into covarying modules. Our results show that individual differences in nest construction are detectable at a level similar to that of other behavioural traits and that these traits are only weakly integrated. This suggests that nest components are capable of independent evolutionary trajectories. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.

The Arabidopsis DCR Encoding a Soluble BAHD Acyltransferase Is Required for Cutin Polyester Formation and Seed Hydration Properties1[C][W][OA

PubMed Central

Panikashvili, David; Shi, Jian Xin; Schreiber, Lukas; Aharoni, Asaph

2009-01-01

The cuticle covering every plant aerial organ is largely made of cutin that consists of fatty acids, glycerol, and aromatic monomers. Despite the huge importance of the cuticle to plant development and fitness, our knowledge regarding the assembly of the cutin polymer and its integration in the complete cuticle structure is limited. Cutin composition implies the action of acyltransferase-type enzymes that mediate polymer construction through ester bond formation. Here, we show that a member of the BAHD family of acyltransferases (DEFECTIVE IN CUTICULAR RIDGES [DCR]) is required for incorporation of the most abundant monomer into the polymeric structure of the Arabidopsis (Arabidopsis thaliana) flower cutin. DCR-deficient plants display phenotypes that are typically associated with a defective cuticle, including altered epidermal cell differentiation and postgenital organ fusion. Moreover, levels of the major cutin monomer in flowers, 9(10),16-dihydroxy-hexadecanoic acid, decreased to an almost undetectable amount in the mutants. Interestingly, dcr mutants exhibit changes in the decoration of petal conical cells and mucilage extrusion in the seed coat, both phenotypes formerly not associated with cutin polymer assembly. Excessive root branching displayed by dcr mutants and the DCR expression pattern in roots pointed to the function of DCR belowground, in shaping root architecture by influencing lateral root emergence and growth. In addition, the dcr mutants were more susceptible to salinity, osmotic, and water deprivation stress conditions. Finally, the analysis of DCR protein localization suggested that cutin polymerization, possibly the oligomerization step, is partially carried out in the cytoplasmic space. Therefore, this study extends our knowledge regarding the functionality of the cuticular layer and the formation of its major constituent the polymer cutin. PMID:19828672

The Arabidopsis DCR encoding a soluble BAHD acyltransferase is required for cutin polyester formation and seed hydration properties.

PubMed

Panikashvili, David; Shi, Jian Xin; Schreiber, Lukas; Aharoni, Asaph

2009-12-01

The cuticle covering every plant aerial organ is largely made of cutin that consists of fatty acids, glycerol, and aromatic monomers. Despite the huge importance of the cuticle to plant development and fitness, our knowledge regarding the assembly of the cutin polymer and its integration in the complete cuticle structure is limited. Cutin composition implies the action of acyltransferase-type enzymes that mediate polymer construction through ester bond formation. Here, we show that a member of the BAHD family of acyltransferases (DEFECTIVE IN CUTICULAR RIDGES [DCR]) is required for incorporation of the most abundant monomer into the polymeric structure of the Arabidopsis (Arabidopsis thaliana) flower cutin. DCR-deficient plants display phenotypes that are typically associated with a defective cuticle, including altered epidermal cell differentiation and postgenital organ fusion. Moreover, levels of the major cutin monomer in flowers, 9(10),16-dihydroxy-hexadecanoic acid, decreased to an almost undetectable amount in the mutants. Interestingly, dcr mutants exhibit changes in the decoration of petal conical cells and mucilage extrusion in the seed coat, both phenotypes formerly not associated with cutin polymer assembly. Excessive root branching displayed by dcr mutants and the DCR expression pattern in roots pointed to the function of DCR belowground, in shaping root architecture by influencing lateral root emergence and growth. In addition, the dcr mutants were more susceptible to salinity, osmotic, and water deprivation stress conditions. Finally, the analysis of DCR protein localization suggested that cutin polymerization, possibly the oligomerization step, is partially carried out in the cytoplasmic space. Therefore, this study extends our knowledge regarding the functionality of the cuticular layer and the formation of its major constituent the polymer cutin.

Spread of Plasmids Carrying Multiple GES Variants

PubMed Central

Cuzon, Gaelle; Bogaerts, Pierre; Bauraing, Caroline; Huang, Te-Din; Glupczynski, Youri

2016-01-01

Five GES-producing Enterobacteriaceae isolates that displayed an extended-spectrum β-lactamase (ESBL) phenotype harbored two GES variants: GES-7 ESBL and GES-6 carbapenemase. In all isolates, the two GES alleles were located on the same integron that was inserted into an 80-kb IncM1 self-conjugative plasmid. Whole-genome sequencing suggested in vivo horizontal gene transfer of the plasmid along with clonal diffusion of Enterobacter cloacae. To our knowledge, this is the first description in Europe of clustered Enterobacteriaceae isolates carrying two GES β-lactamases, of which one has extended activity toward carbapenems. PMID:27216071

Formation of new chromatin domains determines pathogenicity of genomic duplications.

PubMed

Franke, Martin; Ibrahim, Daniel M; Andrey, Guillaume; Schwarzer, Wibke; Heinrich, Verena; Schöpflin, Robert; Kraft, Katerina; Kempfer, Rieke; Jerković, Ivana; Chan, Wing-Lee; Spielmann, Malte; Timmermann, Bernd; Wittler, Lars; Kurth, Ingo; Cambiaso, Paola; Zuffardi, Orsetta; Houge, Gunnar; Lambie, Lindsay; Brancati, Francesco; Pombo, Ana; Vingron, Martin; Spitz, Francois; Mundlos, Stefan

2016-10-13

Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.

Effects of Clonal Reproduction on Evolutionary Lag and Evolutionary Rescue.

PubMed

Orive, Maria E; Barfield, Michael; Fernandez, Carlos; Holt, Robert D

2017-10-01

Evolutionary lag-the difference between mean and optimal phenotype in the current environment-is of keen interest in light of rapid environmental change. Many ecologically important organisms have life histories that include stage structure and both sexual and clonal reproduction, yet how stage structure and clonality interplay to govern a population's rate of evolution and evolutionary lag is unknown. Effects of clonal reproduction on mean phenotype partition into two portions: one that is phenotype dependent, and another that is genotype dependent. This partitioning is governed by the association between the nonadditive genetic plus random environmental component of phenotype of clonal offspring and their parents. While clonality slows phenotypic evolution toward an optimum, it can dramatically increase population survival after a sudden step change in optimal phenotype. Increased adult survival slows phenotypic evolution but facilitates population survival after a step change; this positive effect can, however, be lost given survival-fecundity trade-offs. Simulations indicate that the benefits of increased clonality under environmental change greatly depend on the nature of that change: increasing population persistence under a step change while decreasing population persistence under a continuous linear change requiring de novo variation. The impact of clonality on the probability of persistence for species in a changing world is thus inexorably linked to the temporal texture of the change they experience.

Palisade endings are present in canine extraocular muscles and have a cholinergic phenotype

PubMed Central

RUNGALDIER, Stefanie; POMIKAL, Christine; STREICHER, Johannes; BLUMER, Roland

2016-01-01

Classical proprioceptors, like Golgi tendon organs and muscle spindles are absent in the extraocular muscles (EOMs) of most mammals. Instead, a nerve end organ was detected in the EOMs of each species including sheep, cats, rabbits, rats, monkeys, and man examined so far: the palisade ending. Until now no evidence appeared that palisade endings are present in canine EOMs. We analyzed dog EOMs by confocal laser scanning microscopy, 3D reconstruction, and transmission electron microscopy. In EOM wholemount preparations stained with antibodies against neurofilament and synaptophysin we found typical palisade endings. Nerve fibers coming from the muscle extended into the tendon. There, the nerve fibers turned 180° and returned to branch into preterminal axons which established nerve terminals around a single muscle fiber tip. Fine structural analyses revealed that each palisade ending in dog EOMs established nerve terminals on the tendon. In some palisade endings we found nerve terminals contacting the muscle fiber as well. Such neuromuscular contacts had a basal lamina in the synaptic cleft thereby resembling motor terminals. By using antibodies against choline acetyltransferase (ChAT) we proved that canine palisade endings are ChAT-immunoreactive. This study shows that palisade endings are present in canine EOMs. In line with prior findings in cat and monkey, palisade endings in dog have a cholinergic phenotype. PMID:19766165

Evolution of phenotypic clusters through competition and local adaptation along an environmental gradient.

PubMed

Leimar, Olof; Doebeli, Michael; Dieckmann, Ulf

2008-04-01

We have analyzed the evolution of a quantitative trait in populations that are spatially extended along an environmental gradient, with gene flow between nearby locations. In the absence of competition, there is stabilizing selection toward a locally best-adapted trait that changes gradually along the gradient. According to traditional ideas, gradual spatial variation in environmental conditions is expected to lead to gradual variation in the evolved trait. A contrasting possibility is that the trait distribution instead breaks up into discrete clusters. Doebeli and Dieckmann (2003) argued that competition acting locally in trait space and geographical space can promote such clustering. We have investigated this possibility using deterministic population dynamics for asexual populations, analyzing our model numerically and through an analytical approximation. We examined how the evolution of clusters is affected by the shape of competition kernels, by the presence of Allee effects, and by the strength of gene flow along the gradient. For certain parameter ranges clustering was a robust outcome, and for other ranges there was no clustering. Our analysis shows that the shape of competition kernels is important for clustering: the sign structure of the Fourier transform of a competition kernel determines whether the kernel promotes clustering. Also, we found that Allee effects promote clustering, whereas gene flow can have a counteracting influence. In line with earlier findings, we could demonstrate that phenotypic clustering was favored by gradients of intermediate slope.

Constructing Adverse Outcome Pathways: a Demonstration of ...

EPA Pesticide Factsheets

Adverse outcome pathway (AOP) provides a conceptual framework to evaluate and integrate chemical toxicity and its effects across the levels of biological organization. As such, it is essential to develop a resource-efficient and effective approach to extend molecular initiating events (MIEs) of chemicals to their downstream phenotypes of a greater regulatory relevance. A number of ongoing public phenomics (high throughput phenotyping) efforts have been generating abundant phenotypic data annotated with ontology terms. These phenotypes can be analyzed semantically and linked to MIEs of interest, all in the context of a knowledge base integrated from a variety of ontologies for various species and knowledge domains. In such analyses, two phenotypic profiles (PPs; anchored by genes or diseases) each characterized by multiple ontology terms are compared for their semantic similarities within a common ontology graph, but across boundaries of species and knowledge domains. Taking advantage of publicly available ontologies and software tool kits, we have implemented an OS-Mapping (Ontology-based Semantics Mapping) approach as a Java application, and constructed a network of 19383 PPs as nodes with edges weighed by their pairwise semantic similarity scores. Individual PPs were assembled from public phenomics data. Out of possible 1.87×108 pairwise connections among these nodes, about 71% of them have similarity scores between 0.2 and the maximum possible of 1.0.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

PubMed

Frejo, L; Martin-Sanz, E; Teggi, R; Trinidad, G; Soto-Varela, A; Santos-Perez, S; Manrique, R; Perez, N; Aran, I; Almeida-Branco, M S; Batuecas-Caletrio, A; Fraile, J; Espinosa-Sanchez, J M; Perez-Guillen, V; Perez-Garrigues, H; Oliva-Dominguez, M; Aleman, O; Benitez, J; Perez, P; Lopez-Escamez, J A

2017-12-01

To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. A cross-sectional study with a two-step cluster analysis. A tertiary referral multicenter study. Nine hundred and eighty-eight adult patients with unilateral MD. best predictors to define clinical subgroups with potential different aetiologies. We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials. © 2017 John Wiley & Sons Ltd.

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.

A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping. IV. Nested Analyses with Cladogram Uncertainty and Recombination

PubMed Central

Templeton, A. R.; Sing, C. F.

1993-01-01

We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely cladograms and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects. PMID:8100789

Microbial Community Analysis of Field-Grown Soybeans with Different Nodulation Phenotypes▿

PubMed Central

Ikeda, Seishi; Rallos, Lynn Esther E.; Okubo, Takashi; Eda, Shima; Inaba, Shoko; Mitsui, Hisayuki; Minamisawa, Kiwamu

2008-01-01

Microorganisms associated with the stems and roots of nonnodulated (Nod−), wild-type nodulated (Nod+), and hypernodulated (Nod++) soybeans [Glycine max (L.) Merril] were analyzed by ribosomal intergenic transcribed spacer analysis (RISA) and automated RISA (ARISA). RISA of stem samples detected no bands specific to the nodulation phenotype, whereas RISA of root samples revealed differential bands for the nodulation phenotypes. Pseudomonas fluorescens was exclusively associated with Nod+ soybean roots. Fusarium solani was stably associated with nodulated (Nod+ and Nod++) roots and less abundant in Nod− soybeans, whereas the abundance of basidiomycetes was just the opposite. The phylogenetic analyses suggested that these basidiomycetous fungi might represent a root-associated group in the Auriculariales. Principal-component analysis of the ARISA results showed that there was no clear relationship between nodulation phenotype and bacterial community structure in the stem. In contrast, both the bacterial and fungal community structures in the roots were related to nodulation phenotype. The principal-component analysis further suggested that bacterial community structure in roots could be classified into three groups according to the nodulation phenotype (Nod−, Nod+, or Nod++). The analysis of root samples indicated that the microbial community in Nod− soybeans was more similar to that in Nod++ soybeans than to that in Nod+ soybeans. PMID:18658280

Structural phenotyping of stem cell-derived cardiomyocytes.

PubMed

Pasqualini, Francesco Silvio; Sheehy, Sean Paul; Agarwal, Ashutosh; Aratyn-Schaus, Yvonne; Parker, Kevin Kit

2015-03-10

Structural phenotyping based on classical image feature detection has been adopted to elucidate the molecular mechanisms behind genetically or pharmacologically induced changes in cell morphology. Here, we developed a set of 11 metrics to capture the increasing sarcomere organization that occurs intracellularly during striated muscle cell development. To test our metrics, we analyzed the localization of the contractile protein α-actinin in a variety of primary and stem-cell derived cardiomyocytes. Further, we combined these metrics with data mining algorithms to unbiasedly score the phenotypic maturity of human-induced pluripotent stem cell-derived cardiomyocytes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Genomic scan as a tool for assessing the genetic component of phenotypic variance in wild populations.

PubMed

Herrera, Carlos M

2012-01-01

Methods for estimating quantitative trait heritability in wild populations have been developed in recent years which take advantage of the increased availability of genetic markers to reconstruct pedigrees or estimate relatedness between individuals, but their application to real-world data is not exempt from difficulties. This chapter describes a recent marker-based technique which, by adopting a genomic scan approach and focusing on the relationship between phenotypes and genotypes at the individual level, avoids the problems inherent to marker-based estimators of relatedness. This method allows the quantification of the genetic component of phenotypic variance ("degree of genetic determination" or "heritability in the broad sense") in wild populations and is applicable whenever phenotypic trait values and multilocus data for a large number of genetic markers (e.g., amplified fragment length polymorphisms, AFLPs) are simultaneously available for a sample of individuals from the same population. The method proceeds by first identifying those markers whose variation across individuals is significantly correlated with individual phenotypic differences ("adaptive loci"). The proportion of phenotypic variance in the sample that is statistically accounted for by individual differences in adaptive loci is then estimated by fitting a linear model to the data, with trait value as the dependent variable and scores of adaptive loci as independent ones. The method can be easily extended to accommodate quantitative or qualitative information on biologically relevant features of the environment experienced by each sampled individual, in which case estimates of the environmental and genotype × environment components of phenotypic variance can also be obtained.

A Complex Structural Variation on Chromosome 27 Leads to the Ectopic Expression of HOXB8 and the Muffs and Beard Phenotype in Chickens

PubMed Central

Wang, Yanqiang; Luo, Chenglong; Liu, Ranran; Qu, Hao; Shu, Dingming; Wen, Jie; Crooijmans, Richard P. M. A.; Zhao, Yiqiang; Hu, Xiaoxiang; Li, Ning

2016-01-01

Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. Here we use genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele causing the Mb phenotype is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to that of the tandem repeat around 1.70 Mb on GGA27. The duplications contain total seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens, strongly suggesting that HOXB8 directs this regional feather-development. In conclusion, our results provide an interesting example of how genomic structural rearrangements alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation. PMID:27253709

The Paradox of Mitochondrial Dysfunction and Extended Longevity

PubMed Central

Munkácsy, Erin; Rea, Shane L.

2014-01-01

Mitochondria play numerous, essential roles in the life of eukaryotes. Disruption of mitochondrial function in humans is often pathological or even lethal. Surprisingly, in some organisms mitochondrial dysfunction can result in life extension. This paradox has been studied most extensively in the long-lived Mit mutants of the nematode Caenorhabditis elegans. In this review, we explore the major responses that are activated following mitochondrial dysfunction in these animals and how these responses potentially act to extend their life. We focus our attention on five broad areas of current research – reactive oxygen species signaling, the mitochondrial unfolded protein response, autophagy, metabolic adaptation, and the roles played by various transcription factors. Lastly, we also examine why disruption of complexes I and II differ in their ability to induce the Mit phenotype and extend lifespan. PMID:24699406

Three-dimensional scaffolding to investigate neuronal derivatives of human embryonic stem cells.

PubMed

Soman, Pranav; Tobe, Brian T D; Lee, Jin Woo; Winquist, Alicia M; Singec, Ilyas; Vecchio, Kenneth S; Snyder, Evan Y; Chen, Shaochen

2012-10-01

Access to unlimited numbers of live human neurons derived from stem cells offers unique opportunities for in vitro modeling of neural development, disease-related cellular phenotypes, and drug testing and discovery. However, to develop informative cellular in vitro assays, it is important to consider the relevant in vivo environment of neural tissues. Biomimetic 3D scaffolds are tools to culture human neurons under defined mechanical and physico-chemical properties providing an interconnected porous structure that may potentially enable a higher or more complex organization than traditional two-dimensional monolayer conditions. It is known that even minor variations in the internal geometry and mechanical properties of 3D scaffolds can impact cell behavior including survival, growth, and cell fate choice. In this report, we describe the design and engineering of 3D synthetic polyethylene glycol (PEG)-based and biodegradable gelatin-based scaffolds generated by a free form fabrication technique with precise internal geometry and elastic stiffnesses. We show that human neurons, derived from human embryonic stem (hESC) cells, are able to adhere to these scaffolds and form organoid structures that extend in three dimensions as demonstrated by confocal and electron microscopy. Future refinements of scaffold structure, size and surface chemistries may facilitate long term experiments and designing clinically applicable bioassays.

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

PubMed

Sporn, Zachary A; Hines, Justin K

2015-01-01

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.

The Crystal Structure of Peroxiredoxin Asp f3 Provides Mechanistic Insight into Oxidative Stress Resistance and Virulence of Aspergillus fumigatus.

PubMed

Hillmann, Falk; Bagramyan, Karine; Straßburger, Maria; Heinekamp, Thorsten; Hong, Teresa B; Bzymek, Krzysztof P; Williams, John C; Brakhage, Axel A; Kalkum, Markus

2016-09-14

Invasive aspergillosis and other fungal infections occur in immunocompromised individuals, including patients who received blood-building stem cell transplants, patients with chronic granulomatous disease (CGD), and others. Production of reactive oxygen species (ROS) by immune cells, which incidentally is defective in CGD patients, is considered to be a fundamental process in inflammation and antifungal immune response. Here we show that the peroxiredoxin Asp f3 of Aspergillus fumigatus inactivates ROS. We report the crystal structure and the catalytic mechanism of Asp f3, a two-cysteine type peroxiredoxin. The latter exhibits a thioredoxin fold and a homodimeric structure with two intermolecular disulfide bonds in its oxidized state. Replacement of the Asp f3 cysteines with serine residues retained its dimeric structure, but diminished Asp f3's peroxidase activity, and extended the alpha-helix with the former peroxidatic cysteine residue C61 by six residues. The asp f3 deletion mutant was sensitive to ROS, and this phenotype was rescued by ectopic expression of Asp f3. Furthermore, we showed that deletion of asp f3 rendered A. fumigatus avirulent in a mouse model of pulmonary aspergillosis. The conserved expression of Asp f3 homologs in medically relevant molds and yeasts prompts future evaluation of Asp f3 as a potential therapeutic target.

Electronic Health Record Phenotypes for Precision Medicine: Perspectives and Caveats From Treatment of Breast Cancer at a Single Institution

PubMed Central

Liu, Hongfang; Maxwell, Kara N.; Pathak, Jyotishman; Zhang, Rui

2018-01-01

Abstract Precision medicine is at the forefront of biomedical research. Cancer registries provide rich perspectives and electronic health records (EHRs) are commonly utilized to gather additional clinical data elements needed for translational research. However, manual annotation is resource‐intense and not readily scalable. Informatics‐based phenotyping presents an ideal solution, but perspectives obtained can be impacted by both data source and algorithm selection. We derived breast cancer (BC) receptor status phenotypes from structured and unstructured EHR data using rule‐based algorithms, including natural language processing (NLP). Overall, the use of NLP increased BC receptor status coverage by 39.2% from 69.1% with structured medication information alone. Using all available EHR data, estrogen receptor‐positive BC cases were ascertained with high precision (P = 0.976) and recall (R = 0.987) compared with gold standard chart‐reviewed patients. However, status negation (R = 0.591) decreased 40.2% when relying on structured medications alone. Using multiple EHR data types (and thorough understanding of the perspectives offered) are necessary to derive robust EHR‐based precision medicine phenotypes. PMID:29084368

Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors.

PubMed

Lorz, Alexander; Lorenzi, Tommaso; Clairambault, Jean; Escargueil, Alexandre; Perthame, Benoît

2015-01-01

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang-bang delivery of cytotoxic and cytostatic drugs.

Atomic force microscopy captures length phenotypes in single proteins

PubMed Central

Carrion-Vazquez, Mariano; Marszalek, Piotr E.; Oberhauser, Andres F.; Fernandez, Julio M.

1999-01-01

We use single-protein atomic force microscopy techniques to detect length phenotypes in an Ig module. To gain amino acid resolution, we amplify the mechanical features of a single module by engineering polyproteins composed of up to 12 identical repeats. We show that on mechanical unfolding, mutant polyproteins containing five extra glycine residues added to the folded core of the module extend 20 Å per module farther than the wild-type polyproteins. By contrast, similar insertions near the N or C termini have no effect. Hence, our atomic force microscopy measurements readily discriminate the location of the insert and measure its size with a resolution similar to that of NMR and x-ray crystallography. PMID:10500169

Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

PubMed Central

Ogungbenro, Kayode; Aarons, Leon

2015-01-01

Aims To extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine. Methods The developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data. Results The model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses. Conclusions The developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity. PMID:25614061

Immunometabolic phenotype alterations associated with the induction of disease tolerance and persistent asymptomatic infection of Salmonella in the chicken intestine

USDA-ARS?s Scientific Manuscript database

The adaptation of Salmonella enterica to the eukaryotic host is a key process that enables the bacterium to survive in a hostile environment. Salmonella has evolved an intimate relationship with its host that extends to their cellular and molecular levels. Colonization, invasion, and replication o...

Grammar Clinical Marker Yields Substantial Heritability for Language Impairments in 16-Year-Old Twins

ERIC Educational Resources Information Center

Dale, Philip S.; Rice, Mabel L.; Rimfeld, Kaili; Hayiou-Thomas, Marianna E.

2018-01-01

Purpose: There is a need for well-defined language phenotypes suitable for adolescents in twin studies and other large-scale research projects. Rice, Hoffman, and Wexler (2009) have developed a grammatical judgment measure as a clinical marker of language impairment, which has an extended developmental range to adolescence. Method: We conducted…

A Gene for an Extended Phenotype

Treesearch

K. Hoover; M. Grove; M. Gardner; D. P. Hughes; J. McNeil; J. Slavicek

2011-01-01

Manipulation of host behavior by parasites and pathogens has been widely observed, but the basis for these behaviors has remained elusive. Gypsy moths infected by a baculovirus climb to the top of trees to die, liquefy, and "rain" virus on the foliage below to infect new hosts. The viral gene that manipulates climbing behavior of the host was identified,...

Selective Spatial Processing Deficits in an At-Risk Subgroup of the Fragile X Premutation

ERIC Educational Resources Information Center

Hocking, Darren R.; Kogan, Cary S.; Cornish, Kim M.

2012-01-01

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated…

Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures

PubMed Central

Cerruti, Benedetta; Puliafito, Alberto; Shewan, Annette M.; Yu, Wei; Combes, Alexander N.; Little, Melissa H.; Chianale, Federica; Primo, Luca; Serini, Guido; Mostov, Keith E.; Celani, Antonio

2013-01-01

The growth of a well-formed epithelial structure is governed by mechanical constraints, cellular apico-basal polarity, and spatially controlled cell division. Here we compared the predictions of a mathematical model of epithelial growth with the morphological analysis of 3D epithelial structures. In both in vitro cyst models and in developing epithelial structures in vivo, epithelial growth could take place close to or far from mechanical equilibrium, and was determined by the hierarchy of time-scales of cell division, cell–cell rearrangements, and lumen dynamics. Equilibrium properties could be inferred by the analysis of cell–cell contact topologies, and the nonequilibrium phenotype was altered by inhibiting ROCK activity. The occurrence of an aberrant multilumen phenotype was linked to fast nonequilibrium growth, even when geometric control of cell division was correctly enforced. We predicted and verified experimentally that slowing down cell division partially rescued a multilumen phenotype induced by altered polarity. These results improve our understanding of the development of epithelial organs and, ultimately, of carcinogenesis. PMID:24145168

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

Neuroanatomical phenotyping of the mouse brain with three-dimensional autofluorescence imaging

PubMed Central

Wong, Michael D.; Dazai, Jun; Altaf, Maliha; Mark Henkelman, R.; Lerch, Jason P.; Nieman, Brian J.

2012-01-01

The structural organization of the brain is important for normal brain function and is critical to understand in order to evaluate changes that occur during disease processes. Three-dimensional (3D) imaging of the mouse brain is necessary to appreciate the spatial context of structures within the brain. In addition, the small scale of many brain structures necessitates resolution at the ∼10 μm scale. 3D optical imaging techniques, such as optical projection tomography (OPT), have the ability to image intact large specimens (1 cm3) with ∼5 μm resolution. In this work we assessed the potential of autofluorescence optical imaging methods, and specifically OPT, for phenotyping the mouse brain. We found that both specimen size and fixation methods affected the quality of the OPT image. Based on these findings we developed a specimen preparation method to improve the images. Using this method we assessed the potential of optical imaging for phenotyping. Phenotypic differences between wild-type male and female mice were quantified using computer-automated methods. We found that optical imaging of the endogenous autofluorescence in the mouse brain allows for 3D characterization of neuroanatomy and detailed analysis of brain phenotypes. This will be a powerful tool for understanding mouse models of disease and development and is a technology that fits easily within the workflow of biology and neuroscience labs. PMID:22718750

Selection for territory acquisition is modulated by social network structure in a wild songbird

PubMed Central

Farine, D R; Sheldon, B C

2015-01-01

The social environment may be a key mediator of selection that operates on animals. In many cases, individuals may experience selection not only as a function of their phenotype, but also as a function of the interaction between their phenotype and the phenotypes of the conspecifics they associate with. For example, when animals settle after dispersal, individuals may benefit from arriving early, but, in many cases, these benefits will be affected by the arrival times of other individuals in their local environment. We integrated a recently described method for calculating assortativity on weighted networks, which is the correlation between an individual's phenotype and that of its associates, into an existing framework for measuring the magnitude of social selection operating on phenotypes. We applied this approach to large-scale data on social network structure and the timing of arrival into the breeding area over three years. We found that late-arriving individuals had a reduced probability of breeding. However, the probability of breeding was also influenced by individuals’ social networks. Associating with late-arriving conspecifics increased the probability of successfully acquiring a breeding territory. Hence, social selection could offset the effects of nonsocial selection. Given parallel theoretical developments of the importance of local network structure on population processes, and increasing data being collected on social networks in free-living populations, the integration of these concepts could yield significant insights into social evolution. PMID:25611344

Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery

PubMed Central

2018-01-01

Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compounds discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chemical validation is in vitro evolution and whole genome analysis (IVIEWGA). Here, small molecules from phenotypic screens with demonstrated antiparasitic activity are used in genome-based target discovery methods. In this Review, we discuss the newest, most promising druggable targets discovered or further validated by evolution-based methods, as well as some exceptions. PMID:29451780

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.

A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of WDR45.

PubMed

Hermann, Andreas; Kitzler, Hagen H; Pollack, Tobias; Biskup, Saskia; Krüger, Stefanie; Funke, Claudia; Terrile, Caterina; Haack, Tobias B

2017-01-01

Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). WDR45 mutations were recently identified as causal. WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN). Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of WDR45 . An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the WDR45 coding regions was undertaken, and this showed a reduction of the gene dosage by 50% compared with controls. An extended search for deletions should be performed in apparently WDR45- negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia.

Landscape genomic prediction for restoration of a Eucalyptus foundation species under climate change.

PubMed

Supple, Megan Ann; Bragg, Jason G; Broadhurst, Linda M; Nicotra, Adrienne B; Byrne, Margaret; Andrew, Rose L; Widdup, Abigail; Aitken, Nicola C; Borevitz, Justin O

2018-04-24

As species face rapid environmental change, we can build resilient populations through restoration projects that incorporate predicted future climates into seed sourcing decisions. Eucalyptus melliodora is a foundation species of a critically endangered community in Australia that is a target for restoration. We examined genomic and phenotypic variation to make empirical based recommendations for seed sourcing. We examined isolation by distance and isolation by environment, determining high levels of gene flow extending for 500 km and correlations with climate and soil variables. Growth experiments revealed extensive phenotypic variation both within and among sampling sites, but no site-specific differentiation in phenotypic plasticity. Model predictions suggest that seed can be sourced broadly across the landscape, providing ample diversity for adaptation to environmental change. Application of our landscape genomic model to E. melliodora restoration projects can identify genomic variation suitable for predicted future climates, thereby increasing the long term probability of successful restoration. © 2018, Supple et al.

A Comparative Study on Multifactor Dimensionality Reduction Methods for Detecting Gene-Gene Interactions with the Survival Phenotype

PubMed Central

Lee, Seungyeoun; Kim, Yongkang; Kwon, Min-Seok; Park, Taesung

2015-01-01

Genome-wide association studies (GWAS) have extensively analyzed single SNP effects on a wide variety of common and complex diseases and found many genetic variants associated with diseases. However, there is still a large portion of the genetic variants left unexplained. This missing heritability problem might be due to the analytical strategy that limits analyses to only single SNPs. One of possible approaches to the missing heritability problem is to consider identifying multi-SNP effects or gene-gene interactions. The multifactor dimensionality reduction method has been widely used to detect gene-gene interactions based on the constructive induction by classifying high-dimensional genotype combinations into one-dimensional variable with two attributes of high risk and low risk for the case-control study. Many modifications of MDR have been proposed and also extended to the survival phenotype. In this study, we propose several extensions of MDR for the survival phenotype and compare the proposed extensions with earlier MDR through comprehensive simulation studies. PMID:26339630

Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

PubMed Central

Gogliotti, Rocky G.; Quinlan, Katharina A.; Barlow, Courtenay B.; Heier, Christopher R.; Heckman, C. J.

2012-01-01

The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction. PMID:22423102

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations

NASA Astrophysics Data System (ADS)

Sardanyés, Josep; Simó, Carles; Martínez, Regina; Solé, Ricard V.; Elena, Santiago F.

2014-04-01

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Exploring sex differences in autistic traits: A factor analytic study of adults with autism.

PubMed

Grove, Rachel; Hoekstra, Rosa A; Wierda, Marlies; Begeer, Sander

2017-08-01

Research has highlighted potential differences in the phenotypic and clinical presentation of autism spectrum conditions across sex. Furthermore, the measures utilised to evaluate autism spectrum conditions may be biased towards the male autism phenotype. It is important to determine whether these instruments measure the autism phenotype consistently in autistic men and women. This study evaluated the factor structure of the Autism Spectrum Quotient Short Form in a large sample of autistic adults. It also systematically explored specific sex differences at the item level, to determine whether the scale assesses the autism phenotype equivalently across males and females. Factor analyses were conducted among 265 males and 285 females. A two-factor structure consisting of a social behaviour and numbers and patterns factor was consistent across groups, indicating that the latent autism phenotype is similar among both autistic men and women. Subtle differences were observed on two social behaviour item thresholds of the Autism Spectrum Quotient Short Form, with women reporting scores more in line with the scores expected in autism on these items than men. However, these differences were not substantial. This study showed that the Autism Spectrum Quotient Short Form detects autistic traits equivalently in males and females and is not biased towards the male autism phenotype.

Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits

PubMed Central

Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L.

2013-01-01

Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays. PMID:23737753

Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.

PubMed

Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L

2013-05-01

Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays.

Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.

PubMed

Simonelli, Francesca; Testa, Francesco; Zernant, Jana; Nesti, Anna; Rossi, Settimio; Rinaldi, Ernesto; Allikmets, Rando

2004-01-01

Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology. Copyright 2004 S. Karger AG, Basel

Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure.

PubMed

Hindman, Andrea R; Mo, Xiaokui Molly; Helber, Hannah L; Kovalchin, Claire E; Ravichandran, Nanditha; Murphy, Alina R; Fagan, Abigail M; St John, Pamela M; Burd, Craig J

2017-10-01

In utero exposure to the endocrine disrupting compound bisphenol A (BPA) is known to disrupt mammary gland development and increase tumor susceptibility in rodents. It is unclear whether different periods of in utero development might be more susceptible to BPA exposure. We exposed pregnant CD-1 mice to BPA at different times during gestation that correspond to specific milestones of in utero mammary gland development. The mammary glands of early-life and adult female mice, exposed in utero to BPA, were morphologically and molecularly (estrogen receptor-α and Ki67) evaluated for developmental abnormalities. We found that BPA treatment occurring before mammary bud invasion into the mesenchyme [embryonic day (E)12.5] incompletely resulted in the measured phenotypes of mammary gland defects. Exposing mice up to the point at which the epithelium extends into the precursor fat pad (E16.5) resulted in a nearly complete BPA phenotype and exposure during epithelial extension (E15.5 to E18.5) resulted in a partial phenotype. Furthermore, the relative differences in phenotypes between exposure windows highlight the substantial correlations between early-life molecular changes (estrogen receptor-α and Ki67) in the stroma and the epithelial elongation defects in mammary development. These data further implicate BPA action in the stroma as a critical mediator of epithelial phenotypes. Copyright © 2017 Endocrine Society.

Disruptive selection as a driver of evolutionary branching and caste evolution in social insects.

PubMed

Planqué, R; Powell, S; Franks, N R; van den Berg, J B

2016-11-01

Theory suggests that evolutionary branching via disruptive selection may be a relatively common and powerful force driving phenotypic divergence. Here, we extend this theory to social insects, which have novel social axes of phenotypic diversification. Our model, built around turtle ant (Cephalotes) biology, is used to explore whether disruptive selection can drive the evolutionary branching of divergent colony phenotypes that include a novel soldier caste. Soldier evolution is a recurrent theme in social insect diversification that is exemplified in the turtle ants. We show that phenotypic mutants can gain competitive advantages that induce disruptive selection and subsequent branching. A soldier caste does not generally appear before branching, but can evolve from subsequent competition. The soldier caste then evolves in association with specialized resource preferences that maximize defensive performance. Overall, our model indicates that resource specialization may occur in the absence of morphological specialization, but that when morphological specialization evolves, it is always in association with resource specialization. This evolutionary coupling of ecological and morphological specialization is consistent with recent empirical evidence, but contrary to predictions of classical caste theory. Our model provides a new theoretical understanding of the ecology of caste evolution that explicitly considers the process of adaptive phenotypic divergence and diversification. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

A comparison of phenotypic variation and covariation patterns and the role of phylogeny, ecology, and ontogeny during cranial evolution of new world monkeys.

PubMed

Marroig, G; Cheverud, J M

2001-12-01

Similarity of genetic and phenotypic variation patterns among populations is important for making quantitative inferences about past evolutionary forces acting to differentiate populations and for evaluating the evolution of relationships among traits in response to new functional and developmental relationships. Here, phenotypic co variance and correlation structure is compared among Platyrrhine Neotropical primates. Comparisons range from among species within a genus to the superfamily level. Matrix correlation followed by Mantel's test and vector correlation among responses to random natural selection vectors (random skewers) were used to compare correlation and variance/covariance matrices of 39 skull traits. Sampling errors involved in matrix estimates were taken into account in comparisons using matrix repeatability to set upper limits for each pairwise comparison. Results indicate that covariance structure is not strictly constant but that the amount of variance pattern divergence observed among taxa is generally low and not associated with taxonomic distance. Specific instances of divergence are identified. There is no correlation between the amount of divergence in covariance patterns among the 16 genera and their phylogenetic distance derived from a conjoint analysis of four already published nuclear gene datasets. In contrast, there is a significant correlation between phylogenetic distance and morphological distance (Mahalanobis distance among genus centroids). This result indicates that while the phenotypic means were evolving during the last 30 millions years of New World monkey evolution, phenotypic covariance structures of Neotropical primate skulls have remained relatively consistent. Neotropical primates can be divided into four major groups based on their feeding habits (fruit-leaves, seed-fruits, insect-fruits, and gum-insect-fruits). Differences in phenotypic covariance structure are correlated with differences in feeding habits, indicating that to some extent changes in interrelationships among skull traits are associated with changes in feeding habits. Finally, common patterns and levels of morphological integration are found among Platyrrhine primates, suggesting that functional/developmental integration could be one major factor keeping covariance structure relatively stable during evolutionary diversification of South American monkeys.

Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns.

PubMed

Vanoli, Alessandro; Di Sabatino, Antonio; Martino, Michele; Klersy, Catherine; Grillo, Federica; Mescoli, Claudia; Nesi, Gabriella; Volta, Umberto; Fornino, Daniele; Luinetti, Ombretta; Fociani, Paolo; Villanacci, Vincenzo; D'Armiento, Francesco P; Cannizzaro, Renato; Latella, Giovanni; Ciacci, Carolina; Biancone, Livia; Paulli, Marco; Sessa, Fausto; Rugge, Massimo; Fiocca, Roberto; Corazza, Gino R; Solcia, Enrico

2017-10-01

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

PubMed

Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

2017-05-18

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

Use of Long-Term E. Coli Cultures: To Study Generation of Genetic Diversity & Teach General Microbiology Laboratory Skills

ERIC Educational Resources Information Center

Petrie, Angela; Finkel, Steven E.; Erbe, Jarrod

2005-01-01

A novel method of studying the generation of genetic diversity in an undergraduate microbiology laboratory is described. The basis of this approach is the accumulation of mutations that confer a competitive advantage, or growth advantage in stationary phase (GASP) phenotype, to E. coli grown in stationary phase for extended periods of time.

Prevalence of the mcr-1 colistin resistance gene in extended-spectrum β-lactamase-producing Escherichia coli from human faecal samples collected in 2012 in rural villages in Shandong Province, China.

PubMed

Bi, Zhenwang; Berglund, Björn; Sun, Qiang; Nilsson, Maud; Chen, Baoli; Tärnberg, Maria; Ding, Lilu; Stålsby Lundborg, Cecilia; Bi, Zhenqiang; Tomson, Göran; Yao, Jingjing; Gu, Zhanying; Yin, Xiao; Kou, Zengqiang; Nilsson, Lennart E

2017-04-01

Since its initial discovery in China in 2015, the plasmid-mediated colistin resistance gene mcr-1 has been reported in Escherichia coli isolated from clinical samples, animals and meat worldwide. In this study, 706 extended-spectrum β-lactamase (ESBL)-producing E. coli from 411 persons were detected in a collection of faecal samples from 1000 rural residents in three counties in Shandong Province, China. These isolates were screened for mcr-1 and phenotypic colistin resistance. The gene was found in 3.5% of the isolates (from 4.9% of persons) from all three counties. All isolates with phenotypic colistin resistance carried mcr-1. These data indicate that commensal carriage of ESBL-producing E. coli with mcr-1 among persons in rural China was already present in 2012 and that mcr-1 was the most important colistin resistance mechanism. Interventions are necessary to minimise further dissemination of mcr-1, which would limit the future usefulness of colistin as a last-resort antibiotic. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Red Cell Alloantibodies in Multiple Transfused Thalassaemia Patients.

PubMed

Chaudhari, C N

2011-01-01

Thalassaemia major patients require lifelong transfusion support due to which they are prone for alloimmunization to foreign RBCs. Alloimmunization can be prevented by extended phenotype match blood transfusion. The study was conducted to know the extent of problem of alloimmunization and to find important red cell antibodies in thalassaemia patients. A cross-sectional study was conducted. A total of 32 thalassaemia patients were enrolled. The specimen was subjected to red cell alloantibody and autoantibody by column gel agglutination technique. R 1 (w) R 1 , R 2 R 2 , rr (papaine and non papain) and 11 cell panel reagent cells were used in screening and identification of alloantibodies respectively. Six (18.8 %) subjects were alloimmunized. All alloimmunized subjects were recipient of more than 20 units of transfusion. Total seven clinically significant alloantibodies were identified. Anti E and anti c were commonest antibodies in four (12.5%) patients. Red cell alloimmunization is an important risk in thalassaemia patient. 71.4% of alloantibodies were anti E and anti c type. Extended phenotype match blood transfusion for Rh-c and Rh-E antigens or level 2 antigen matching stringency needs to be explored in preventing alloimmunization in thalassaemia patients.

Nosocomial bacteremia and urinary tract infections caused by extended-spectrum beta -lactamase-producing Klebsiella pneumoniae with plasmids carrying both SHV-5 and TLA-1 genes.

PubMed

Alcantar-Curiel, Dolores; Tinoco, Juan Carlos; Gayosso, Catalina; Carlos, Angeles; Daza, Carlos; Perez-Prado, Maria C; Salcido, Lorena; Santos, Jose I; Alpuche-Aranda, Celia M

2004-04-15

We describe the prevalence and molecular characteristics of extended-spectrum beta -lactamase (ESBL)-producing Klebsiella pneumoniae causing nosocomial bacteremia and urinary tract infections in a Mexican general hospital. We analyzed 82 episodes of bacteremia (approximately 60% of episodes) and urinary tract infection (approximately 40% of episodes) due to K. pneumoniae during a 23-month surveillance period. The neonatal intensive care unit accounted for 49% of all episodes. All strains were imipenem susceptible; 62.2% of the strains were resistant to ceftazidime, cefotaxime, and aztreonam; 69.5% were resistant to amikacin; 58.5% were resistant to gentamicin; and 7.3% were resistant to ciprofloxacin. All strains were associated with 28 pulsed-field gel electrophoresis patterns, and dissemination of 2 ceftazidime-resistant clones produced 44% of the cases. The ESBL phenotype in these clones was transferred by identical or highly related megaplasmids. The ESBL activity corresponded to SHV-5 and TLA-1. Cross-transmission of 2 ceftazidime-resistant clones and the horizontal spread of identical or highly related megaplasmids explain the high prevalence of ESBL phenotype in these infections.

PRIMARY CILIARY DYSKINESIA: DIAGNOSTIC AND PHENOTYPIC FEATURES

EPA Science Inventory

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. ...

Structuring evolution: biochemical networks and metabolic diversification in birds.

PubMed

Morrison, Erin S; Badyaev, Alexander V

2016-08-25

Recurrence and predictability of evolution are thought to reflect the correspondence between genomic and phenotypic dimensions of organisms, and the connectivity in deterministic networks within these dimensions. Direct examination of the correspondence between opportunities for diversification imbedded in such networks and realized diversity is illuminating, but is empirically challenging because both the deterministic networks and phenotypic diversity are modified in the course of evolution. Here we overcome this problem by directly comparing the structure of a "global" carotenoid network - comprising of all known enzymatic reactions among naturally occurring carotenoids - with the patterns of evolutionary diversification in carotenoid-producing metabolic networks utilized by birds. We found that phenotypic diversification in carotenoid networks across 250 species was closely associated with enzymatic connectivity of the underlying biochemical network - compounds with greater connectivity occurred the most frequently across species and were the hotspots of metabolic pathway diversification. In contrast, we found no evidence for diversification along the metabolic pathways, corroborating findings that the utilization of the global carotenoid network was not strongly influenced by history in avian evolution. The finding that the diversification in species-specific carotenoid networks is qualitatively predictable from the connectivity of the underlying enzymatic network points to significant structural determinism in phenotypic evolution.

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data

PubMed Central

Koscielny, Gautier; Yaikhom, Gagarine; Iyer, Vivek; Meehan, Terrence F.; Morgan, Hugh; Atienza-Herrero, Julian; Blake, Andrew; Chen, Chao-Kung; Easty, Richard; Di Fenza, Armida; Fiegel, Tanja; Grifiths, Mark; Horne, Alan; Karp, Natasha A.; Kurbatova, Natalja; Mason, Jeremy C.; Matthews, Peter; Oakley, Darren J.; Qazi, Asfand; Regnart, Jack; Retha, Ahmad; Santos, Luis A.; Sneddon, Duncan J.; Warren, Jonathan; Westerberg, Henrik; Wilson, Robert J.; Melvin, David G.; Smedley, Damian; Brown, Steve D. M.; Flicek, Paul; Skarnes, William C.; Mallon, Ann-Marie; Parkinson, Helen

2014-01-01

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated ‘data wranglers’ work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases. PMID:24194600

Myotilinopathy in a family with late onset myopathy.

PubMed

Pénisson-Besnier, Isabelle; Talvinen, Kati; Dumez, Catherine; Vihola, Anna; Dubas, Frédéric; Fardeau, Michel; Hackman, Peter; Carpen, Olli; Udd, Bjarne

2006-07-01

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.

Using text mining techniques to extract phenotypic information from the PhenoCHF corpus

PubMed Central

2015-01-01

Background Phenotypic information locked away in unstructured narrative text presents significant barriers to information accessibility, both for clinical practitioners and for computerised applications used for clinical research purposes. Text mining (TM) techniques have previously been applied successfully to extract different types of information from text in the biomedical domain. They have the potential to be extended to allow the extraction of information relating to phenotypes from free text. Methods To stimulate the development of TM systems that are able to extract phenotypic information from text, we have created a new corpus (PhenoCHF) that is annotated by domain experts with several types of phenotypic information relating to congestive heart failure. To ensure that systems developed using the corpus are robust to multiple text types, it integrates text from heterogeneous sources, i.e., electronic health records (EHRs) and scientific articles from the literature. We have developed several different phenotype extraction methods to demonstrate the utility of the corpus, and tested these methods on a further corpus, i.e., ShARe/CLEF 2013. Results Evaluation of our automated methods showed that PhenoCHF can facilitate the training of reliable phenotype extraction systems, which are robust to variations in text type. These results have been reinforced by evaluating our trained systems on the ShARe/CLEF corpus, which contains clinical records of various types. Like other studies within the biomedical domain, we found that solutions based on conditional random fields produced the best results, when coupled with a rich feature set. Conclusions PhenoCHF is the first annotated corpus aimed at encoding detailed phenotypic information. The unique heterogeneous composition of the corpus has been shown to be advantageous in the training of systems that can accurately extract phenotypic information from a range of different text types. Although the scope of our annotation is currently limited to a single disease, the promising results achieved can stimulate further work into the extraction of phenotypic information for other diseases. The PhenoCHF annotation guidelines and annotations are publicly available at https://code.google.com/p/phenochf-corpus. PMID:26099853

Using text mining techniques to extract phenotypic information from the PhenoCHF corpus.

PubMed

Alnazzawi, Noha; Thompson, Paul; Batista-Navarro, Riza; Ananiadou, Sophia

2015-01-01

Phenotypic information locked away in unstructured narrative text presents significant barriers to information accessibility, both for clinical practitioners and for computerised applications used for clinical research purposes. Text mining (TM) techniques have previously been applied successfully to extract different types of information from text in the biomedical domain. They have the potential to be extended to allow the extraction of information relating to phenotypes from free text. To stimulate the development of TM systems that are able to extract phenotypic information from text, we have created a new corpus (PhenoCHF) that is annotated by domain experts with several types of phenotypic information relating to congestive heart failure. To ensure that systems developed using the corpus are robust to multiple text types, it integrates text from heterogeneous sources, i.e., electronic health records (EHRs) and scientific articles from the literature. We have developed several different phenotype extraction methods to demonstrate the utility of the corpus, and tested these methods on a further corpus, i.e., ShARe/CLEF 2013. Evaluation of our automated methods showed that PhenoCHF can facilitate the training of reliable phenotype extraction systems, which are robust to variations in text type. These results have been reinforced by evaluating our trained systems on the ShARe/CLEF corpus, which contains clinical records of various types. Like other studies within the biomedical domain, we found that solutions based on conditional random fields produced the best results, when coupled with a rich feature set. PhenoCHF is the first annotated corpus aimed at encoding detailed phenotypic information. The unique heterogeneous composition of the corpus has been shown to be advantageous in the training of systems that can accurately extract phenotypic information from a range of different text types. Although the scope of our annotation is currently limited to a single disease, the promising results achieved can stimulate further work into the extraction of phenotypic information for other diseases. The PhenoCHF annotation guidelines and annotations are publicly available at https://code.google.com/p/phenochf-corpus.

Epistasis and Pleiotropy Affect the Modularity of the Genotype-Phenotype Map of Cross-Resistance in HIV-1.

PubMed

Polster, Robert; Petropoulos, Christos J; Bonhoeffer, Sebastian; Guillaume, Frédéric

2016-12-01

The genotype-phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Developmental mechanisms underlying variation in craniofacial disease and evolution.

PubMed

Fish, Jennifer L

2016-07-15

Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2-mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype-phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the "black box" between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies. Copyright © 2015 Elsevier Inc. All rights reserved.

Present Day Biology seen in the Looking Glass of Physics of Complexity

NASA Astrophysics Data System (ADS)

Schuster, P.

Darwin's theory of variation and selection in its simplest form is directly applicable to RNA evolution in vitro as well as to virus evolution, and it allows for quantitative predictions. Understanding evolution at the molecular level is ultimately related to the central paradigm of structural biology: sequence⇒ structure ⇒ function. We elaborate on the state of the art in modeling and understanding evolution of RNA driven by reproduction and mutation. The focus will be laid on the landscape concept—originally introduced by Sewall Wright—and its application to problems in biology. The relation between genotypes and phenotypes is the result of two consecutive mappings from a space of genotypes called sequence space onto a space of phenotypes or structures, and fitness is the result of a mapping from phenotype space into non-negative real numbers. Realistic landscapes as derived from folding of RNA sequences into structures are characterized by two properties: (i) they are rugged in the sense that sequences lying nearby in sequence space may have very different fitness values and (ii) they are characterized by an appreciable degree of neutrality implying that a certain fraction of genotypes and/or phenotypes cannot be distinguished in the selection process. Evolutionary dynamics on realistic landscapes will be studied as a function of the mutation rate, and the role of neutrality in the selection process will be discussed.

Mycobacterium tuberculosis toxin Rv2872 is an RNase involved in vancomycin stress response and biofilm development.

PubMed

Wang, Xiaoyu; Zhao, Xiaokang; Wang, Hao; Huang, Xue; Duan, Xiangke; Gu, Yinzhong; Lambert, Nzungize; Zhang, Ke; Kou, Zhenhao; Xie, Jianping

2018-06-11

Bacterial toxin-antitoxin (TA) systems are emerging important regulators of multiple cellular physiological events and candidates for novel antibiotic targets. To explore the role of Mycobacterium tuberculosis function, unknown toxin gene Rv2872 was heterologously expressed in Mycobacterium smegmatis (MS_Rv2872). Upon induction, MS_Rv2872 phenotype differed significantly from the control, such as increased vancomycin resistance, retarded growth, cell wall, and biofilm structure. This phenotype change might result from the RNase activity of Rv2872 as purified Rv2872 toxin protein can cleave the products of several key genes involved in abovementioned phenotypes. In summary, toxin Rv2872 was firstly reported to be a endonuclease involved in antibiotic stress responses, cell wall structure, and biofilm development.

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

PubMed Central

Schroeder, Barbara; Park, Cheol Hong; Chandra Mohan, KVP; Khurana, Ashwani; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás; Kleer, Celina; Menendez, Javier A.; Lupu, Ruth

2016-01-01

The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies. PMID:27223424

Structural gene (prME) chimeras of St Louis encephalitis virus and West Nile virus exhibit altered in vitro cytopathic and growth phenotypes

PubMed Central

Maharaj, Payal D.; Anishchenko, Michael; Langevin, Stanley A.; Fang, Ying; Reisen, William K.

2012-01-01

Despite utilizing the same avian hosts and mosquito vectors, St Louis encephalitis virus (SLEV) and West Nile virus (WNV) display dissimilar vector-infectivity and vertebrate-pathogenic phenotypes. SLEV exhibits a low oral infection threshold for Culex mosquito vectors and is avirulent in avian hosts, producing low-magnitude viraemias. In contrast, WNV is less orally infective to mosquitoes and elicits high-magnitude viraemias in a wide range of avian species. In order to identify the genetic determinants of these different phenotypes and to assess the utility of mosquito and vertebrate cell lines for recapitulating in vivo differences observed between these viruses, reciprocal WNV and SLEV pre-membrane and envelope protein (prME) chimeric viruses were generated and growth of these mutant viruses was characterized in mammalian (Vero), avian (duck) and mosquito [Aedes (C6/36) and Culex (CT)] cells. In both vertebrate lines, WNV grew to 100-fold higher titres than SLEV, and growth and cytopathogenicity phenotypes, determined by chimeric phenotypes, were modulated by genetic elements outside the prME gene region. Both chimeras exhibited distinctive growth patterns from those of SLEV in C6/36 cells, indicating the role of both structural and non-structural gene regions for growth in this cell line. In contrast, growth of chimeric viruses was indistinguishable from that of virus containing homologous prME genes in CT cells, indicating that structural genetic elements could specifically dictate growth differences of these viruses in relevant vectors. These data provide genetic insight into divergent enzootic maintenance strategies that could also be useful for the assessment of emergence mechanisms of closely related flaviviruses. PMID:21940408

Snake fangs: 3D morphological and mechanical analysis by microCT, simulation, and physical compression testing.

PubMed

du Plessis, Anton; Broeckhoven, Chris; le Roux, Stephan G

2018-01-01

This Data Note provides data from an experimental campaign to analyse the detailed internal and external morphology and mechanical properties of venomous snake fangs. The aim of the experimental campaign was to investigate the evolutionary development of 3 fang phenotypes and investigate their mechanical behaviour. The study involved the use of load simulations to compare maximum Von Mises stress values when a load is applied to the tip of the fang. The conclusions of this study have been published elsewhere, but in this data note we extend the analysis, providing morphological comparisons including details such as curvature comparisons, thickness, etc. Physical compression results of individual fangs, though reported in the original paper, were also extended here by calculating the effective elastic modulus of the entire snake fang structure including internal cavities for the first time. This elastic modulus of the entire fang is significantly lower than the locally measured values previously reported from indentation experiments, highlighting the possibility that the elastic modulus is higher on the surface than in the rest of the material. The micro-computed tomography (microCT) data are presented both in image stacks and in the form of STL files, which simplifies the handling of the data and allows its re-use for future morphological studies. These fangs might also serve as bio-inspiration for future hypodermic needles. © The Author 2017. Published by Oxford University Press.

Quality Control Test for Sequence-Phenotype Assignments

PubMed Central

Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; Del Rio, Gabriel

2015-01-01

Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10–20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas. PMID:25700273

Corticotropin releasing factor: a key role in the neurobiology of addiction.

PubMed

Zorrilla, Eric P; Logrip, Marian L; Koob, George F

2014-04-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body's response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. Copyright © 2014 Elsevier Inc. All rights reserved.

A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion.

PubMed

Leshinsky-Silver, E; Michelson, M; Cohen, S; Ginsberg, M; Sadeh, M; Barash, V; Lerman-Sagie, T; Lev, D

2008-07-01

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

11,670 whole-genome sequences representative of the Han Chinese population from the CONVERGE project.

PubMed

Cai, Na; Bigdeli, Tim B; Kretzschmar, Warren W; Li, Yihan; Liang, Jieqin; Hu, Jingchu; Peterson, Roseann E; Bacanu, Silviu; Webb, Bradley Todd; Riley, Brien; Li, Qibin; Marchini, Jonathan; Mott, Richard; Kendler, Kenneth S; Flint, Jonathan

2017-02-14

The China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) project on Major Depressive Disorder (MDD) sequenced 11,670 female Han Chinese at low-coverage (1.7X), providing the first large-scale whole genome sequencing resource representative of the largest ethnic group in the world. Samples are collected from 58 hospitals from 23 provinces around China. We are able to call 22 million high quality single nucleotide polymorphisms (SNP) from the nuclear genome, representing the largest SNP call set from an East Asian population to date. We use these variants for imputation of genotypes across all samples, and this has allowed us to perform a successful genome wide association study (GWAS) on MDD. The utility of these data can be extended to studies of genetic ancestry in the Han Chinese and evolutionary genetics when integrated with data from other populations. Molecular phenotypes, such as copy number variations and structural variations can be detected, quantified and analysed in similar ways.

Corticotropin Releasing Factor: A Key Role in the Neurobiology of Addiction

PubMed Central

Zorrilla, Eric P.; Logrip, Marian L.; Koob, George F.

2014-01-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body’s response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction.. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. PMID:24456850

Small indels induced by CRISPR/Cas9 in the 5' region of microRNA lead to its depletion and Drosha processing retardance.

PubMed

Jiang, Qian; Meng, Xing; Meng, Lingwei; Chang, Nannan; Xiong, Jingwei; Cao, Huiqing; Liang, Zicai

2014-01-01

MicroRNA knockout by genome editing technologies is promising. In order to extend the application of the technology and to investigate the function of a specific miRNA, we used CRISPR/Cas9 to deplete human miR-93 from a cluster by targeting its 5' region in HeLa cells. Various small indels were induced in the targeted region containing the Drosha processing site and seed sequences. Interestingly, we found that even a single nucleotide deletion led to complete knockout of the target miRNA with high specificity. Functional knockout was confirmed by phenotype analysis. Furthermore, de novo microRNAs were not found by RNA-seq. Nevertheless, expression of the pri-microRNAs was increased. When combined with structural analysis, the data indicated that biogenesis was impaired. Altogether, we showed that small indels in the 5' region of a microRNA result in sequence depletion as well as Drosha processing retard.

Leaf bacterial diversity mediates plant diversity and ecosystem function relationships.

PubMed

Laforest-Lapointe, Isabelle; Paquette, Alain; Messier, Christian; Kembel, Steven W

2017-06-01

Research on biodiversity and ecosystem functioning has demonstrated links between plant diversity and ecosystem functions such as productivity. At other trophic levels, the plant microbiome has been shown to influence host plant fitness and function, and host-associated microbes have been proposed to influence ecosystem function through their role in defining the extended phenotype of host organisms However, the importance of the plant microbiome for ecosystem function has not been quantified in the context of the known importance of plant diversity and traits. Here, using a tree biodiversity-ecosystem functioning experiment, we provide strong support for the hypothesis that leaf bacterial diversity is positively linked to ecosystem productivity, even after accounting for the role of plant diversity. Our results also show that host species identity, functional identity and functional diversity are the main determinants of leaf bacterial community structure and diversity. Our study provides evidence of a positive correlation between plant-associated microbial diversity and terrestrial ecosystem productivity, and a new mechanism by which models of biodiversity-ecosystem functioning relationships can be improved.

A Molecular Perspective on Systematics, Taxonomy and Classification Amazonian Discus Fishes of the Genus Symphysodon

PubMed Central

Amado, Manuella Villar; Farias, Izeni P.; Hrbek, Tomas

2011-01-01

With the goal of contributing to the taxonomy and systematics of the Neotropical cichlid fishes of the genus Symphysodon, we analyzed 336 individuals from 24 localities throughout the entire distributional range of the genus. We analyzed variation at 13 nuclear microsatellite markers, and subjected the data to Bayesian analysis of genetic structure. The results indicate that Symphysodon is composed of four genetic groups: group PURPLE—phenotype Heckel and abacaxi; group GREEN—phenotype green; group RED—phenotype blue and brown; and group PINK—populations of Xingú and Cametá. Although the phenotypes blue and brown are predominantly biological group RED, they also have substantial contributions from other biological groups, and the patterns of admixture of the two phenotypes are different. The two phenotypes are further characterized by distinct and divergent mtDNA haplotype groups, and show differences in mean habitat use measured as pH and conductivity. Differences in mean habitat use is also observed between most other biological groups. We therefore conclude that Symphysodon comprises five evolutionary significant units: Symphysodon discus (Heckel and abacaxi phenotypes), S. aequifasciatus (brown phenotype), S. tarzoo (green phenotype), Symphysodon sp. 1 (blue phenotype) and Symphysodon sp. 2 (Xingú group). PMID:21811676

Has snake fang evolution lost its bite? New insights from a structural mechanics viewpoint.

PubMed

Broeckhoven, Chris; du Plessis, Anton

2017-08-01

Venomous snakes-the pinnacle of snake evolution-are characterized by their possession of venom-conducting fangs ranging from grooved phenotypes characterizing multiple lineages of rear-fanged taxa to tubular phenotypes present in elapids, viperids and atractaspidines. Despite extensive research, controversy still exists on the selective pressures involved in fang phenotype diversification. Here, we test the hypothesis that larger fangs and consequently a shift to an anterior position in the maxilla evolved to compensate for the costs of structural changes, i.e. higher stress upon impact in tubular fangs compared to grooved fangs. Direct voxel-based stress simulations conducted on high-resolution µCT scans, analysed within a phylogenetic framework, showed no differences in stress distribution between the three fang phenotypes, despite differences in (relative) fang length. These findings suggest that additional compensatory mechanisms are responsible for the biomechanical optimization and that fang length might instead be related to differential striking behaviour strategies. © 2017 The Author(s).

Imaging techniques for visualizing and phenotyping congenital heart defects in murine models.

PubMed

Liu, Xiaoqin; Tobita, Kimimasa; Francis, Richard J B; Lo, Cecilia W

2013-06-01

Mouse model is ideal for investigating the genetic and developmental etiology of congenital heart disease. However, cardiovascular phenotyping for the precise diagnosis of structural heart defects in mice remain challenging. With rapid advances in imaging techniques, there are now high throughput phenotyping tools available for the diagnosis of structural heart defects. In this review, we discuss the efficacy of four different imaging modalities for congenital heart disease diagnosis in fetal/neonatal mice, including noninvasive fetal echocardiography, micro-computed tomography (micro-CT), micro-magnetic resonance imaging (micro-MRI), and episcopic fluorescence image capture (EFIC) histopathology. The experience we have gained in the use of these imaging modalities in a large-scale mouse mutagenesis screen have validated their efficacy for congenital heart defect diagnosis in the tiny hearts of fetal and newborn mice. These cutting edge phenotyping tools will be invaluable for furthering our understanding of the developmental etiology of congenital heart disease. Copyright © 2013 Wiley Periodicals, Inc.

Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations.

PubMed

Barradas-Bautista, Didier; Fernández-Recio, Juan

2017-01-01

Next-generation sequencing (NGS) technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level.

Microsatellite and Wolbachia analysis in Rhagoletis cerasi natural populations: population structuring and multiple infections.

PubMed

Augustinos, Antonios A; Asimakopoulou, Anastasia K; Moraiti, Cleopatra A; Mavragani-Tsipidou, Penelope; Papadopoulos, Nikolaos T; Bourtzis, Kostas

2014-05-01

Rhagoletis cerasi (Diptera: Tephritidae) is a major pest of sweet and sour cherries in Europe and parts of Asia. Despite its economic significance, there is a lack of studies on the genetic structure of R. cerasi populations. Elucidating the genetic structure of insects of economic importance is crucial for developing phenological-predictive models and environmental friendly control methods. All natural populations of R. cerasi have been found to harbor the endosymbiont Wolbachia pipientis, which widely affects multiple biological traits contributing to the evolution of its hosts, and has been suggested as a tool for the biological control of insect pests and disease vectors. In the current study, the analysis of 18 R. cerasi populations collected in Greece, Germany, and Russia using 13 microsatellite markers revealed structuring of R. cerasi natural populations, even at close geographic range. We also analyzed the Wolbachia infection status of these populations using 16S rRNA-, MLST- and wsp-based approaches. All 244 individuals screened were positive for Wolbachia. Our results suggest the fixation of the wCer1 strain in Greece while wCer2, wCer4, wCer5, and probably other uncharacterized strains were also detected in multiply infected individuals. The role of Wolbachia and its potential extended phenotypes needs a thorough investigation in R. cerasi. Our data suggest an involvement of this symbiont in the observed restriction in the gene flow in addition to a number of different ecological factors.

Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations

PubMed Central

2017-01-01

Next-generation sequencing (NGS) technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level. PMID:28841721

Microsatellite and Wolbachia analysis in Rhagoletis cerasi natural populations: population structuring and multiple infections

PubMed Central

Augustinos, Antonios A; Asimakopoulou, Anastasia K; Moraiti, Cleopatra A; Mavragani-Tsipidou, Penelope; Papadopoulos, Nikolaos T; Bourtzis, Kostas

2014-01-01

Rhagoletis cerasi (Diptera: Tephritidae) is a major pest of sweet and sour cherries in Europe and parts of Asia. Despite its economic significance, there is a lack of studies on the genetic structure of R. cerasi populations. Elucidating the genetic structure of insects of economic importance is crucial for developing phenological-predictive models and environmental friendly control methods. All natural populations of R. cerasi have been found to harbor the endosymbiont Wolbachia pipientis, which widely affects multiple biological traits contributing to the evolution of its hosts, and has been suggested as a tool for the biological control of insect pests and disease vectors. In the current study, the analysis of 18 R. cerasi populations collected in Greece, Germany, and Russia using 13 microsatellite markers revealed structuring of R. cerasi natural populations, even at close geographic range. We also analyzed the Wolbachia infection status of these populations using 16S rRNA-, MLST- and wsp-based approaches. All 244 individuals screened were positive for Wolbachia. Our results suggest the fixation of the wCer1 strain in Greece while wCer2, wCer4, wCer5, and probably other uncharacterized strains were also detected in multiply infected individuals. The role of Wolbachia and its potential extended phenotypes needs a thorough investigation in R. cerasi. Our data suggest an involvement of this symbiont in the observed restriction in the gene flow in addition to a number of different ecological factors. PMID:24963388

Mechanics and energetics in tool manufacture and use: a synthetic approach.

PubMed

Wang, Liyu; Brodbeck, Luzius; Iida, Fumiya

2014-11-06

Tool manufacture and use are observed not only in humans but also in other animals such as mammals, birds and insects. Manufactured tools are used for biomechanical functions such as effective control of fluids and small solid objects and extension of reaching. These tools are passive and used with gravity and the animal users' own energy. From the perspective of evolutionary biology, manufactured tools are extended phenotypes of the genes of the animal and exhibit phenotypic plasticity. This incurs energetic cost of manufacture as compared to the case with a fixed tool. This paper studies mechanics and energetics aspects of tool manufacture and use in non-human beings. Firstly, it investigates possible mechanical mechanisms of the use of passive manufactured tools. Secondly, it formulates the energetic cost of manufacture and analyses when phenotypic plasticity benefits an animal tool maker and user. We take a synthetic approach and use a controlled physical model, i.e. a robot arm. The robot is capable of additively manufacturing scoop and gripper structures from thermoplastic adhesives to pick and place fluid and solid objects, mimicking primates and birds manufacturing tools for a similar function. We evaluate the effectiveness of tool use in pick-and-place and explain the mechanism for gripper tools picking up solid objects with a solid-mechanics model. We propose a way to formulate the energetic cost of tool manufacture that includes modes of addition and reshaping, and use it to analyse the case of scoop tools. Experiment results show that with a single motor trajectory, the robot was able to effectively pick and place water, rice grains, a pebble and a plastic box with a scoop tool or gripper tools that were manufactured by itself. They also show that by changing the dimension of scoop tools, the energetic cost of tool manufacture and use could be reduced. The work should also be interesting for engineers to design adaptive machines. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Mechanics and energetics in tool manufacture and use: a synthetic approach

PubMed Central

Wang, Liyu; Brodbeck, Luzius; Iida, Fumiya

2014-01-01

Tool manufacture and use are observed not only in humans but also in other animals such as mammals, birds and insects. Manufactured tools are used for biomechanical functions such as effective control of fluids and small solid objects and extension of reaching. These tools are passive and used with gravity and the animal users' own energy. From the perspective of evolutionary biology, manufactured tools are extended phenotypes of the genes of the animal and exhibit phenotypic plasticity. This incurs energetic cost of manufacture as compared to the case with a fixed tool. This paper studies mechanics and energetics aspects of tool manufacture and use in non-human beings. Firstly, it investigates possible mechanical mechanisms of the use of passive manufactured tools. Secondly, it formulates the energetic cost of manufacture and analyses when phenotypic plasticity benefits an animal tool maker and user. We take a synthetic approach and use a controlled physical model, i.e. a robot arm. The robot is capable of additively manufacturing scoop and gripper structures from thermoplastic adhesives to pick and place fluid and solid objects, mimicking primates and birds manufacturing tools for a similar function. We evaluate the effectiveness of tool use in pick-and-place and explain the mechanism for gripper tools picking up solid objects with a solid-mechanics model. We propose a way to formulate the energetic cost of tool manufacture that includes modes of addition and reshaping, and use it to analyse the case of scoop tools. Experiment results show that with a single motor trajectory, the robot was able to effectively pick and place water, rice grains, a pebble and a plastic box with a scoop tool or gripper tools that were manufactured by itself. They also show that by changing the dimension of scoop tools, the energetic cost of tool manufacture and use could be reduced. The work should also be interesting for engineers to design adaptive machines. PMID:25209405

Cross-Disorder Genetic Analysis of Tic Disorders, Obsessive-Compulsive, and Hoarding Symptoms.

PubMed

Zilhão, Nuno R; Smit, Dirk J; Boomsma, Dorret I; Cath, Danielle C

2016-01-01

Hoarding, obsessive-compulsive disorder (OCD), and Tourette's disorder (TD) are psychiatric disorders that share symptom overlap, which might partly be the result of shared genetic variation. Population-based twin studies have found significant genetic correlations between hoarding and OCD symptoms, with genetic correlations varying between 0.1 and 0.45. For tic disorders, studies examining these correlations are lacking. Other lines of research, including clinical samples and GWAS or CNV data to explore genetic relationships between tic disorders and OCD, have only found very modest if any shared genetic variation. Our aim was to extend current knowledge on the genetic structure underlying hoarding, OC symptoms (OCS), and lifetime tic symptoms and, in a trivariate analysis, assess the degree of common and unique genetic factors contributing to the etiology of these disorders. Data have been gathered from participants in the Netherlands Twin Register comprising a total of 5293 individuals from a sample of adult monozygotic (n = 2460) and dizygotic (n = 2833) twin pairs (mean age 33.61 years). The data on Hoarding, OCS, and tic symptoms were simultaneously analyzed in Mplus. A liability threshold model was fitted to the twin data, analyzing heritability of phenotypes and of their comorbidity. Following the criteria for a probable clinical diagnosis in all phenotypes, 6.8% of participants had a diagnosis of probable hoarding disorder (HD), 6.3% of OCS, and 12.8% of any probable lifetime tic disorder. Genetic factors explained 50.4, 70.1, and 61.1% of the phenotypic covariance between hoarding-OCS, hoarding-tics, and OCS-tics, respectively. Substantial genetic correlations were observed between hoarding and OCS (0.41), hoarding and tics (0.35), and between OCS and tics (0.37). These results support the contribution of genetic factors in the development of these disorders and their comorbidity. Furthermore, tics were mostly influenced by specific environmental factors unshared with OCS and HD.

Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

PubMed

Heikkinen, Taneli; Lehtimäki, Kimmo; Vartiainen, Nina; Puoliväli, Jukka; Hendricks, Susan J; Glaser, Jack R; Bradaia, Amyaouch; Wadel, Kristian; Touller, Chrystelle; Kontkanen, Outi; Yrjänheikki, Juha M; Buisson, Bruno; Howland, David; Beaumont, Vahri; Munoz-Sanjuan, Ignacio; Park, Larry C

2012-01-01

Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.

How did Metabolism and Genetic Replication Get Married?

NASA Astrophysics Data System (ADS)

Norris, Vic; Loutelier-Bourhis, Corinne; Thierry, Alain

2012-10-01

In addressing the question of the origins of the relationship between metabolism and genetic replication, we consider the implications of a prebiotic, fission-fusion, ecology of composomes. We emphasise the importance of structures and non-specific catalysis on interfaces created by structures. From the assumption that the bells of the metabolism-replication wedding still echo in modern cells, we argue that the functional assemblies of macromolecules that constitute hyperstructures in modern bacteria are the descendants of composomes and that interactions at the hyperstructure level control the cell cycle. A better understanding of the cell cycle should help understand the original metabolism-replication marriage. This understanding requires new concepts such as metabolic signalling, metabolic sensing and Dualism, which entails the cells in a population varying the ratios of equilibrium to non-equilibrium hyperstructures so as to maximise the chances of both survival and growth. A deeper understanding of the coupling between metabolism and replication may also require a new view of cell cycle functions in creating a coherent diversity of phenotypes and in narrowing the combinatorial catalytic space. To take these ideas into account, we propose the Accordion model in which a dynamic interface between lipid domains catalysed monomer to polymer reactions and became decorated with peptides and nucleotides that favoured their own catalysis. In this model, metabolism, replication, differentiation and division all began together at the interface between extended equilibrium structures within protocells or composomes.

Short-range phenotypic divergence among genetically distinct parapatric populations of an Australian funnel-web spider.

PubMed

Wong, Mark K L; Woodman, James D; Rowell, David M

2017-07-01

Speciation involves divergence at genetic and phenotypic levels. Where substantial genetic differentiation exists among populations, examining variation in multiple phenotypic characters may elucidate the mechanisms by which divergence and speciation unfold. Previous work on the Australian funnel-web spider Atrax sutherlandi Gray (2010; Records of the Australian Museum 62 , 285-392; Mygalomorphae: Hexathelidae: Atracinae) has revealed a marked genetic structure along a 110-kilometer transect, with six genetically distinct, parapatric populations attributable to past glacial cycles. In the present study, we explore variation in three classes of phenotypic characters (metabolic rate, water loss, and morphological traits) within the context of this phylogeographic structuring. Variation in metabolic and water loss rates shows no detectable association with genetic structure; the little variation observed in these rates may be due to the spiders' behavioral adaptations (i.e., burrowing), which buffer the effects of climatic gradients across the landscape. However, of 17 morphological traits measured, 10 show significant variation among genetic populations, in a disjunct manner that is clearly not latitudinal. Moreover, patterns of variation observed for morphological traits serving different organismic functions (e.g., prey capture, burrowing, and locomotion) are dissimilar. In contrast, a previous study of an ecologically similar sympatric spider with little genetic structure indicated a strong latitudinal response in 10 traits over the same range. The congruence of morphological variation with deep phylogeographic structure in Tallaganda's A. sutherlandi populations, as well as the inconsistent patterns of variation across separate functional traits, suggest that the spiders are likely in early stages of speciation, with parapatric populations independently responding to local selective forces.

A NAP-AAO3 Regulatory Module Promotes Chlorophyll Degradation via ABA Biosynthesis in Arabidopsis Leaves[W][OPEN

PubMed Central

Yang, Jiading; Worley, Eric

2014-01-01

Chlorophyll degradation is an important part of leaf senescence, but the underlying regulatory mechanisms are largely unknown. Excised leaves of an Arabidopsis thaliana NAC-LIKE, ACTIVATED BY AP3/PI (NAP) transcription factor mutant (nap) exhibited lower transcript levels of known chlorophyll degradation genes, STAY-GREEN1 (SGR1), NON-YELLOW COLORING1 (NYC1), PHEOPHYTINASE (PPH), and PHEIDE a OXYGENASE (PaO), and higher chlorophyll retention than the wild type during dark-induced senescence. Transcriptome coexpression analysis revealed that abscisic acid (ABA) metabolism/signaling genes were disproportionately represented among those positively correlated with NAP expression. ABA levels were abnormally low in nap leaves during extended darkness. The ABA biosynthetic genes 9-CIS-EPOXYCAROTENOID DIOXYGENASE2, ABA DEFICIENT3, and ABSCISIC ALDEHYDE OXIDASE3 (AAO3) exhibited abnormally low transcript levels in dark-treated nap leaves. NAP transactivated the promoter of AAO3 in mesophyll cell protoplasts, and electrophoretic mobility shift assays showed that NAP can bind directly to a segment (−196 to −162 relative to the ATG start codon) of the AAO3 promoter. Exogenous application of ABA increased the transcript levels of SGR1, NYC1, PPH, and PaO and suppressed the stay-green phenotype of nap leaves during extended darkness. Overexpression of AAO3 in nap leaves also suppressed the stay-green phenotype under extended darkness. Collectively, the results show that NAP promotes chlorophyll degradation by enhancing transcription of AAO3, which leads to increased levels of the senescence-inducing hormone ABA. PMID:25516602

Socio-Cognitive Phenotypes Differentially Modulate Large-Scale Structural Covariance Networks.

PubMed

Valk, Sofie L; Bernhardt, Boris C; Böckler, Anne; Trautwein, Fynn-Mathis; Kanske, Philipp; Singer, Tania

2017-02-01

Functional neuroimaging studies have suggested the existence of 2 largely distinct social cognition networks, one for theory of mind (taking others' cognitive perspective) and another for empathy (sharing others' affective states). To address whether these networks can also be dissociated at the level of brain structure, we combined behavioral phenotyping across multiple socio-cognitive tasks with 3-Tesla MRI cortical thickness and structural covariance analysis in 270 healthy adults, recruited across 2 sites. Regional thickness mapping only provided partial support for divergent substrates, highlighting that individual differences in empathy relate to left insular-opercular thickness while no correlation between thickness and mentalizing scores was found. Conversely, structural covariance analysis showed clearly divergent network modulations by socio-cognitive and -affective phenotypes. Specifically, individual differences in theory of mind related to structural integration between temporo-parietal and dorsomedial prefrontal regions while empathy modulated the strength of dorsal anterior insula networks. Findings were robust across both recruitment sites, suggesting generalizability. At the level of structural network embedding, our study provides a double dissociation between empathy and mentalizing. Moreover, our findings suggest that structural substrates of higher-order social cognition are reflected rather in interregional networks than in the the local anatomical markup of specific regions per se. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The finite state projection approach to analyze dynamics of heterogeneous populations

NASA Astrophysics Data System (ADS)

Johnson, Rob; Munsky, Brian

2017-06-01

Population modeling aims to capture and predict the dynamics of cell populations in constant or fluctuating environments. At the elementary level, population growth proceeds through sequential divisions of individual cells. Due to stochastic effects, populations of cells are inherently heterogeneous in phenotype, and some phenotypic variables have an effect on division or survival rates, as can be seen in partial drug resistance. Therefore, when modeling population dynamics where the control of growth and division is phenotype dependent, the corresponding model must take account of the underlying cellular heterogeneity. The finite state projection (FSP) approach has often been used to analyze the statistics of independent cells. Here, we extend the FSP analysis to explore the coupling of cell dynamics and biomolecule dynamics within a population. This extension allows a general framework with which to model the state occupations of a heterogeneous, isogenic population of dividing and expiring cells. The method is demonstrated with a simple model of cell-cycle progression, which we use to explore possible dynamics of drug resistance phenotypes in dividing cells. We use this method to show how stochastic single-cell behaviors affect population level efficacy of drug treatments, and we illustrate how slight modifications to treatment regimens may have dramatic effects on drug efficacy.

Epidemiology and Antibiotic Resistance Phenotypes of Diarrheagenic Escherichia Coli Responsible for Infantile Gastroenteritis in Ouagadougou, Burkina Faso

PubMed Central

Konaté, Ali; Dembélé, René; Guessennd, Nathalie K.; Kouadio, Fernique Konan; Kouadio, Innocent Kouamé; Ouattara, Mohamed Baguy; Kaboré, Wendpoulomdé A. D.; Kagambèga, Assèta; Cissé, Haoua; Ibrahim, Hadiza Bawa; Bagré, Touwendsida Serge; Traoré, Alfred S.; Barro, Nicolas

2017-01-01

The emergence and persistence of multidrug-resistant (MDR) diarrheagenic Escherichia coli (DEC) causing acute diarrhea is a major public health challenge in developing countries. The aim of this study was to evaluate the resistance phenotypes of DEC isolated from stool samples collected from children less than 5 years of age with acute diarrhea living in Ouagadougou/Burkina Faso. From August 2013 to October 2015, this study was carried out on 31 DEC strains of our study conducted in “Centre Médical avec Antenne Chirurgicale (CMA)” Paul VI and CMA of Schiphra. DEC were isolated and identified by standard microbiological methods and polymerase chain reaction (PCR) method was used to further characterize them. Antimicrobial susceptibility testing was done based on the disk diffusion method. DEC isolates were high resistant to tetracycline (83.9%), amoxicillin (77.4%), amoxicillin clavulanic acid (77.4%), piperacillin (64.5%), and colistin sulfate (61.3%). The most resistant phenotype represented was the extended spectrum β-lactamase (ESBL) phenotype (67.7%). Aminoglycosides were 100% active on enteroinvasive E. coli (EIEC) and enterohemorrhagic E. coli (EHEC). All the DEC isolates exhibited absolute (100%) sensitivity to ciprofloxacin. Monitoring and studying the resistance profile of DEC to antibiotics are necessary to guide probabilistic antibiotic therapy, especially in pediatric patients. PMID:29034106

X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations.

PubMed

Pauws, E; Peskett, E; Boissin, C; Hoshino, A; Mengrelis, K; Carta, E; Abruzzo, M A; Lees, M; Moore, G E; Erickson, R P; Stanier, P

2013-04-01

X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the Tbx22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Estrogen receptor-α, progesterone receptor, and c-erbB/HER-family receptor mRNA detection and phenotype analysis in spontaneous canine models of breast cancer

PubMed Central

Kabir, Farruk M. Lutful; DeInnocentes, Patricia; Agarwal, Payal; Mill, Christopher P.; Riese, David J.

2017-01-01

Well characterized, stable, p16-defective canine mammary cancer (CMT) cell lines and normal canine mammary epithelial cells were used to investigate expression of the major breast cancer-specific hormone receptors estrogen receptor alpha (ER1) and progesterone receptor (PR) as well as luminal epithelial-specific proto-oncogenes encoding c-erbB-1 (epidermal growth factor receptor/EGFr), c-erbB-2/HER2, c-erbB-3, and c-erbB-4 receptors. The investigation developed and validated quantitative reverse transcriptase polymerase chain reaction assays for each transcript to provide rapid assessment of breast cancer phenotypes for canine cancers, based on ER1, PR, and c-erbB-2/HER2 expressions, similar to those in human disease. Roles for relatively underexplored c-erbB-3 and c-erbB-4 receptor expressions in each of these breast cancer phenotypes were also evaluated. Each quantitative assay was validated by assessment of amplicon size and DNA sequencing following amplification. Differential expression of ER1, PR, and c-erbB-2 in CMT cell lines clearly defined distinct human-like breast cancer phenotypes for a selection of CMT-derived cell lines. Expression profiles for EGFr family genes c-erbB-3 and c-erbB-4 in CMT models also provided an enriched classification of canine breast cancer identifying new extended phenotypes beyond the conventional luminal-basal characterization used in human breast cancer. PMID:27515268

Genotype, Phenotype, and Protein Structure in a Regulator of Sporulation: Effects of Mutations in the spoIIAA Gene of Bacillus subtilis

PubMed Central

Barillà, Daniela; Lucet, Isabelle; Kuhlmann, Anne; Yudkin, Michael D.

1999-01-01

SpoIIAA, a phosphorylatable protein, is essential to the regulation of ςF, the first sporulation-specific transcription factor of Bacillus subtilis. The solution structure of SpoIIAA has recently been published. Here we examine four mutant SpoIIAA proteins and correlate their properties with the phenotypes of the corresponding B. subtilis mutant strains. Two of the mutations severely disrupted the structure of the protein, a third greatly diminished the rate of its phosphorylation and abolished dephosphorylation, and the fourth left phosphorylation unaffected but reduced the rate of dephosphorylation about 10-fold. PMID:10368168

Allelic variants of the amylose extender mutation of maize demonstrate phenotypic variation in starch structure resulting from modified protein–protein interactions

PubMed Central

Liu, Fushan; Ahmed, Zaheer; Lee, Elizabeth A.; Donner, Elizabeth; Liu, Qiang; Ahmed, Regina; Morell, Matthew K.; Emes, Michael J.; Tetlow, Ian J.

2012-01-01

amylose extender (ae−) starches characteristically have modified starch granule morphology resulting from amylopectin with reduced branch frequency and longer glucan chains in clusters, caused by the loss of activity of the major starch branching enzyme (SBE), which in maize endosperm is SBEIIb. A recent study with ae− maize lacking the SBEIIb protein (termed ae1.1 herein) showed that novel protein–protein interactions between enzymes of starch biosynthesis in the amyloplast could explain the starch phenotype of the ae1.1 mutant. The present study examined an allelic variant of the ae− mutation, ae1.2, which expresses a catalytically inactive form of SBEIIb. The catalytically inactive SBEIIb in ae1.2 lacks a 28 amino acid peptide (Val272–Pro299) and is unable to bind to amylopectin. Analysis of starch from ae1.2 revealed altered granule morphology and physicochemical characteristics distinct from those of the ae1.1 mutant as well as the wild-type, including altered apparent amylose content and gelatinization properties. Starch from ae1.2 had fewer intermediate length glucan chains (degree of polymerization 16–20) than ae1.1. Biochemical analysis of ae1.2 showed that there were differences in the organization and assembly of protein complexes of starch biosynthetic enzymes in comparison with ae1.1 (and wild-type) amyloplasts, which were also reflected in the composition of starch granule-bound proteins. The formation of stromal protein complexes in the wild-type and ae1.2 was strongly enhanced by ATP, and broken by phosphatase treatment, indicating a role for protein phosphorylation in their assembly. Labelling experiments with [γ-32P]ATP showed that the inactive form of SBEIIb in ae1.2 was phosphorylated, both in the monomeric form and in association with starch synthase isoforms. Although the inactive SBEIIb was unable to bind starch directly, it was strongly associated with the starch granule, reinforcing the conclusion that its presence in the granules is a result of physical association with other enzymes of starch synthesis. In addition, an Mn2+-based affinity ligand, specific for phosphoproteins, was used to show that the granule-bound forms of SBEIIb in the wild-type and ae1.2 were phosphorylated, as was the granule-bound form of SBEI found in ae1.2 starch. The data strongly support the hypothesis that the complement of heteromeric complexes of proteins involved in amylopectin synthesis contributes to the fine structure and architecture of the starch granule. PMID:22121198

The Population Structure and Diversity of Eggplant from Asia and the Mediterranean Basin

PubMed Central

Cericola, Fabio; Portis, Ezio; Toppino, Laura; Barchi, Lorenzo; Acciarri, Nazareno; Ciriaci, Tommaso; Sala, Tea; Rotino, Giuseppe Leonardo; Lanteri, Sergio

2013-01-01

A collection of 238 eggplant breeding lines, heritage varieties and selections within local landraces provenanced from Asia and the Mediterranean Basin was phenotyped with respect to key plant and fruit traits, and genotyped using 24 microsatellite loci distributed uniformly throughout the genome. STRUCTURE analysis based on the genotypic data identified two major sub-groups, which to a large extent mirrored the provenance of the entries. With the goal to identify true-breeding types, 38 of the entries were discarded on the basis of microsatellite-based residual heterozygosity, along with a further nine which were not phenotypically uniform. The remaining 191 entries were scored for a set of 19 fruit and plant traits in a replicated experimental field trial. The phenotypic data were subjected to principal component and hierarchical principal component analyses, allowing three major morphological groups to be identified. All three morphological groups were represented in both the “Occidental” and the “Oriental” germplasm, so the correlation between the phenotypic and the genotypic data sets was quite weak. The relevance of these results for evolutionary studies and the further improvement of eggplant are discussed. The population structure of the core set of germplasm shows that it can be used as a basis for an association mapping approach. PMID:24040032

Incubation temperature influences trade-off between structural size and energy reserves in mallard hatchlings.

PubMed

Koláčková, Martina; Prokůpková, Ludmila; Albrecht, Tomáš; Hořák, David

2015-01-01

The reproductive success of precocial birds depends on investments in clutch formation and incubation. Egg quality strongly affects the phenotypic traits correlated with survival of the hatchling, but parental ability to maintain incubation temperature can also influence hatchling outcomes. The effect of incubation temperature on hatchling phenotype has been widely studied in reptiles but not in birds. The aim of this study was to explore the effects of egg mass and incubation temperature on the incubation period, hatchability, and hatchling phenotype of the mallard (Anas platyrhynchos). Mallard eggs were incubated under six constant incubation temperatures (ranging from 35.0° to 39.0°C). Hatchlings were weighed, and their structural size was measured. Some hatchlings were used for an examination of residual yolk sac mass and basic chemical composition of the yolk-free body. All investigated phenotypic traits except for chemical composition were positively correlated with egg mass. Incubation temperature did not affect hatchling body mass, but increased temperatures led to a decreased yolk-free body mass and structural size of hatchlings and to increased yolk sac mass. Our results suggest that there is a trade-off between the yolk-free body size and energetic reserves in the form of the yolk sac and that this trade-off is modulated by incubation temperature.

The population structure and diversity of eggplant from Asia and the Mediterranean Basin.

PubMed

Cericola, Fabio; Portis, Ezio; Toppino, Laura; Barchi, Lorenzo; Acciarri, Nazareno; Ciriaci, Tommaso; Sala, Tea; Rotino, Giuseppe Leonardo; Lanteri, Sergio

2013-01-01

A collection of 238 eggplant breeding lines, heritage varieties and selections within local landraces provenanced from Asia and the Mediterranean Basin was phenotyped with respect to key plant and fruit traits, and genotyped using 24 microsatellite loci distributed uniformly throughout the genome. STRUCTURE analysis based on the genotypic data identified two major sub-groups, which to a large extent mirrored the provenance of the entries. With the goal to identify true-breeding types, 38 of the entries were discarded on the basis of microsatellite-based residual heterozygosity, along with a further nine which were not phenotypically uniform. The remaining 191 entries were scored for a set of 19 fruit and plant traits in a replicated experimental field trial. The phenotypic data were subjected to principal component and hierarchical principal component analyses, allowing three major morphological groups to be identified. All three morphological groups were represented in both the "Occidental" and the "Oriental" germplasm, so the correlation between the phenotypic and the genotypic data sets was quite weak. The relevance of these results for evolutionary studies and the further improvement of eggplant are discussed. The population structure of the core set of germplasm shows that it can be used as a basis for an association mapping approach.

Spatial phenotypic and genetic structure of threespine stickleback (Gasterosteus aculeatus) in a heterogeneous natural system, Lake Mývatn, Iceland.

PubMed

Millet, Antoine; Kristjánsson, Bjarni K; Einarsson, Arni; Räsänen, Katja

2013-09-01

Eco-evolutionary responses of natural populations to spatial environmental variation strongly depend on the relative strength of environmental differences/natural selection and dispersal/gene flow. In absence of geographic barriers, as often is the case in lake ecosystems, gene flow is expected to constrain adaptive divergence between environments - favoring phenotypic plasticity or high trait variability. However, if divergent natural selection is sufficiently strong, adaptive divergence can occur in face of gene flow. The extent of divergence is most often studied between two contrasting environments, whereas potential for multimodal divergence is little explored. We investigated phenotypic (body size, defensive structures, and feeding morphology) and genetic (microsatellites) structure in threespine stickleback (Gasterosteus aculeatus) across five habitat types and two basins (North and South) within the geologically young and highly heterogeneous Lake Mývatn, North East Iceland. We found that (1) North basin stickleback were, on average, larger and had relatively longer spines than South basin stickleback, whereas (2) feeding morphology (gill raker number and gill raker gap width) differed among three of five habitat types, and (3) there was only subtle genetic differentiation across the lake. Overall, our results indicate predator and prey mediated phenotypic divergence across multiple habitats in the lake, in face of gene flow.

Spatial phenotypic and genetic structure of threespine stickleback (Gasterosteus aculeatus) in a heterogeneous natural system, Lake Mývatn, Iceland

PubMed Central

Millet, Antoine; Kristjánsson, Bjarni K; Einarsson, Árni; Räsänen, Katja

2013-01-01

Eco-evolutionary responses of natural populations to spatial environmental variation strongly depend on the relative strength of environmental differences/natural selection and dispersal/gene flow. In absence of geographic barriers, as often is the case in lake ecosystems, gene flow is expected to constrain adaptive divergence between environments – favoring phenotypic plasticity or high trait variability. However, if divergent natural selection is sufficiently strong, adaptive divergence can occur in face of gene flow. The extent of divergence is most often studied between two contrasting environments, whereas potential for multimodal divergence is little explored. We investigated phenotypic (body size, defensive structures, and feeding morphology) and genetic (microsatellites) structure in threespine stickleback (Gasterosteus aculeatus) across five habitat types and two basins (North and South) within the geologically young and highly heterogeneous Lake Mývatn, North East Iceland. We found that (1) North basin stickleback were, on average, larger and had relatively longer spines than South basin stickleback, whereas (2) feeding morphology (gill raker number and gill raker gap width) differed among three of five habitat types, and (3) there was only subtle genetic differentiation across the lake. Overall, our results indicate predator and prey mediated phenotypic divergence across multiple habitats in the lake, in face of gene flow. PMID:24223263

Adaptive self-organization during growth of bacterial colonies

NASA Astrophysics Data System (ADS)

Ben-Jacob, Eshel; Shmueli, Haim; Shochet, Ofer; Tenenbaum, Adam

1992-09-01

We present a study of interfacial pattern formation during diffusion-limited growth of Bacillus subtilis. It is demonstrated that bacterial colonies can develop patterns similar to morphologies observed during diffusion-limited growth in non-living (azoic) systems such as solidification and electro-chemical deposition. The various growth morphologies, that is the global structure of the colony, are observed as we vary the growth conditions. These include fractal growth, dense-branching growth, compact growth, dendritic growth and chiral growth. The results demonstrate the action of a singular interplay between the micro-level (individual bacterium) and macro-level (the colony) in selecting the observed morphologies as is understood for non-living systems. Furthermore, the observed morphologies can be organized within a morphology diagram indicating the existence of a morphology selection principle similar to the one proposed for azoic systems. We propose a phase-field-like model (the phase being the bacterial concentration and the field being the nutrient concentration) to describe the growth. The bacteria-bacteria interaction is manifested as a phase dependent diffusion constant. Growth of a bacterial colony presents an inherent additional level of complexity compared to azoic systems, since the building blocks themselves are living systems. Thus, our studies also focus on the transition between morphologies. We have observed extended morphology transitions due to phenotypic changes of the bacteria, as well as bursts of new morphologies resulting from genotypic changes. In addition, we have observed extended and heritable transitions (mainly between dense branching growth and chiral growth) as well as phenotypic transitions that turn genotypic over time. We discuss the implications of our results in the context of the evolving picture of genome cybernetics. Diffusion limited growth of bacterial colonies combined with new understanding of pattern formation in azoic systems provide new tools for the study of adaptive self-organization and mutation in the presence of selective pressures. We include brief reviews of both the recent developments in the study of interfacial pattern formation in non-living systems and the current trends in the view of mutation dynamics.

Methodology for the inference of gene function from phenotype data.

PubMed

Ascensao, Joao A; Dolan, Mary E; Hill, David P; Blake, Judith A

2014-12-12

Biomedical ontologies are increasingly instrumental in the advancement of biological research primarily through their use to efficiently consolidate large amounts of data into structured, accessible sets. However, ontology development and usage can be hampered by the segregation of knowledge by domain that occurs due to independent development and use of the ontologies. The ability to infer data associated with one ontology to data associated with another ontology would prove useful in expanding information content and scope. We here focus on relating two ontologies: the Gene Ontology (GO), which encodes canonical gene function, and the Mammalian Phenotype Ontology (MP), which describes non-canonical phenotypes, using statistical methods to suggest GO functional annotations from existing MP phenotype annotations. This work is in contrast to previous studies that have focused on inferring gene function from phenotype primarily through lexical or semantic similarity measures. We have designed and tested a set of algorithms that represents a novel methodology to define rules for predicting gene function by examining the emergent structure and relationships between the gene functions and phenotypes rather than inspecting the terms semantically. The algorithms inspect relationships among multiple phenotype terms to deduce if there are cases where they all arise from a single gene function. We apply this methodology to data about genes in the laboratory mouse that are formally represented in the Mouse Genome Informatics (MGI) resource. From the data, 7444 rule instances were generated from five generalized rules, resulting in 4818 unique GO functional predictions for 1796 genes. We show that our method is capable of inferring high-quality functional annotations from curated phenotype data. As well as creating inferred annotations, our method has the potential to allow for the elucidation of unforeseen, biologically significant associations between gene function and phenotypes that would be overlooked by a semantics-based approach. Future work will include the implementation of the described algorithms for a variety of other model organism databases, taking full advantage of the abundance of available high quality curated data.

Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability

PubMed Central

Greenbury, Sam F.; Schaper, Steffen; Ahnert, Sebastian E.; Louis, Ard A.

2016-01-01

Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps—a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure—to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability. PMID:26937652

Breeding to adapt agriculture to climate change: affordable phenotyping solutions.

PubMed

Araus, José L; Kefauver, Shawn C

2018-05-28

Breeding is one of the central pillars of adaptation of crops to climate change. However, phenotyping is a key bottleneck that is limiting breeding efficiency. The awareness of phenotyping as a breeding limitation is not only sustained by the lack of adequate approaches, but also by the perception that phenotyping is an expensive activity. Phenotyping is not just dependent on the choice of appropriate traits and tools (e.g. sensors) but relies on how these tools are deployed on their carrying platforms, the speed and volume of data extraction and analysis (throughput), the handling of spatial variability and characterization of environmental conditions, and finally how all the information is integrated and processed. Affordable high throughput phenotyping aims to achieve reasonably priced solutions for all the components comprising the phenotyping pipeline. This mini-review will cover current and imminent solutions for all these components, from the increasing use of conventional digital RGB cameras, within the category of sensors, to open-access cloud-structured data processing and the use of smartphones. Emphasis will be placed on field phenotyping, which is really the main application for day-to-day phenotyping. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phenotype detection in morphological mutant mice using deformation features.

PubMed

Roy, Sharmili; Liang, Xi; Kitamoto, Asanobu; Tamura, Masaru; Shiroishi, Toshihiko; Brown, Michael S

2013-01-01

Large-scale global efforts are underway to knockout each of the approximately 25,000 mouse genes and interpret their roles in shaping the mammalian embryo. Given the tremendous amount of data generated by imaging mutated prenatal mice, high-throughput image analysis systems are inevitable to characterize mammalian development and diseases. Current state-of-the-art computational systems offer only differential volumetric analysis of pre-defined anatomical structures between various gene-knockout mice strains. For subtle anatomical phenotypes, embryo phenotyping still relies on the laborious histological techniques that are clearly unsuitable in such big data environment. This paper presents a system that automatically detects known phenotypes and assists in discovering novel phenotypes in muCT images of mutant mice. Deformation features obtained from non-linear registration of mutant embryo to a normal consensus average image are extracted and analyzed to compute phenotypic and candidate phenotypic areas. The presented system is evaluated using C57BL/10 embryo images. All cases of ventricular septum defect and polydactyly, well-known to be present in this strain, are successfully detected. The system predicts potential phenotypic areas in the liver that are under active histological evaluation for possible phenotype of this mouse line.

Long-term phenotypic evolution of bacteria.

PubMed

Plata, Germán; Henry, Christopher S; Vitkup, Dennis

2015-01-15

For many decades comparative analyses of protein sequences and structures have been used to investigate fundamental principles of molecular evolution. In contrast, relatively little is known about the long-term evolution of species' phenotypic and genetic properties. This represents an important gap in our understanding of evolution, as exactly these proprieties play key roles in natural selection and adaptation to diverse environments. Here we perform a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models. Overall, bacterial phenotypic evolution can be described by a two-stage process with a rapid initial phenotypic diversification followed by a slow long-term exponential divergence. The observed average divergence trend, with approximately similar fractions of phenotypic properties changing per unit time, continues for billions of years. We experimentally confirm the predicted divergence trend using the phenotypic profiles of 40 diverse bacterial species across more than 60 growth conditions. Our analysis suggests that, at long evolutionary distances, gene essentiality is significantly more conserved than the ability to utilize different nutrients, while synthetic lethality is significantly less conserved. We also find that although a rapid phenotypic evolution is sometimes observed within the same species, a transition from high to low phenotypic similarity occurs primarily at the genus level.

WormSizer: high-throughput analysis of nematode size and shape.

PubMed

Moore, Brad T; Jordan, James M; Baugh, L Ryan

2013-01-01

The fundamental phenotypes of growth rate, size and morphology are the result of complex interactions between genotype and environment. We developed a high-throughput software application, WormSizer, which computes size and shape of nematodes from brightfield images. Existing methods for estimating volume either coarsely model the nematode as a cylinder or assume the worm shape or opacity is invariant. Our estimate is more robust to changes in morphology or optical density as it only assumes radial symmetry. This open source software is written as a plugin for the well-known image-processing framework Fiji/ImageJ. It may therefore be extended easily. We evaluated the technical performance of this framework, and we used it to analyze growth and shape of several canonical Caenorhabditis elegans mutants in a developmental time series. We confirm quantitatively that a Dumpy (Dpy) mutant is short and fat and that a Long (Lon) mutant is long and thin. We show that daf-2 insulin-like receptor mutants are larger than wild-type upon hatching but grow slow, and WormSizer can distinguish dauer larvae from normal larvae. We also show that a Small (Sma) mutant is actually smaller than wild-type at all stages of larval development. WormSizer works with Uncoordinated (Unc) and Roller (Rol) mutants as well, indicating that it can be used with mutants despite behavioral phenotypes. We used our complete data set to perform a power analysis, giving users a sense of how many images are needed to detect different effect sizes. Our analysis confirms and extends on existing phenotypic characterization of well-characterized mutants, demonstrating the utility and robustness of WormSizer.

[Phenotypic and molecular identification of extended-spectrum beta-lactamase (ESBL) TEM and SHV produced by clinical isolates Escherichia coli and Klebsiella spp. in hospitals].

PubMed

González Mesa, Leonora; Ramos Morí, Astrid; Nadal Becerra, Loreta; Morffi Figueroa, Janet; Hernández Robledo, Ernesto; Alvarez, Ana Berta; Marchena Bequer, Juan J; González Alemán, Mabel; Villain Plous, Carlos

2007-01-01

Nosocomial infections caused by gram-negative bacilli which produce extended spectrum beta-lactamase (ESBL) are associated with the increase of morbidity and mortality in hospitals. The objective of this study was to evaluate the frequency of ESBL, specifically the TEM and SHV type, produced by Escherichia coli and Klebsiella spp. strains, and also to determine the antimicrobial susceptibility of these isolates in comparison with other antibiotic families. A total of 326 strains were collected between 2002-2004 from hospitals in Havana City. The susceptibility tests were carried out according to the NCCLS guides and they were confirmed as. ESBL producers by the double disk diffusion method. The molecular characterization of these enzymes was determined by polymerase chain reaction (PCR), using two sets of oligonucleotides to amplify genes encoding TEM and SHV type beta-lactamase. The ESBL phenotype was detected in 31 (10%) Escherichia coli isolates, 19 of these strains (61%) carried the blaTEM genes, 5 (16%) blaSHV genes, 4 (12%) strains carried both genes and 11 strains (35%) carried the non-ESBL blaTEM and blaSHV genes. In Klebsiella spp. the ESBL phenotype was detected in 10 (36 %) isolates, only one strain carried the blaTEM gene. The most active antimicrobials against Escherichia coli were ciprofloxacin (64.5%) and gentamicin (58.07%); in the case of Klebsiella spp. the same antimicrobials were the most active with similar susceptibility (70%) for both. The carbapenems still remain the most active antibiotics against Escherichia coli and Klebsiella spp. strains, which are ESBL producers. However, their use should be closely controlled.

A Novel GABRG2 Mutation, p.R136*, in a family with GEFS+ and extended phenotypes

PubMed Central

Shen, Wangzhen; Pickrell, William O.; Cushion, Thomas D.; Davies, Jeffrey S.; Baer, Kristin; Mullins, Jonathan G.L.; Hammond, Carrie L.; Chung, Seo-Kyung; Thomas, Rhys H.; White, Cathy; Smith, Phil E.M.

2014-01-01

Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and autism spectrum disorder (ASD). The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136*) subunits were co-expressed with α1 and β2 subunits in HEK 293T cells, GABA–evoked currents were reduced. Furthermore, γ2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism. PMID:24407264

Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability.

PubMed

Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko; Mang, Yuan; ur Rehman, Shoaib; Buchert, Rebecca; Schaffer, Stefanie; Muhammad, Safia; Bak, Mads; Nöthen, Markus M; Bennett, Eric P; Maeda, Yusuke; Aigner, Michael; Reis, André; Kinoshita, Taroh; Tommerup, Niels; Baig, Shahid Mahmood; Abou Jamra, Rami

2013-04-04

PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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.

Phenotypic and genetic structure of traits delineating personality disorder.

PubMed

Livesley, W J; Jang, K L; Vernon, P A

1998-10-01

The evidence suggests that personality traits are hierarchically organized with more specific or lower-order traits combining to form more generalized higher-order traits. Agreement exists across studies regarding the lower-order traits that delineate personality disorder but not the higher-order traits. This study seeks to identify the higher-order structure of personality disorder by examining the phenotypic and genetic structures underlying lower-order traits. Eighteen lower-order traits were assessed using the Dimensional Assessment of Personality Disorder-Basic Questionnaire in samples of 656 personality disordered patients, 939 general population subjects, and a volunteer sample of 686 twin pairs. Principal components analysis yielded 4 components, labeled Emotional Dysregulation, Dissocial Behavior, Inhibitedness, and Compulsivity, that were similar across the 3 samples. Multivariate genetic analyses also yielded 4 genetic and environmental factors that were remarkably similar to the phenotypic factors. Analysis of the residual heritability of the lower-order traits when the effects of the higher-order factors were removed revealed a substantial residual heritable component for 12 of the 18 traits. The results support the following conclusions. First, the stable structure of traits across clinical and nonclinical samples is consistent with dimensional representations of personality disorders. Second, the higher-order traits of personality disorder strongly resemble dimensions of normal personality. This implies that a dimensional classification should be compatible with normative personality. Third, the residual heritability of the lower-order traits suggests that the personality phenotypes are based on a large number of specific genetic components.

Detecting phenotype-driven transitions in regulatory network structure.

PubMed

Padi, Megha; Quackenbush, John

2018-01-01

Complex traits and diseases like human height or cancer are often not caused by a single mutation or genetic variant, but instead arise from functional changes in the underlying molecular network. Biological networks are known to be highly modular and contain dense "communities" of genes that carry out cellular processes, but these structures change between tissues, during development, and in disease. While many methods exist for inferring networks and analyzing their topologies separately, there is a lack of robust methods for quantifying differences in network structure. Here, we describe ALPACA (ALtered Partitions Across Community Architectures), a method for comparing two genome-scale networks derived from different phenotypic states to identify condition-specific modules. In simulations, ALPACA leads to more nuanced, sensitive, and robust module discovery than currently available network comparison methods. As an application, we use ALPACA to compare transcriptional networks in three contexts: angiogenic and non-angiogenic subtypes of ovarian cancer, human fibroblasts expressing transforming viral oncogenes, and sexual dimorphism in human breast tissue. In each case, ALPACA identifies modules enriched for processes relevant to the phenotype. For example, modules specific to angiogenic ovarian tumors are enriched for genes associated with blood vessel development, and modules found in female breast tissue are enriched for genes involved in estrogen receptor and ERK signaling. The functional relevance of these new modules suggests that not only can ALPACA identify structural changes in complex networks, but also that these changes may be relevant for characterizing biological phenotypes.

Who Matters for Children’s Early Development? Race/Ethnicity and Extended Household Structures in the United States

PubMed Central

Fomby, Paula; Dennis, Jeff A.

2011-01-01

Taking advantage of recent data that permit an assessment of the importance of extended household members in operationalizing the relationship between family structure and children’s early development, this study incorporated coresident grandparents, other kin, and nonkin to investigate the associations between extended household structure and U.S. children’s cognitive and behavioral outcomes at age 2. Analyses assessed whether these relationships differed for Latino, African American, and White children and tested four potential explanations for such differences. Nationally representative data came from the Early Childhood Longitudinal Study-Birth Cohort of 2001 (N ≈ 8,450). Extended household structures were much more prevalent in households of young African American and Latino children than among Whites. Nuclear households were beneficial for White children, but living with a grandparent was associated with the highest cognitive scores for African American children. Nuclear, vertically extended, and laterally extended households had similar associations with Latino children’s cognitive and behavior scores. Results suggest that expanded indicators of household structure that include grandparents, other kin, and nonkin are useful for understanding children’s early development. PMID:21927627

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

Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent.

PubMed

Schmechel, Donald E; Edwards, Christopher L

2012-12-01

Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a diagnosis of juvenile rheumatoid or idiopathic arthritis (JRA, JIA) had a significantly high proportion of A1AT polymorphisms (63%), suggesting a spectrum for JRA to later FMS presentations. Likewise, persons reporting a history of attention deficit disorder (ADD) had an increased proportion of A1AT polymorphisms (26%) compared to non-ADD persons (13%). Toxic environmental exposures are common (23%) and associated with diagnoses of PSP, PPA, FTD, FTD-PD, PD and ADVD. A1AT carriers were increased in cases of toxic exposure and PSP, PPA and FTD-PD. Our findings support the ICE behavioral phenotype for A1AT polymorphism carriers and the reported association with anxiety and bipolar spectrum disorders. We now extend that phenotype to apparent vulnerability to inflammatory muscle disease in a spectrum from JRA to fibromyalgia (FMS) and specific behavioral subsets of ADD, PTSD, and specific late onset neurological syndromes (FTD-PD and PPA). High and low risk FMS subsets can be defined using A1AT, MTHFR and APOE genotyping. Clinical diagnoses associated with A1AT polymorphisms included fibromyalgia, JRA/JIA, bipolar disorder, PTSD, primary progressive aphasia and FTDPD, but not most Alzheimer Disease subtypes. These results support an extended phenotype for A1AT mutation carriers beyond liver and lung vulnerability to selective advantages: ICE phenotype and disadvantages: fibromyalgia, affective disorders, and selected late onset neurological syndromes. Copyright © 2012 Elsevier Inc. All rights reserved.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

PubMed

van de Kamp, J M; Betsalel, O T; Mercimek-Mahmutoglu, S; Abulhoul, L; Grünewald, S; Anselm, I; Azzouz, H; Bratkovic, D; de Brouwer, A; Hamel, B; Kleefstra, T; Yntema, H; Campistol, J; Vilaseca, M A; Cheillan, D; D'Hooghe, M; Diogo, L; Garcia, P; Valongo, C; Fonseca, M; Frints, S; Wilcken, B; von der Haar, S; Meijers-Heijboer, H E; Hofstede, F; Johnson, D; Kant, S G; Lion-Francois, L; Pitelet, G; Longo, N; Maat-Kievit, J A; Monteiro, J P; Munnich, A; Muntau, A C; Nassogne, M C; Osaka, H; Ounap, K; Pinard, J M; Quijano-Roy, S; Poggenburg, I; Poplawski, N; Abdul-Rahman, O; Ribes, A; Arias, A; Yaplito-Lee, J; Schulze, A; Schwartz, C E; Schwenger, S; Soares, G; Sznajer, Y; Valayannopoulos, V; Van Esch, H; Waltz, S; Wamelink, M M C; Pouwels, P J W; Errami, A; van der Knaap, M S; Jakobs, C; Mancini, G M; Salomons, G S

2013-07-01

Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights.

PubMed

Rayner, Genevieve; Jackson, Graeme D; Wilson, Sarah J

2016-11-01

Depression is common but underdiagnosed in epilepsy. A quarter of patients meet criteria for a depressive disorder, yet few receive active treatment. We hypothesize that the presentation of depression is less recognizable in epilepsy because the symptoms are heterogeneous and often incorrectly attributed to the secondary effects of seizures or medication. Extending the ILAE's new phenomenological approach to classification of the epilepsies to include psychiatric comorbidity, we use data-driven profiling of the symptoms of depression to perform a preliminary investigation of whether there is a distinctive symptom-based phenotype of depression in epilepsy that could facilitate its recognition in the neurology clinic. The psychiatric and neuropsychological functioning of 91 patients with focal epilepsy was compared with that of 77 healthy controls (N=168). Cluster analysis of current depressive symptoms identified three clusters: one comprising nondepressed patients and two symptom-based phenotypes of depression. The 'Cognitive' phenotype (base rate=17%) was characterized by symptoms taking the form of self-critical cognitions and dysphoria and was accompanied by pervasive memory deficits. The 'Somatic' phenotype (7%) was characterized by vegetative depressive symptoms and anhedonia and was accompanied by greater anxiety. It is hoped that identification of the features of these two phenotypes will ultimately facilitate improved detection and diagnosis of depression in patients with epilepsy and thereby lead to appropriate and timely treatment, to the benefit of patient wellbeing and the potential efficacy of treatment of the seizure disorder. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy". Copyright © 2016 Elsevier Inc. All rights reserved.

Dynamic impact of brief electrical nerve stimulation on the neural immune axis-polarization of macrophages toward a pro-repair phenotype in demyelinated peripheral nerve.

PubMed

McLean, Nikki A; Verge, Valerie M K

2016-09-01

Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546-1561. © 2016 Wiley Periodicals, Inc.

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

PubMed

Smith, Douglas R; Stanley, Christine M; Foss, Theodore; Boles, Richard G; McKernan, Kevin

2017-01-01

Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

Phenotypic and molecular detection of BLACTX-M gene extended-spectrum beta-lactamases in escherichia coli and klebsiella pneumoniae of north sumatera isolates

NASA Astrophysics Data System (ADS)

Hasibuan, Mirzan; Suryanto, Dwi; Lia Kusumawati, R.

2018-03-01

The application of antibiotics expanded-spectrum third-generation cephalosporin for the treatment of infectious diseases in hospitals is known contribute to increasing resistance due to the presence of the blaCTX-M gene in the bacteria producing ESBLs. This study was aimed to detect ESBLs, isolate phenotype and blaCTX-M genes on Escherichia coli and Klebsiella pneumoniae collected from H. Adam Malik Central Hospital. Phenotypes of the bacterial were detection using Vitek two compact, while the blaCTX-M genes were detection using polymerase chain reaction technique. The results showed that 85 (100%) isolates were ESBLs consisted of 41(48%) of Escherichia coli, and 44 (52%) of Klebsiella pneumoniae, respectively. blaCTX-M genes were detection in 62 (72.94%) of the isolates which 31 (36.47%) were Escherichia coli, and 31 (36.47%) of the isolates were Klebsiella pneumoniae, respectively. This study indicates the high prevalence of blaCTX-M genes in Escherichia coli and Klebsiella pneumoniea causing bacterial antibiotic resistance.

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

PubMed

Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

2017-03-02

Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Staurosporine and Extracellular Matrix Proteins Mediate the Conversion of Small Cell Lung Carcinoma Cells into a Neuron-Like Phenotype

PubMed Central

Veit, Nadine; Courts, Cornelius; Glassmann, Alexander; Janzen, Viktor; Madea, Burkhard; Reinartz, Markus; Harzen, Anne; Nowak, Michael; Perner, Sven; Winter, Jochen; Probstmeier, Rainer

2014-01-01

Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions. PMID:24586258

Linkage disequilibrium and signatures of positive selection around LINE-1 retrotransposons in the human genome.

PubMed

Kuhn, Alexandre; Ong, Yao Min; Cheng, Ching-Yu; Wong, Tien Yin; Quake, Stephen R; Burkholder, William F

2014-06-03

Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium with their surrounding genomic regions and that they were well tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity was detected around several L1 insertions. This finding suggests that some of these L1 insertions may have been the target of recent positive selection.

Why and How We Age, and Is That Process Modifiable?

NASA Astrophysics Data System (ADS)

Arking, R.

Aging is an almost-universal biological process that is better understood in terms of an evolutionary explanation than in terms of a medical or adaptationist explanation. The major advances in human longevity which took place in developed countries during the past century arose from decreases in external (e.g., environmental) sources of mortality, and not from any effect on the aging process. Laboratory studies show that the aging process is under genetic control, can be manipulated, and can be expressed in three different phenotypes. The adult lifespan consists of the health span (ages 20-55 yrs) and the senescent span (ages 55+), with a relatively short but variable transition phase between the two. The most socially desirable phenotype would be that where the transition phase is delayed and the health span extended with little effect on the senescent span. The genetic, nutritional, cell-signaling and pharmecutical interventions inducing this phenotype are discussed. The genetic architecture of senescence is discussed and its stochastic nature made clear. The social and ethical consequences of pharmecutical intervention into the aging process are briefly discussed.

Asymmetry and polymorphism of hybrid male sterility during the early stages of speciation in house mice.

PubMed

Good, Jeffrey M; Handel, Mary Ann; Nachman, Michael W

2008-01-01

House mice offer a powerful system for dissecting the genetic basis of phenotypes that isolate species in the early stages of speciation. We used a series of reciprocal crosses between wild-derived strains of Mus musculus and M. domesticus to examine F(1) hybrid male sterility, one of the primary phenotypes thought to isolate these species. We report four main results. First, we found significantly smaller testes and fewer sperm in hybrid male progeny of most crosses. Second, in some crosses hybrid male sterility was asymmetric and depended on the species origin of the X chromosome. These observations confirm and extend previous findings, underscoring the central role that the M. musculus X chromosome plays in reproductive isolation. Third, comparisons among reciprocal crosses revealed polymorphism at one or more hybrid incompatibilities within M. musculus. Fourth, the spermatogenic phenotype of this polymorphic interaction appears distinct from previously described hybrid incompatibilities between these species. These data build on previous studies of speciation in house mice and show that the genetic basis of hybrid male sterility is fairly complex, even at this early stage of divergence.

Use of Monoclonal Antibodies for the Diagnosis of T-cell Malignancies: Applications and Limitations.

PubMed

Hastrup, N; Pallesen, G; Ralfikiaer, E

1990-01-01

Biopsy samples from 136 peripheral T-cell lymphomas have been examined and compared with benign inflammatory T-cell infiltrates in an attempt to establish whether immunohistological methods may help to improve the distinction between these conditions. The results confirm and extend previous reports and indicate that the aberrant T-cell phenotypes constitute the single most reliable criterion for the distinction between benign and malignant T-cell infiltrates. These phenotypes are expressed frequently in T-cell malignancies in. lymphoid organs and are also seen in a substantial number of biopsy samples from advanced cutaneous T-cell lymphomas (CTCL). In contrast, early CTCL do not express aberrant T-cell phenotypes and are indistinguishable from benign cutaneous conditions in terms of their immunophenotypic properties. It is concluded that immunophenotypic techniques form a valuable supplement to routine histological methods for the diagnosis of T-cell lymphomas in lymphoid organs. The methods may also help to improve the diagnosis of advanced CTCL, but are of no or only limited help for the recognition of the early stages.

Draft Genome Sequences of Escherichia coli Isolates from Wounded Military Personnel.

PubMed

Arivett, Brock A; Ream, Dave C; Fiester, Steven E; Kidane, Destaalem; Actis, Luis A

2016-08-11

Members of the Escherichia coli bacterial family have been grouped as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens because of their extensive drug resistance phenotypes and increasing threat to human health. The genomes of six extended-spectrum β-lactamase (ESBL)-producing E. coli strains isolated from wounded military personnel were sequenced and annotated. Copyright © 2016 Arivett et al.

Conflict between biotic and climatic selective pressures acting on an extended phenotype in a subarctic, but not temperate, environment.

PubMed

Rohwer, V G; Bonier, F; Martin, P R

2015-10-22

Climatic selective pressures are thought to dominate biotic selective pressures at higher latitudes. However, few studies have experimentally tested how these selective pressures differentially act on traits across latitudes because traits can rarely be manipulated independently of the organism in nature. We overcame this challenge by using an extended phenotype-active bird nests-and conducted reciprocal transplant experiments between a subarctic and temperate site, separated by 14° of latitude. At the subarctic site, biotic selective pressures (nest predation) favoured smaller, non-local temperate nests, whereas climatic selective pressures (temperature) favoured larger local nests, particularly at colder temperatures. By contrast, at the temperate site, climatic and biotic selective pressures acted similarly on temperate and subarctic nests. Our results illustrate a functional trade-off in the subarctic between nest morphologies favoured by biotic versus climatic selective pressures, with climate favouring local nest morphologies. At our temperate site, however, allocative trade-offs in the time and effort devoted to nest construction favour smaller, local nests. Our findings illustrate a conflict between biotic and climatic selective pressures at the northern extremes of a species geographical range, and suggest that trade-offs between trait function and trait elaboration act differentially across latitude to create broad geographic variation in traits. © 2015 The Author(s).

The influence of gene flow and drift on genetic and phenotypic divergence in two species of Zosterops in Vanuatu

PubMed Central

Clegg, Sonya M.; Phillimore, Albert B.

2010-01-01

Colonization of an archipelago sets the stage for adaptive radiation. However, some archipelagos are home to spectacular radiations, while others have much lower levels of diversification. The amount of gene flow among allopatric populations is one factor proposed to contribute to this variation. In island colonizing birds, selection for reduced dispersal ability is predicted to produce changing patterns of regional population genetic structure as gene flow-dominated systems give way to drift-mediated divergence. If this transition is important in facilitating phenotypic divergence, levels of genetic and phenotypic divergence should be associated. We consider population genetic structure and phenotypic divergence among two co-distributed, congeneric (Genus: Zosterops) bird species inhabiting the Vanuatu archipelago. The more recent colonist, Z. lateralis, exhibits genetic patterns consistent with a strong influence of distance-mediated gene flow. However, complex patterns of asymmetrical gene flow indicate variation in dispersal ability or inclination among populations. The endemic species, Z. flavifrons, shows only a partial transition towards a drift-mediated system, despite a long evolutionary history on the archipelago. We find no strong evidence that gene flow constrains phenotypic divergence in either species, suggesting that levels of inter-island gene flow do not explain the absence of a radiation across this archipelago. PMID:20194170

Protein change in plant evolution: tracing one thread connecting molecular and phenotypic diversity

PubMed Central

Bartlett, Madelaine E.; Whipple, Clinton J.

2013-01-01

Proteins change over the course of evolutionary time. New protein-coding genes and gene families emerge and diversify, ultimately affecting an organism’s phenotype and interactions with its environment. Here we survey the range of structural protein change observed in plants and review the role these changes have had in the evolution of plant form and function. Verified examples tying evolutionary change in protein structure to phenotypic change remain scarce. We will review the existing examples, as well as draw from investigations into domestication, and quantitative trait locus (QTL) cloning studies searching for the molecular underpinnings of natural variation. The evolutionary significance of many cloned QTL has not been assessed, but all the examples identified so far have begun to reveal the extent of protein structural diversity tolerated in natural systems. This molecular (and phenotypic) diversity could come to represent part of natural selection’s source material in the adaptive evolution of novel traits. Protein structure and function can change in many distinct ways, but the changes we identified in studies of natural diversity and protein evolution were predicted to fall primarily into one of six categories: altered active and binding sites; altered protein–protein interactions; altered domain content; altered activity as an activator or repressor; altered protein stability; and hypomorphic and hypermorphic alleles. There was also variability in the evolutionary scale at which particular changes were observed. Some changes were detected at both micro- and macroevolutionary timescales, while others were observed primarily at deep or shallow phylogenetic levels. This variation might be used to determine the trajectory of future investigations in structural molecular evolution. PMID:24124420

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.

Single Cell Mathematical Model Successfully Replicates Key Features of GBM: Go-Or-Grow Is Not Necessary.

PubMed

Scribner, Elizabeth; Fathallah-Shaykh, Hassan M

2017-01-01

Glioblastoma (GBM) is a malignant brain tumor that continues to be associated with neurological morbidity and poor survival times. Brain invasion is a fundamental property of malignant glioma cells. The Go-or-Grow (GoG) phenotype proposes that cancer cell motility and proliferation are mutually exclusive. Here, we construct and apply a single glioma cell mathematical model that includes motility and angiogenesis and lacks the GoG phenotype. Simulations replicate key features of GBM including its multilayer structure (i.e.edema, enhancement, and necrosis), its progression patterns associated with bevacizumab treatment, and replicate the survival times of GBM treated or untreated with bevacizumab. These results suggest that the GoG phenotype is not a necessary property for the formation of the multilayer structure, recurrence patterns, and the poor survival times of patients diagnosed with GBM.

The Genetics of a Small Autosomal Region of DROSOPHILA MELANOGASTER Containing the Structural Gene for Alcohol Dehydrogenase. I. Characterization of Deficiencies and Mapping of ADH and Visible Mutations

PubMed Central

Woodruff, R. C.; Ashburner, M.

1979-01-01

The position of the structural gene coding for alcohol dehydrogenase (ADH) in Drosophila melanogaster has been shown to be within polytene chromosome bands 35B1 and 35B3, most probably within 35B2. The genetic and cytological properties of twelve deficiencies in polytene chromosome region 34–35 have been characterized, eleven of which include Adh. Also mapped cytogenetically are seven other recessive visible mutant loci. Flies heterozygous for overlapping deficiencies that include both the Adh locus and that for the outspread mutant (osp: a recessive wing phenotype) are homozygous viable and show a complete ADH negative phenotype and strong osp phenotype. These deficiencies probably include two polytene chromosome bands, 35B2 and 35B3. PMID:115743

The Stochastic Evolutionary Game for a Population of Biological Networks Under Natural Selection

PubMed Central

Chen, Bor-Sen; Ho, Shih-Ju

2014-01-01

In this study, a population of evolutionary biological networks is described by a stochastic dynamic system with intrinsic random parameter fluctuations due to genetic variations and external disturbances caused by environmental changes in the evolutionary process. Since information on environmental changes is unavailable and their occurrence is unpredictable, they can be considered as a game player with the potential to destroy phenotypic stability. The biological network needs to develop an evolutionary strategy to improve phenotypic stability as much as possible, so it can be considered as another game player in the evolutionary process, ie, a stochastic Nash game of minimizing the maximum network evolution level caused by the worst environmental disturbances. Based on the nonlinear stochastic evolutionary game strategy, we find that some genetic variations can be used in natural selection to construct negative feedback loops, efficiently improving network robustness. This provides larger genetic robustness as a buffer against neutral genetic variations, as well as larger environmental robustness to resist environmental disturbances and maintain a network phenotypic traits in the evolutionary process. In this situation, the robust phenotypic traits of stochastic biological networks can be more frequently selected by natural selection in evolution. However, if the harbored neutral genetic variations are accumulated to a sufficiently large degree, and environmental disturbances are strong enough that the network robustness can no longer confer enough genetic robustness and environmental robustness, then the phenotype robustness might break down. In this case, a network phenotypic trait may be pushed from one equilibrium point to another, changing the phenotypic trait and starting a new phase of network evolution through the hidden neutral genetic variations harbored in network robustness by adaptive evolution. Further, the proposed evolutionary game is extended to an n-tuple evolutionary game of stochastic biological networks with m players (competitive populations) and k environmental dynamics. PMID:24558296

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.

Collagen organization in the chicken cornea and structural alterations in the retinopathy, globe enlarged (rge) phenotype--an X-ray diffraction study.

PubMed

Boote, Craig; Hayes, Sally; Jones, Simon; Quantock, Andrew J; Hocking, Paul M; Inglehearn, Chris F; Ali, Manir; Meek, Keith M

2008-01-01

An investigation into the collagenous structure of the mature avian cornea is presented. Wide-angle X-ray diffraction is employed to assess collagen organization in 9-month-old chicken corneas. The central 2-4mm corneal region features a preponderance of fibrils directed along the superior-inferior and nasal-temporal orthogonal meridians. More peripherally the orientation of fibrils alters in favor of a predominantly tangential arrangement. The chicken cornea appears to be circumscribed by an annulus of fibrils that extends into the limbus. The natural arrangement of collagen in the chicken cornea is discussed in relation to corneal shape and the mechanical requirements of avian corneal accommodation. Equivalent data are also presented from age-matched blind chickens affected with the retinopathy, globe enlarged (rge) mutation, characterized by an abnormally thick and flat cornea. The data indicate considerable realignment and redistribution of collagen lamellae in the peripheral rge cornea. In contrast to normal chickens, no obvious tangential collagen alignment was evident in the periphery of rge corneas. In mammals, the presence of a limbal fibril annulus is believed to be important in corneal shape preservation. We postulate that corneal flattening in rge chickens may be related to biomechanical changes brought about by an alteration in collagen arrangement at the corneal periphery.

Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner

NASA Technical Reports Server (NTRS)

Bancroft, Gregory N.; Sikavitsas, Vassilios I.; van den Dolder, Juliette; Sheffield, Tiffany L.; Ambrose, Catherine G.; Jansen, John A.; Mikos, Antonios G.; McIntire, L. V. (Principal Investigator)

2002-01-01

Bone is a complex highly structured mechanically active 3D tissue composed of cellular and matrix elements. The true biological environment of a bone cell is thus derived from a dynamic interaction between responsively active cells experiencing mechanical forces and a continuously changing 3D matrix architecture. To investigate this phenomenon in vitro, marrow stromal osteoblasts were cultured on 3D scaffolds under flow perfusion with different rates of flow for an extended period to permit osteoblast differentiation and significant matrix production and mineralization. With all flow conditions, mineralized matrix production was dramatically increased over statically cultured constructs with the total calcium content of the cultured scaffolds increasing with increasing flow rate. Flow perfusion induced de novo tissue modeling with the formation of pore-like structures in the scaffolds and enhanced the distribution of cells and matrix throughout the scaffolds. These results represent reporting of the long-term effects of fluid flow on primary differentiating osteoblasts and indicate that fluid flow has far-reaching effects on osteoblast differentiation and phenotypic expression in vitro. Flow perfusion culture permits the generation and study of a 3D, actively modeled, mineralized matrix and can therefore be a valuable tool for both bone biology and tissue engineering.

GC[Formula: see text]NMF: A Novel Matrix Factorization Framework for Gene-Phenotype Association Prediction.

PubMed

Zhang, Yaogong; Liu, Jiahui; Liu, Xiaohu; Hong, Yuxiang; Fan, Xin; Huang, Yalou; Wang, Yuan; Xie, Maoqiang

2018-04-24

Gene-phenotype association prediction can be applied to reveal the inherited basis of human diseases and facilitate drug development. Gene-phenotype associations are related to complex biological processes and influenced by various factors, such as relationship between phenotypes and that among genes. While due to sparseness of curated gene-phenotype associations and lack of integrated analysis of the joint effect of multiple factors, existing applications are limited to prediction accuracy and potential gene-phenotype association detection. In this paper, we propose a novel method by exploiting weighted graph constraint learned from hierarchical structures of phenotype data and group prior information among genes by inheriting advantages of Non-negative Matrix Factorization (NMF), called Weighted Graph Constraint and Group Centric Non-negative Matrix Factorization (GC[Formula: see text]NMF). Specifically, first we introduce the depth of parent-child relationships between two adjacent phenotypes in hierarchical phenotypic data as weighted graph constraint for a better phenotype understanding. Second, we utilize intra-group correlation among genes in a gene group as group constraint for gene understanding. Such information provides us with the intuition that genes in a group probably result in similar phenotypes. The model not only allows us to achieve a high-grade prediction performance, but also helps us to learn interpretable representation of genes and phenotypes simultaneously to facilitate future biological analysis. Experimental results on biological gene-phenotype association datasets of mouse and human demonstrate that GC[Formula: see text]NMF can obtain superior prediction accuracy and good understandability for biological explanation over other state-of-the-arts methods.

A phenome database (NEAUHLFPD) designed and constructed for broiler lines divergently selected for abdominal fat content.

PubMed

Li, Min; Dong, Xiang-yu; Liang, Hao; Leng, Li; Zhang, Hui; Wang, Shou-zhi; Li, Hui; Du, Zhi-Qiang

2017-05-20

Effective management and analysis of precisely recorded phenotypic traits are important components of the selection and breeding of superior livestocks. Over two decades, we divergently selected chicken lines for abdominal fat content at Northeast Agricultural University (Northeast Agricultural University High and Low Fat, NEAUHLF), and collected large volume of phenotypic data related to the investigation on molecular genetic basis of adipose tissue deposition in broilers. To effectively and systematically store, manage and analyze phenotypic data, we built the NEAUHLF Phenome Database (NEAUHLFPD). NEAUHLFPD included the following phenotypic records: pedigree (generations 1-19) and 29 phenotypes, such as body sizes and weights, carcass traits and their corresponding rates. The design and construction strategy of NEAUHLFPD were executed as follows: (1) Framework design. We used Apache as our web server, MySQL and Navicat as database management tools, and PHP as the HTML-embedded language to create dynamic interactive website. (2) Structural components. On the main interface, detailed introduction on the composition, function, and the index buttons of the basic structure of the database could be found. The functional modules of NEAUHLFPD had two main components: the first module referred to the physical storage space for phenotypic data, in which functional manipulation on data can be realized, such as data indexing, filtering, range-setting, searching, etc.; the second module related to the calculation of basic descriptive statistics, where data filtered from the database can be used for the computation of basic statistical parameters and the simultaneous conditional sorting. NEAUHLFPD could be used to effectively store and manage not only phenotypic, but also genotypic and genomics data, which can facilitate further investigation on the molecular genetic basis of chicken adipose tissue growth and development, and expedite the selection and breeding of broilers with low fat content.

Structure-Based Systematic Isolation of Conditional-Lethal Mutations in the Single Yeast Calmodulin Gene

PubMed Central

Ohya, Y.; Botstein, D.

1994-01-01

Conditional-lethal mutations of the single calmodulin gene in Saccharomyces cerevisiae have been very difficult to isolate by random and systematic methods, despite the fact that deletions cause recessive lethality. We report here the isolation of numerous conditional-lethal mutants that were recovered by systematically altering phenylalanine residues. The phenylalanine residues of calmodulin were implicated in function both by structural studies of calmodulin bound to target peptides and by their extraordinary conservation in evolution. Seven single and 26 multiple Phe -> Ala mutations were constructed. Mutant phenotypes were examined in a haploid cmd1 disrupted strain under three conditions: single copy, low copy, and overexpressed. Whereas all but one of the single mutations caused no obvious phenotype, most of the multiple mutations caused obvious growth phenotypes. Five were lethal, 6 were lethal only in synthetic medium, 13 were temperature-sensitive lethal and 2 had no discernible phenotypic consequences. Overexpression of some of the mutant genes restored the phenotype to nearly wild type. Several temperature-sensitive calmodulin mutations were suppressed by elevated concentration of CaCl(2) in the medium. Mutant calmodulin protein was detected at normal levels in extracts of most of the lethal mutant cells, suggesting that the deleterious phenotypes were due to loss of the calmodulin function and not protein instability. Analysis of diploid strains heterozygous for all combinations of cmd1-ts alleles revealed four intragenic complementation groups. The contributions of individual phe->ala changes to mutant phenotypes support the idea of internal functional redundancy in the symmetrical calmodulin protein molecule. These results suggest that the several phenylalanine residues in calmodulin are required to different extents in different combinations in order to carry out each of the several essential tasks. PMID:7896089

Beyond DNA: integrating inclusive inheritance into an extended theory of evolution.

PubMed

Danchin, Étienne; Charmantier, Anne; Champagne, Frances A; Mesoudi, Alex; Pujol, Benoit; Blanchet, Simon

2011-06-17

Many biologists are calling for an 'extended evolutionary synthesis' that would 'modernize the modern synthesis' of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions.

Parental effects and the evolution of phenotypic memory.

PubMed

Kuijper, B; Johnstone, R A

2016-02-01

Despite growing evidence for nongenetic inheritance, the ecological conditions that favour the evolution of heritable parental or grandparental effects remain poorly understood. Here, we systematically explore the evolution of parental effects in a patch-structured population with locally changing environments. When selection favours the production of a mix of offspring types, this mix differs according to the parental phenotype, implying that parental effects are favoured over selection for bet-hedging in which the mixture of offspring phenotypes produced does not depend on the parental phenotype. Positive parental effects (generating a positive correlation between parental and offspring phenotype) are favoured in relatively stable habitats and when different types of local environment are roughly equally abundant, and can give rise to long-term parental inheritance of phenotypes. By contrast, unstable habitats can favour negative parental effects (generating a negative correlation between parental and offspring phenotype), and under these circumstances, even slight asymmetries in the abundance of local environmental states select for marked asymmetries in transmission fidelity. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.

Phenotypic covariance at species’ borders

PubMed Central

2013-01-01

Background Understanding the evolution of species limits is important in ecology, evolution, and conservation biology. Despite its likely importance in the evolution of these limits, little is known about phenotypic covariance in geographically marginal populations, and the degree to which it constrains, or facilitates, responses to selection. We investigated phenotypic covariance in morphological traits at species’ borders by comparing phenotypic covariance matrices (P), including the degree of shared structure, the distribution of strengths of pair-wise correlations between traits, the degree of morphological integration of traits, and the ranks of matricies, between central and marginal populations of three species-pairs of coral reef fishes. Results Greater structural differences in P were observed between populations close to range margins and conspecific populations toward range centres, than between pairs of conspecific populations that were both more centrally located within their ranges. Approximately 80% of all pair-wise trait correlations within populations were greater in the north, but these differences were unrelated to the position of the sampled population with respect to the geographic range of the species. Conclusions Neither the degree of morphological integration, nor ranks of P, indicated greater evolutionary constraint at range edges. Characteristics of P observed here provide no support for constraint contributing to the formation of these species’ borders, but may instead reflect structural change in P caused by selection or drift, and their potential to evolve in the future. PMID:23714580

Colony social structure in native and invasive populations of the social wasp Vespula pensylvanica

USGS Publications Warehouse

Hanna, Cause; Cook, Erin D.; Thompson, Ariel R.; Dare, Lyndzey E.; Palaski, Amanda L.; Foote, David; Goodisman, Michael A. D.

2014-01-01

Social insects rank among the most invasive of terrestrial species. The success of invasive social insects stems, in part, from the flexibility derived from their social behaviors. We used genetic markers to investigate if the social system of the invasive wasp, Vespula pensylvanica, differed in its introduced and native habitats in order to better understand variation in social phenotype in invasive social species. We found that (1) nestmate workers showed lower levels of relatedness in introduced populations than native populations, (2) introduced colonies contained workers produced by multiple queens whereas native colonies contained workers produced by only a single queen, (3) queen mate number did not differ significantly between introduced and native colonies, and (4) workers from introduced colonies were frequently produced by queens that originated from foreign nests. Thus, overall, native and introduced colonies differed substantially in social phenotype because introduced colonies more frequently contained workers produced by multiple, foreign queens. In addition, the similarity in levels of genetic variation in introduced and native habitats, as well as observed variation in colony social phenotype in native populations, suggest that colony structure in invasive populations may be partially associated with social plasticity. Overall, the differences in social structure observed in invasive V. pensylvanica parallel those in other, distantly related invasive social insects, suggesting that insect societies often develop similar social phenotypes upon introduction into new habitats.

Phenotypic covariance at species' borders.

PubMed

Caley, M Julian; Cripps, Edward; Game, Edward T

2013-05-28

Understanding the evolution of species limits is important in ecology, evolution, and conservation biology. Despite its likely importance in the evolution of these limits, little is known about phenotypic covariance in geographically marginal populations, and the degree to which it constrains, or facilitates, responses to selection. We investigated phenotypic covariance in morphological traits at species' borders by comparing phenotypic covariance matrices (P), including the degree of shared structure, the distribution of strengths of pair-wise correlations between traits, the degree of morphological integration of traits, and the ranks of matricies, between central and marginal populations of three species-pairs of coral reef fishes. Greater structural differences in P were observed between populations close to range margins and conspecific populations toward range centres, than between pairs of conspecific populations that were both more centrally located within their ranges. Approximately 80% of all pair-wise trait correlations within populations were greater in the north, but these differences were unrelated to the position of the sampled population with respect to the geographic range of the species. Neither the degree of morphological integration, nor ranks of P, indicated greater evolutionary constraint at range edges. Characteristics of P observed here provide no support for constraint contributing to the formation of these species' borders, but may instead reflect structural change in P caused by selection or drift, and their potential to evolve in the future.

Structure and development of old-growth, unmanaged second-growth, and extended rotation Pinus resinosa forests in Minnesota, USA

USGS Publications Warehouse

Silver, Emily J.; D'Amato, Anthony W.; Fraver, Shawn; Palik, Brian J.; Bradford, John B.

2013-01-01

The structure and developmental dynamics of old-growth forests often serve as important baselines for restoration prescriptions aimed at promoting more complex structural conditions in managed forest landscapes. Nonetheless, long-term information on natural patterns of development is rare for many commercially important and ecologically widespread forest types. Moreover, the effectiveness of approaches recommended for restoring old-growth structural conditions to managed forests, such as the application of extended rotation forestry, has been little studied. This study uses several long-term datasets from old growth, extended rotation, and unmanaged second growth Pinus resinosa (red pine) forests in northern Minnesota, USA, to quantify the range of variation in structural conditions for this forest type and to evaluate the effectiveness of extended rotation forestry at promoting the development of late-successional structural conditions. Long-term tree population data from permanent plots for one of the old-growth stands and the extended rotation stands (87 and 61 years, respectively) also allowed for an examination of the long-term structural dynamics of these systems. Old-growth forests were more structurally complex than unmanaged second-growth and extended rotation red pine stands, due in large part to the significantly higher volumes of coarse woody debris (70.7 vs. 11.5 and 4.7 m3/ha, respectively) and higher snag basal area (6.9 vs. 2.9 and 0.5 m2/ha, respectively). In addition, old-growth forests, although red pine-dominated, contained a greater abundance of other species, including Pinus strobus, Abies balsamea, and Picea glauca relative to the other stand types examined. These differences between stand types largely reflect historic gap-scale disturbances within the old-growth systems and their corresponding structural and compositional legacies. Nonetheless, extended rotation thinning treatments, by accelerating advancement to larger tree diameter classes, generated diameter distributions more closely approximating those found in old growth within a shorter time frame than depicted in long-term examinations of old-growth structural development. These results suggest that extended rotation treatments may accelerate the development of old-growth structural characteristics, provided that coarse woody debris and snags are deliberately retained and created on site. These and other developmental characteristics of old-growth systems can inform forest management when objectives include the restoration of structural conditions found in late-successional forests.

Directional selection effects on patterns of phenotypic (co)variation in wild populations

PubMed Central

Patton, J. L.; Hubbe, A.; Marroig, G.

2016-01-01

Phenotypic (co)variation is a prerequisite for evolutionary change, and understanding how (co)variation evolves is of crucial importance to the biological sciences. Theoretical models predict that under directional selection, phenotypic (co)variation should evolve in step with the underlying adaptive landscape, increasing the degree of correlation among co-selected traits as well as the amount of genetic variance in the direction of selection. Whether either of these outcomes occurs in natural populations is an open question and thus an important gap in evolutionary theory. Here, we documented changes in the phenotypic (co)variation structure in two separate natural populations in each of two chipmunk species (Tamias alpinus and T. speciosus) undergoing directional selection. In populations where selection was strongest (those of T. alpinus), we observed changes, at least for one population, in phenotypic (co)variation that matched theoretical expectations, namely an increase of both phenotypic integration and (co)variance in the direction of selection and a re-alignment of the major axis of variation with the selection gradient. PMID:27881744

Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Dysostosis type 1.

PubMed

Palagano, Eleonora; Zuccarini, Giulia; Prontera, Paolo; Borgatti, Renato; Stangoni, Gabriela; Elisei, Sandro; Mantero, Stefano; Menale, Ciro; Forlino, Antonella; Uva, Paolo; Oppo, Manuela; Vezzoni, Paolo; Villa, Anna; Merlo, Giorgio R; Sobacchi, Cristina

2018-06-19

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene. Copyright © 2018 Elsevier Inc. All rights reserved.

Whole-Genome Sequencing for Detecting Antimicrobial Resistance in Nontyphoidal Salmonella

PubMed Central

Tyson, Gregory H.; Kabera, Claudine; Chen, Yuansha; Li, Cong; Folster, Jason P.; Ayers, Sherry L.; Lam, Claudia; Tate, Heather P.; Zhao, Shaohua

2016-01-01

Laboratory-based in vitro antimicrobial susceptibility testing is the foundation for guiding anti-infective therapy and monitoring antimicrobial resistance trends. We used whole-genome sequencing (WGS) technology to identify known antimicrobial resistance determinants among strains of nontyphoidal Salmonella and correlated these with susceptibility phenotypes to evaluate the utility of WGS for antimicrobial resistance surveillance. Six hundred forty Salmonella of 43 different serotypes were selected from among retail meat and human clinical isolates that were tested for susceptibility to 14 antimicrobials using broth microdilution. The MIC for each drug was used to categorize isolates as susceptible or resistant based on Clinical and Laboratory Standards Institute clinical breakpoints or National Antimicrobial Resistance Monitoring System (NARMS) consensus interpretive criteria. Each isolate was subjected to whole-genome shotgun sequencing, and resistance genes were identified from assembled sequences. A total of 65 unique resistance genes, plus mutations in two structural resistance loci, were identified. There were more unique resistance genes (n = 59) in the 104 human isolates than in the 536 retail meat isolates (n = 36). Overall, resistance genotypes and phenotypes correlated in 99.0% of cases. Correlations approached 100% for most classes of antibiotics but were lower for aminoglycosides and beta-lactams. We report the first finding of extended-spectrum β-lactamases (ESBLs) (blaCTX-M1 and blaSHV2a) in retail meat isolates of Salmonella in the United States. Whole-genome sequencing is an effective tool for predicting antibiotic resistance in nontyphoidal Salmonella, although the use of more appropriate surveillance breakpoints and increased knowledge of new resistance alleles will further improve correlations. PMID:27381390

Structural Basis of Cerebellar Microcircuits in the Rat

PubMed Central

Cerminara, Nadia L.; Aoki, Hanako; Loft, Michaela; Apps, Richard

2013-01-01

The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed “microzones,” “patches,” and “bands.” These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the “one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype. PMID:24133249

Multivariate Analysis of Genotype-Phenotype Association.

PubMed

Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

2016-04-01

With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map has important consequences for gene identification and may shed light on the evolvability of organisms. Copyright © 2016 by the Genetics Society of America.

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.

Phenotype frequencies of blood group systems (Rh, Kell, Kidd, Duffy, MNS, P, Lewis, and Lutheran) in blood donors of south Gujarat, India

PubMed Central

Kahar, Manoj A.; Patel, Rajnikant. D.

2014-01-01

Background: This is the first study on phenotype frequencies of various blood group systems in blood donors of south Gujarat, India using conventional tube technique. Material and Methods: A total of 115 “O” blood group donors from three different blood banks of south Gujarat were typed for D, C, c, E, e, K, Jka, Lea, Leb, P1, M, and N antigens using monoclonal antisera and k, Kpa, Kpb, Fya,Fyb, Jkb, S,s, Lua, and Lub antigens were typed using polyclonal antisera employing Indirect Antiglobulin Test. Antigens and phenotype frequencies were expressed as percentages. Results: From the 115 blood donor samples used for extended antigen typing in the Rh system, e antigen was found in 100% donors, followed by D [84.35%], C [81.74%], c [56.32%], and E [21.74%] with DCe/DCe (R1 R1, 40.87%) as the most common phenotype. k was found to be positive in 100% of donors and no K+k- phenotype was found in Kell system. For Kidd and Duffy blood group system, Jk(a+b+) and Fy(a-b-) were the most common phenotypes with frequency of 52.17% and 48.69%, respectively. In the MNS system, 39.13% donors were typed as M+N+, 37.39% as M+N-, and 23.48% as M-N+. S+s+ was found in 24.35% of donors, S+s- in 8.69%, and S-s+ as the commonest amongst donors with 66.96%. No Lu(a+b+) or Lu(a+b-) phenotypes were detected in 115 donors typed for Lutheran antigens. A rare Lu(a-b-) phenotype was found in 2.61% donors. Conclusion: Data base for antigen frequency of various blood group systems in local donors help provide antigen negative compatible blood units to patients with multiple antibodies in order to formulate in-house red cells for antibody detection and identification and for preparing donor registry for rare blood groups. PMID:24678176

Salmonella spp. and Extended-Spectrum Cephalosporin-Resistant Escherichia coli Frequently Contaminate Broiler Chicken Transport Cages of an Organic Production Company.

PubMed

Mollenkopf, Dixie F; De Wolf, Brittany; Feicht, Sydnee M; Cenera, Johana K; King, Christy A; van Balen, Joany C; Wittum, Thomas E

2018-06-06

Antimicrobial resistant bacteria in retail meat pose a health hazard to the public, as does contamination of these products with Salmonella. Our aim was to determine the prevalence of Salmonella as well as Escherichia coli expressing AmpC and extended-spectrum beta-lactamase (ESBL) resistance phenotypes contaminating broiler transport cages and fresh, retail ground chicken meat. Sterile gauze sponges were used to collect duplicate cage floor samples from transport trailers that deliver market-ready birds to a single organic poultry-processing facility. With the exception of the first visit (n = 25), 50 duplicate cage floor samples were collected using moistened sterile gauze sponges on each of nine weekly visits during May, June, and July 2013. Additionally, fresh, retail ground chicken meat was sampled at each weekly visit from an on-site retail store located at the same processing facility. A total of 425 cage swabs and 72 ground chicken aliquots from 24 retail packages were collected and screened for the presence of Salmonella as well as E. coli expressing resistance to extended-spectrum cephalosporins using selective culture. We recovered Salmonella from 26.1% of cage swab samples and 2.8% of retail meat samples. E. coli expressing AmpC and ESBL resistance phenotypes were recovered from 84.9% and 22.6% of cage swabs and 77.8% and 11.1% of fresh, retail ground meat samples, respectively. Our results suggest that transport cages could potentially act as a source of broiler exposure to both Salmonella and enteric bacteria resistant to important antimicrobial drugs as they are transported for entry into the food supply as fresh, retail meat products.

Genetic hotels for the standard genetic code: evolutionary analysis based upon novel three-dimensional algebraic models.

PubMed

José, Marco V; Morgado, Eberto R; Govezensky, Tzipe

2011-07-01

Herein, we rigorously develop novel 3-dimensional algebraic models called Genetic Hotels of the Standard Genetic Code (SGC). We start by considering the primeval RNA genetic code which consists of the 16 codons of type RNY (purine-any base-pyrimidine). Using simple algebraic operations, we show how the RNA code could have evolved toward the current SGC via two different intermediate evolutionary stages called Extended RNA code type I and II. By rotations or translations of the subset RNY, we arrive at the SGC via the former (type I) or via the latter (type II), respectively. Biologically, the Extended RNA code type I, consists of all codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The Extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. Since the dimensions of remarkable subsets of the Genetic Hotels are not necessarily integer numbers, we also introduce the concept of algebraic fractal dimension. A general decoding function which maps each codon to its corresponding amino acid or the stop signals is also derived. The Phenotypic Hotel of amino acids is also illustrated. The proposed evolutionary paths are discussed in terms of the existing theories of the evolution of the SGC. The adoption of 3-dimensional models of the Genetic and Phenotypic Hotels will facilitate the understanding of the biological properties of the SGC.

Alternative Sources of Adult Stem Cells: Human Amniotic Membrane

NASA Astrophysics Data System (ADS)

Wolbank, Susanne; van Griensven, Martijn; Grillari-Voglauer, Regina; Peterbauer-Scherb, Anja

Human amniotic membrane is a highly promising cell source for tissue engineering. The cells thereof, human amniotic epithelial cells (hAEC) and human amniotic mesenchymal stromal cells (hAMSC), may be immunoprivileged, they represent an early developmental status, and their application is ethically uncontroversial. Cell banking strategies may use freshly isolated cells or involve in vitro expansion to increase cell numbers. Therefore, we have thoroughly characterized the effect of in vitro cultivation on both phenotype and differentiation potential of hAEC. Moreover, we present different strategies to improve expansion including replacement of animal-derived supplements by human platelet products or the introduction of the catalytic subunit of human telomerase to extend the in vitro lifespan of amniotic cells. Characterization of the resulting cultures includes phenotype, growth characteristics, and differentiation potential, as well as immunogenic and immunomodulatory properties.

Phenotype definition and development--contributions from Group 7.

PubMed

Wilcox, Marsha A; Paterson, Andrew D

2009-01-01

The papers in Genetic Analysis Workshop 16 Group 7 covered a wide range of topics. The effects of confounder misclassification and selection bias on association results were examined by one group. Another focused on bias introduced by various methods of accounting for treatment effects. Two groups used related methods to derive phenotypic traits. They used different analytic strategies for genetic associations with non-overlapping results (but because they used different sets of single-nucleotide polymorphisms (SNPs) and significance criteria, this is not surprising). Another group relied on the well-characterized definition of type 2 diabetes to show benefits of a novel predictive test. Transmission-ratio distortion was the focus of another paper. The results were extended to show a potential secondary benefit of the test to identify potentially mis-called SNPs. (c) 2009 Wiley-Liss, Inc.

The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation.

PubMed

Pronicka, Ewa; Piekutowska-Abramczuk, Dorota; Szymańska-Dębińska, Tamara; Bielecka, Liliana; Kowalski, Paweł; Luczak, Sylwia; Karkucińska-Więckowska, Agnieszka; Migdał, Marek; Kubalska, Jolanta; Zimowski, Janusz; Jamroz, Ewa; Wierzba, Jolanta; Sykut-Cegielska, Jolanta; Pronicki, Maciej; Zaremba, Jacek; Krajewska-Walasek, Małgorzata

2013-11-01

The aim of this study was to assess the natural history of the SCO2 deficiency in relation to the genotype in a cohort of 62 patients with SCO2 mutations (36 this study, 26 previous reports). A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency. The prevalence of SCO2 deficiency in Poland is relatively high. A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate. Copyright © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

De novo direct duplication of chromosome segment 22q11.2-q13.1

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

Fujimoto, Atsuko; Lin, Ming S.

Lindsay et al. [1995] reported a case of de novo duplication of the segment 22q11-q12. Molecular cytogenetics studies showed that the segment includes the regions responsible for the {open_quotes}cat eye,{close_quotes} DiGeorge, and velo-cardio-facial syndrome, and extends distal to the breakpoint cluster region. The phenotype was milder than that of complete trisomy 22 and der(22)t(11;22) (q23;q11) syndrome and was similar in type and severity to that of {open_quotes}cat eye{close_quotes} syndrome (CES). They suggested that trisomy of gene(s) responsible for the CES might have a predominant phenotypic effect over other genes present in the region duplicated in their patient. 3 refs., 2more » figs.« less

Geographical differences in maternal basking behaviour and offspring growth rate in a climatically widespread viviparous reptile.

PubMed

Cadby, Chloé D; Jones, Susan M; Wapstra, Erik

2014-04-01

In reptiles, the thermal environment during embryonic development affects offspring phenotypic traits and potentially offspring fitness. In viviparous species, mothers can potentially manipulate the embryonic thermal environment through their basking behaviour and, thus, may be able to manipulate offspring phenotype and increase offspring fitness. One way in which mothers can maximise offspring phenotype (and thus potentially affect offspring fitness) is by fine-tuning their basking behaviour to the environment in order to buffer the embryo from deleterious developmental temperatures. In widespread species, it is unclear whether populations that have evolved under different climatic conditions will exhibit different maternal behaviours and/or thermal effects on offspring phenotype. To test this, we provided extended or reduced basking opportunity to gravid spotted skinks (Niveoscincus ocellatus) and their offspring from two populations at the climatic extremes of the species' distribution. Gravid females fine-tuned their basking behaviour to the basking opportunity, which allowed them to buffer their embryos from potentially negative thermal effects. This fine-tuning of female basking behaviour appears to have led to the expression of geographical differences in basking behaviour, with females from the cold alpine regions being more opportunistic in their basking behaviour than females from the warmer regions. However, those differences in maternal behaviour did not preclude the evolution of geographic differences in thermal effects: offspring growth varied between populations, potentially suggesting local adaptation to basking conditions. Our results demonstrate that maternal effects and phenotypic plasticity can play a significant role in allowing species to cope in changing environmental conditions, which is particularly relevant in the context of climate change.

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

PubMed Central

Martin-Fernandez, Laura; Ziyatdinov, Andrey; Carrasco, Marina; Millon, Juan Antonio; Martinez-Perez, Angel; Vilalta, Noelia; Brunel, Helena; Font, Montserrat; Hamsten, Anders; Souto, Juan Carlos; Soria, José Manuel

2016-01-01

Background Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. Objectives To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. Patients/Methods Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. Results The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. Conclusions The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results. PMID:26784699

High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences

PubMed Central

Ronninger, Marcus; Shchetynsky, Klementy; Franke, Andre; Nöthen, Markus M.; Müller-Quernheim, Joachim; Schreiber, Stefan; Adrianto, Indra; Karakaya, Bekir; van Moorsel, Coline H. M.; Navratilova, Zdenka; Kolek, Vitezslav; Rybicki, Benjamin A.; Iannuzzi, Michael C.; Petrek, Martin; Grutters, Jan C.; Montgomery, Courtney; Fischer, Annegret; Eklund, Anders; Padyukov, Leonid; Grunewald, Johan

2016-01-01

Rationale: Sarcoidosis is a multisystem disease of unknown cause. Löfgren’s syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. Objectives: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. Methods: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. Measurements and Main Results: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS–associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Conclusions: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region. PMID:26651848

MGAS: a powerful tool for multivariate gene-based genome-wide association analysis.

PubMed

Van der Sluis, Sophie; Dolan, Conor V; Li, Jiang; Song, Youqiang; Sham, Pak; Posthuma, Danielle; Li, Miao-Xin

2015-04-01

Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

Detailed clinical and molecular study of 20 females with Xq deletions with special reference to menstruation and fertility.

PubMed

Mercer, Catherine L; Lachlan, Katherine; Karcanias, Alexandra; Affara, Nabeel; Huang, Shuwen; Jacobs, Patricia A; Thomas, N Simon

2013-01-01

Integrity of the long arm of the X chromosome is important for maintaining female fertility and several critical regions for normal ovarian function have been proposed. In order to understand further the importance of specific areas of the X chromosome, we describe a series of 20 previously unreported patients missing part of Xq in whom detailed phenotypic information has been gathered as well as precise chromosome mapping using array Comparative Genomic Hybridization. Features often associated with Turner syndrome were not common in our study and excluding puberty, menarche and menstruation, the phenotypes observed were present in only a minority of women and were not specific to the X chromosome. The most frequently occurring phenotypic features in our patients were abnormalities of menstruation and fertility. Larger terminal deletions were associated with a higher incidence of primary ovarian failure, occurring at a younger age; however patients with similar or even identical deletions had discordant menstrual phenotypes, making accurate genetic counselling difficult. Nevertheless, large deletions are likely to be associated with complete skewing of X inactivation so that the resulting phenotypes are relatively benign given the amount of genetic material missing, even in cases with unbalanced X;autosome translocations. Some degree of ovarian dysfunction is highly likely, especially for terminal deletions extending proximal to Xq27. In conjunction with patient data from the literature, our study suggests that loss of Xq26-Xq28 has the most significant effect on ovarian function. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Sigma 1 protein of mammalian reoviruses extends from the surfaces of viral particles

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

Furlong, D.B.; Nibert, M.L.; Fields, B.N.

1988-01-01

Electron microscopy revealed structures consisting of long fibers topped with knobs extending from the surfaces of virions of mammalian reoviruses. The morphology of these structures was reminiscent of the fiber protein of adenovirus. Fibers were also seen extending from the reovirus top component and intermediate subviral particles but not from cores, suggesting that the fibers consist of either the ..mu..1C or sigma1 outer capsid protein. Amino acid sequence analysis predicts that the reovirus cell attachment protein sigma1 contains an extended fiber domain. When sigma1 protein was released from viral particles with mild heat and subsequently obtained in isolation, it wasmore » found to have a morphology identical to that of the fiber structures seen extending from the viral particles. The identification of an extended form of sigma1 has important implications for its function in cell attachment. Other evidence suggest that sigma1 protein may occur in virions in both an extended and an unextended state.« less

Landscape patterns of phenotypic variation and population structuring in a selfing grass, Elymus glaucus (blue wildrye).

Treesearch

Vicky J. Erickson; Nancy L. Mandel; Frank C. Sorensen

2004-01-01

Source-related phenotypic variance was investigated in a common garden study of populations of Elymus glaucus Buckley (blue wildrye) from the Blue Mountain Ecological Province of northeastern Oregon and adjoining Washington. The primary objective of this study was to assess geographic patterns of potentially adaptive differentiation in this self-...

Polyploidy and the relationship between leaf structure and function: implications for correlated evolution of anatomy, morphology, and physiology in Brassica.

PubMed

Baker, Robert L; Yarkhunova, Yulia; Vidal, Katherine; Ewers, Brent E; Weinig, Cynthia

2017-01-05

Polyploidy is well studied from a genetic and genomic perspective, but the morphological, anatomical, and physiological consequences of polyploidy remain relatively uncharacterized. Whether these potential changes bear on functional integration or are idiosyncratic remains an open question. Repeated allotetraploid events and multiple genomic combinations as well as overlapping targets of artificial selection make the Brassica triangle an excellent system for exploring variation in the connection between plant structure (anatomy and morphology) and function (physiology). We examine phenotypic integration among structural aspects of leaves including external morphology and internal anatomy with leaf-level physiology among several species of Brassica. We compare diploid and allotetraploid species to ascertain patterns of phenotypic correlations among structural and functional traits and test the hypothesis that allotetraploidy results in trait disintegration allowing for transgressive phenotypes and additional evolutionary and crop improvement potential. Among six Brassica species, we found significant effects of species and ploidy level for morphological, anatomical and physiological traits. We identified three suites of intercorrelated traits in both diploid parents and allotetraploids: Morphological traits (such as leaf area and perimeter) anatomic traits (including ab- and ad- axial epidermis) and aspects of physiology. In general, there were more correlations between structural and functional traits for allotetraploid hybrids than diploid parents. Parents and hybrids did not have any significant structure-function correlations in common. Of particular note, there were no significant correlations between morphological structure and physiological function in the diploid parents. Increased phenotypic integration in the allotetraploid hybrids may be due, in part, to increased trait ranges or simply different structure-function relationships. Genomic and chromosomal instability in early generation allotetraploids may allow Brassica species to explore new trait space and potentially reach higher adaptive peaks than their progenitor species could, despite temporary fitness costs associated with unstable genomes. The trait correlations that disappear after hybridization as well as the novel trait correlations observed in allotetraploid hybrids may represent relatively evolutionarily labile associations and therefore could be ideal targets for artificial selection and crop improvement.

Structural Integrity of the Greek Key Motif in βγ-Crystallins Is Vital for Central Eye Lens Transparency

PubMed Central

Vendra, Venkata Pulla Rao; Agarwal, Garima; Chandani, Sushil; Talla, Venu; Srinivasan, Narayanaswamy; Balasubramanian, Dorairajan

2013-01-01

Background We highlight an unrecognized physiological role for the Greek key motif, an evolutionarily conserved super-secondary structural topology of the βγ-crystallins. These proteins constitute the bulk of the human eye lens, packed at very high concentrations in a compact, globular, short-range order, generating transparency. Congenital cataract (affecting 400,000 newborns yearly worldwide), associated with 54 mutations in βγ-crystallins, occurs in two major phenotypes nuclear cataract, which blocks the central visual axis, hampering the development of the growing eye and demanding earliest intervention, and the milder peripheral progressive cataract where surgery can wait. In order to understand this phenotypic dichotomy at the molecular level, we have studied the structural and aggregation features of representative mutations. Methods Wild type and several representative mutant proteins were cloned, expressed and purified and their secondary and tertiary structural details, as well as structural stability, were compared in solution, using spectroscopy. Their tendencies to aggregate in vitro and in cellulo were also compared. In addition, we analyzed their structural differences by molecular modeling in silico. Results Based on their properties, mutants are seen to fall into two classes. Mutants A36P, L45PL54P, R140X, and G165fs display lowered solubility and structural stability, expose several buried residues to the surface, aggregate in vitro and in cellulo, and disturb/distort the Greek key motif. And they are associated with nuclear cataract. In contrast, mutants P24T and R77S, associated with peripheral cataract, behave quite similar to the wild type molecule, and do not affect the Greek key topology. Conclusion When a mutation distorts even one of the four Greek key motifs, the protein readily self-aggregates and precipitates, consistent with the phenotype of nuclear cataract, while mutations not affecting the motif display ‘native state aggregation’, leading to peripheral cataract, thus offering a protein structural rationale for the cataract phenotypic dichotomy “distort motif, lose central vision”. PMID:23936409

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.

Associations of mental health with cardiovascular risk phenotypes and adiposity in adolescence: A cross-sectional community-based study.

PubMed

Lycett, Kate; McNamara, Clare; Mensah, Fiona K; Burgner, David; Kerr, Jessica A; Muller, Josh; Wake, Melissa

2018-06-01

Cardiovascular disease and mental illness commonly co-occur in later life, but it is unknown how early these associations arise. We aimed to determine the extent to which: (i) childhood mental health is associated with functional and structural cardiovascular risk phenotypes and adiposity in late childhood/adolescence, and (ii) associations between mental health and cardiovascular phenotypes may be explained by differential body mass index. This cross-sectional study drew on three longitudinal community-based cohort studies (two enriched for overweight/obesity) in metropolitan Melbourne, Australia, with harmonized follow-up in 2014. Mental health exposures included emotional and behavioural problems (Strength and Difficulties Questionnaire) and psychosocial health and general well-being (Pediatric Quality of Life Inventory (PedsQL)), which were assessed by self- and parent-proxy report. Cardiovascular risk phenotypes and adiposity measures included mean arterial pressure, pulse wave velocity, carotid artery intima-media thickness, retinal arterioleto-venule ratio, waist circumference, % body fat, and BMI z-score. We used multivariable linear regression models, adjusting for age, sex and neighbourhood disadvantage, to examine associations. Of the 364 participants (mean age 14.7, standard deviation 2.0, years), 30% were overweight and 16% obese. All adiposity indicators were positively associated with higher behavioural/emotional problems and poorer psychosocial health and negatively associated with better ratings of positive general well-being, as reported by parents and children (all P ≤ 0.03). However, there was little evidence that cardiovascular functional or structural phenotypes varied by mental health. By late childhood/adolescence, mental health is strongly associated with adiposity but not with cardiovascular structure or function. This suggests that the known relationship between these constructs may not develop until early or mid-adulthood. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan.

PubMed

Bilal, Erhan; Rabadan, Raul; Alexe, Gabriela; Fuku, Noriyuki; Ueno, Hitomi; Nishigaki, Yutaka; Fujita, Yasunori; Ito, Masafumi; Arai, Yasumichi; Hirose, Nobuyoshi; Ruckenstein, Andrei; Bhanot, Gyan; Tanaka, Masashi

2008-06-11

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99-105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain "beneficial" patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

Mitochondrial DNA Haplogroup D4a Is a Marker for Extreme Longevity in Japan

PubMed Central

Bilal, Erhan; Rabadan, Raul; Alexe, Gabriela; Fuku, Noriyuki; Ueno, Hitomi; Nishigaki, Yutaka; Fujita, Yasunori; Ito, Masafumi; Arai, Yasumichi; Hirose, Nobuyoshi; Ruckenstein, Andrei; Bhanot, Gyan; Tanaka, Masashi

2008-01-01

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99–105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain “beneficial” patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations. PMID:18545700

Age- and Activity-Related Differences in the Abundance of Myosin Essential and Regulatory Light Chains in Human Muscle

PubMed Central

Cobley, James N.; Ab. Malik, Zulezwan; Morton, James P.; Close, Graeme L.; Edwards, Ben J.; Burniston, Jatin G.

2016-01-01

Traditional methods for phenotyping skeletal muscle (e.g., immunohistochemistry) are labor-intensive and ill-suited to multixplex analysis, i.e., assays must be performed in a series. Addressing these concerns represents a largely unmet research need but more comprehensive parallel analysis of myofibrillar proteins could advance knowledge regarding age- and activity-dependent changes in human muscle. We report a label-free, semi-automated and time efficient LC-MS proteomic workflow for phenotyping the myofibrillar proteome. Application of this workflow in old and young as well as trained and untrained human skeletal muscle yielded several novel observations that were subsequently verified by multiple reaction monitoring (MRM). We report novel data demonstrating that human ageing is associated with lesser myosin light chain 1 content and greater myosin light chain 3 content, consistent with an age-related reduction in type II muscle fibers. We also disambiguate conflicting data regarding myosin regulatory light chain, revealing that age-related changes in this protein more closely reflect physical activity status than ageing per se. This finding reinforces the need to control for physical activity levels when investigating the natural process of ageing. Taken together, our data confirm and extend knowledge regarding age- and activity-related phenotypes. In addition, the MRM transitions described here provide a methodological platform that can be fine-tuned to suite multiple research needs and thus advance myofibrillar phenotyping. PMID:28248225

Strategies for assessment of Botanical action on Metabolic Syndrome in the mouse and evidence for a Genotype-specific effect of Russian Tarragon in the regulation of insulin sensitivity

PubMed Central

Zuberi, Aamir R.

2008-01-01

Published reports of botanical action are often hampered by lack of generalized systematic approaches or by the failure to explore mechanisms that could confirm and extend the reported observations. Choice of housing conditions (singly or group housed) and imposed stress during handling procedures are often variable and can contribute significantly to differences in base-line phenotypes measured across studies. Differences can also be observed in the role of the extract in either the treatment of the metabolic syndrome or roles in the regulation of the emergence of metabolic syndrome. The choice of diet used can also vary between the different studies and diet-botanical interactions must be considered. This mini-review highlights the strategies being pursued by the Botanical Research Center Animal Research Core to evaluate the in vivo phenotypes of several Botanical extracts during chronic feeding studies. We describe a phenotyping strategy that promotes a more rigorous interpretation of botanical action and can suggest or eliminate possible mechanisms that may be involved. We discuss the importance of selecting the mouse model, as background strain can significantly alter the underlying susceptibilities to the various components of Metabolic Syndrome. Finally, we present data suggesting the one of the major botanical extracts being studied, an extract of Russian Tarragon, may manifest a mouse strain genotypic-specific insulin-sensitizing phenotype. PMID:18555848

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

metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis.

PubMed

Cichonska, Anna; Rousu, Juho; Marttinen, Pekka; Kangas, Antti J; Soininen, Pasi; Lehtimäki, Terho; Raitakari, Olli T; Järvelin, Marjo-Riitta; Salomaa, Veikko; Ala-Korpela, Mika; Ripatti, Samuli; Pirinen, Matti

2016-07-01

A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. Code is available at https://github.com/aalto-ics-kepaco anna.cichonska@helsinki.fi or matti.pirinen@helsinki.fi Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis

PubMed Central

Cichonska, Anna; Rousu, Juho; Marttinen, Pekka; Kangas, Antti J.; Soininen, Pasi; Lehtimäki, Terho; Raitakari, Olli T.; Järvelin, Marjo-Riitta; Salomaa, Veikko; Ala-Korpela, Mika; Ripatti, Samuli; Pirinen, Matti

2016-01-01

Motivation: A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. Results: We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness. Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. Availability and implementation: Code is available at https://github.com/aalto-ics-kepaco Contacts: anna.cichonska@helsinki.fi or matti.pirinen@helsinki.fi Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153689

Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

PubMed

Abou Al-Shaar, Hussam; Qadi, Najeeb; Al-Hamed, Mohamed H; Meyer, Brian F; Bohlega, Saeed

2016-08-15

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic. To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation. The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing. Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts. This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Centrifugation assay for measuring adhesion of serially passaged bovine chondrocytes to polystyrene surfaces.

PubMed

Kaplan, David S; Hitchins, Victoria M; Vegella, Thomas J; Malinauskas, Richard A; Ferlin, Kimberly M; Fisher, John P; Frondoza, Carmelita G

2012-07-01

A major obstacle in chondrocyte-based therapy for cartilage repair is the limited availability of cells that maintain their original phenotype. Propagation of chondrocytes as monolayer cultures on polystyrene surfaces is used extensively for amplifying cell numbers. However, chondrocytes undergo a phenotypic shift when propagated in this manner and display characteristics of more adherent fibroblastic cells. Little information is available about the effect of this phenotypic shift on cellular adhesion properties. We evaluated changes in adhesion property as bovine chondrocytes were serially propagated up to five passages in monolayer culture using a centrifugation cell adhesion assay, which was based on counting of cells before and after being exposed to centrifugal dislodgement forces of 120 and 350 g. Chondrocytes proliferated well in a monolayer culture with doubling times of 2-3 days, but they appeared more fibroblastic and exhibited elongated cell morphology with continued passage. The centrifugation cell adhesion assay showed that chondrocytes became more adhesive with passage as the percentage of adherent cells after centrifugation increased and was not statistically different from the adhesion of the fibroblast cell line, L929, starting at passage 3. This increased adhesiveness correlated with a shift to a fibroblastic morphology and increased collagen I mRNA expression starting at passage 2. Our findings indicate that the centrifugation cell adhesion assay may serve as a reproducible tool to track alterations in chondrocyte phenotype during their extended propagation in culture.

Testing Specific Hypotheses Concerning Latent Group Differences in Multi-group Covariance Structure Analysis with Structured Means.

ERIC Educational Resources Information Center

Dolan, Conor V.; Molenaar, Peter C. M.

1994-01-01

In multigroup covariance structure analysis with structured means, the traditional latent selection model is formulated as a special case of phenotypic selection. Illustrations with real and simulated data demonstrate how one can test specific hypotheses concerning selection on latent variables. (SLD)

Efficient protein structure search using indexing methods

PubMed Central

2013-01-01

Understanding functions of proteins is one of the most important challenges in many studies of biological processes. The function of a protein can be predicted by analyzing the functions of structurally similar proteins, thus finding structurally similar proteins accurately and efficiently from a large set of proteins is crucial. A protein structure can be represented as a vector by 3D-Zernike Descriptor (3DZD) which compactly represents the surface shape of the protein tertiary structure. This simplified representation accelerates the searching process. However, computing the similarity of two protein structures is still computationally expensive, thus it is hard to efficiently process many simultaneous requests of structurally similar protein search. This paper proposes indexing techniques which substantially reduce the search time to find structurally similar proteins. In particular, we first exploit two indexing techniques, i.e., iDistance and iKernel, on the 3DZDs. After that, we extend the techniques to further improve the search speed for protein structures. The extended indexing techniques build and utilize an reduced index constructed from the first few attributes of 3DZDs of protein structures. To retrieve top-k similar structures, top-10 × k similar structures are first found using the reduced index, and top-k structures are selected among them. We also modify the indexing techniques to support θ-based nearest neighbor search, which returns data points less than θ to the query point. The results show that both iDistance and iKernel significantly enhance the searching speed. In top-k nearest neighbor search, the searching time is reduced 69.6%, 77%, 77.4% and 87.9%, respectively using iDistance, iKernel, the extended iDistance, and the extended iKernel. In θ-based nearest neighbor serach, the searching time is reduced 80%, 81%, 95.6% and 95.6% using iDistance, iKernel, the extended iDistance, and the extended iKernel, respectively. PMID:23691543

Efficient protein structure search using indexing methods.

PubMed

Kim, Sungchul; Sael, Lee; Yu, Hwanjo

2013-01-01

Understanding functions of proteins is one of the most important challenges in many studies of biological processes. The function of a protein can be predicted by analyzing the functions of structurally similar proteins, thus finding structurally similar proteins accurately and efficiently from a large set of proteins is crucial. A protein structure can be represented as a vector by 3D-Zernike Descriptor (3DZD) which compactly represents the surface shape of the protein tertiary structure. This simplified representation accelerates the searching process. However, computing the similarity of two protein structures is still computationally expensive, thus it is hard to efficiently process many simultaneous requests of structurally similar protein search. This paper proposes indexing techniques which substantially reduce the search time to find structurally similar proteins. In particular, we first exploit two indexing techniques, i.e., iDistance and iKernel, on the 3DZDs. After that, we extend the techniques to further improve the search speed for protein structures. The extended indexing techniques build and utilize an reduced index constructed from the first few attributes of 3DZDs of protein structures. To retrieve top-k similar structures, top-10 × k similar structures are first found using the reduced index, and top-k structures are selected among them. We also modify the indexing techniques to support θ-based nearest neighbor search, which returns data points less than θ to the query point. The results show that both iDistance and iKernel significantly enhance the searching speed. In top-k nearest neighbor search, the searching time is reduced 69.6%, 77%, 77.4% and 87.9%, respectively using iDistance, iKernel, the extended iDistance, and the extended iKernel. In θ-based nearest neighbor serach, the searching time is reduced 80%, 81%, 95.6% and 95.6% using iDistance, iKernel, the extended iDistance, and the extended iKernel, respectively.

Pragmatic Abilities of Children with Williams Syndrome: A Longitudinal Examination

PubMed Central

John, Angela E.; Dobson, Lauren A.; Thomas, Lauren E.; Mervis, Carolyn B.

2012-01-01

Prior research has indicated that pragmatics is an area of particular weakness for individuals with Williams syndrome (WS). To further address this aspect of the WS social phenotype, we used an individual differences approach to consider both cross-sectional and longitudinal relations among different pragmatic abilities for 14 children with WS, taking into account individual differences in non-verbal reasoning abilities. We also considered the relations between pragmatic abilities and expressive vocabulary ability. Participants were tested at two time points: as 4-year-olds during a 30-min play session with their mothers (Time 1) and an average of 5.87 years later during a one-on-one conversation with a familiar researcher (Time 2). Children’s intellectual and expressive vocabulary abilities were assessed at both time points. Results indicated that the ability to verbally contribute information beyond what was required in response to a question (ExtendQ) was significantly related to the ability to verbally contribute new information in the absence of a question (ExtendS) both at age 4 years and during primary school. At age 4, both the ability to pair verbalizations with eye contact in triadic interactions (secondary intersubjectivity) and expressive vocabulary ability were related to both ExtendQ and ExtendS. Finally, both ExtendQ and the ability to pair verbalizations with eye contact (intersubjectivity) at age 4 years predicted ExtendQ at age 9–12 years. The theoretical implications of our findings and the importance of early pragmatic language intervention for children who have WS are discussed. PMID:22719734

Developmental Coordination Disorder in a Patient with Mental Disability and a Mild Phenotype Carrying Terminal 6q26-qter Deletion

PubMed Central

De Cinque, Marianna; Palumbo, Orazio; Mazzucco, Ermelinda; Simone, Antonella; Palumbo, Pietro; Ciavatta, Renata; Maria, Giuliana; Ferese, Rosangela; Gambardella, Stefano; Angiolillo, Antonella; Carella, Massimo; Garofalo, Silvio

2017-01-01

Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype–phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes. PMID:29270193

Translation of Genotype to Phenotype by a Hierarchy of Cell Subsystems.

PubMed

Yu, Michael Ku; Kramer, Michael; Dutkowski, Janusz; Srivas, Rohith; Licon, Katherine; Kreisberg, Jason; Ng, Cherie T; Krogan, Nevan; Sharan, Roded; Ideker, Trey

2016-02-24

Accurately translating genotype to phenotype requires accounting for the functional impact of genetic variation at many biological scales. Here we present a strategy for genotype-phenotype reasoning based on existing knowledge of cellular subsystems. These subsystems and their hierarchical organization are defined by the Gene Ontology or a complementary ontology inferred directly from previously published datasets. Guided by the ontology's hierarchical structure, we organize genotype data into an "ontotype," that is, a hierarchy of perturbations representing the effects of genetic variation at multiple cellular scales. The ontotype is then interpreted using logical rules generated by machine learning to predict phenotype. This approach substantially outperforms previous, non-hierarchical methods for translating yeast genotype to cell growth phenotype, and it accurately predicts the growth outcomes of two new screens of 2,503 double gene knockouts impacting DNA repair or nuclear lumen. Ontotypes also generalize to larger knockout combinations, setting the stage for interpreting the complex genetics of disease.

Neopolyploidy and diversification in Heuchera grossulariifolia

PubMed Central

Oswald, Benjamin P.; Nuismer, Scott L.

2013-01-01

Newly formed polyploid lineages must contend with several obstacles to avoid extinction, including minority cytotype exclusion, competition, and inbreeding depression. If polyploidization results in immediate divergence of phenotypic characters these hurdles may be reduced and establishment made more likely. In addition, if polyploidization alters the phenotypic and genotypic associations between traits, i.e. the P and G matrices, polyploids may be able to explore novel evolutionary paths, facilitating their divergence and successful establishment. Here we report results from a study of the perennial plant Heuchera grossulariifolia in which the phenotypic divergence and changes in phenotypic and genotypic covariance matrices caused by neopolyploidization have been estimated. Our results reveal that polyploidization causes immediate divergence for traits relevant to establishment and results in significant changes in the structure of the phenotypic covariance matrix. In contrast, our results do not provide evidence that polyploidization results in immediate and substantial shifts in the genetic covariance matrix. PMID:21143472

In Amnio MRI of Mouse Embryos

PubMed Central

Roberts, Thomas A.; Norris, Francesca C.; Carnaghan, Helen; Savery, Dawn; Wells, Jack A.; Siow, Bernard; Scambler, Peter J.; Pierro, Agostino; De Coppi, Paolo; Eaton, Simon; Lythgoe, Mark F.

2014-01-01

Mouse embryo imaging is conventionally carried out on ex vivo embryos excised from the amniotic sac, omitting vital structures and abnormalities external to the body. Here, we present an in amnio MR imaging methodology in which the mouse embryo is retained in the amniotic sac and demonstrate how important embryonic structures can be visualised in 3D with high spatial resolution (100 µm/px). To illustrate the utility of in amnio imaging, we subsequently apply the technique to examine abnormal mouse embryos with abdominal wall defects. Mouse embryos at E17.5 were imaged and compared, including three normal phenotype embryos, an abnormal embryo with a clear exomphalos defect, and one with a suspected gastroschisis phenotype. Embryos were excised from the mother ensuring the amnion remained intact and stereo microscopy was performed. Embryos were next embedded in agarose for 3D, high resolution MRI on a 9.4T scanner. Identification of the abnormal embryo phenotypes was not possible using stereo microscopy or conventional ex vivo MRI. Using in amnio MRI, we determined that the abnormal embryos had an exomphalos phenotype with varying severities. In amnio MRI is ideally suited to investigate the complex relationship between embryo and amnion, together with screening for other abnormalities located outside of the mouse embryo, providing a valuable complement to histology and existing imaging methods available to the phenotyping community. PMID:25330230

[Polymorphism and structure of the population of Proteocephalus longicollis Zeder, 1800 (Cestoda: Proteocephalidae) in the vendace Coregonus albula L].

PubMed

Anikieva, L V; Kharin, V N; Spektor, E N

2004-01-01

Polymorphism and phenotypic diversity of a hostal ecoform of Proteocephalus longicollis from its typical host, the vendace, Coregonus albula L., were studied. A complex phenotypic structure of the parasite population and presence of morphologically different groupings were revealed. We distinguished four groupings based on the external characters and three groupings based on the feed and reproduction features; among latter groupings one has very specific variations of features. We conclude that P. longicollis has high intraspecific and intrapopulation heterogeneity, and the host plays a stabilising role in the parasite species formation.

IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells.

PubMed

Mellough, Carla B; Collin, Joseph; Khazim, Mahmoud; White, Kathryn; Sernagor, Evelyne; Steel, David H W; Lako, Majlinda

2015-08-01

We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling. © 2015 AlphaMed Press.

Neuroanatomical correlates of negative emotionality-related traits: A systematic review and meta-analysis.

PubMed

Mincic, Adina M

2015-10-01

Two central traits present in the most influential models of personality characterize the response to positive and, respectively, negative emotional events. Negative emotionality (NE)-related traits are linked to vulnerability to mood and anxiety disorders; this has fuelled a special interest in examining stable differences in brain morphology associated to these traits. Structural imaging methods including voxel-based morphometry, cortical thickness analysis and diffusion tensor imaging (DTI) have yielded inconclusive and sometimes contradictory results. This review summarizes the findings reported to date through these methods and discusses them in relation to the functional imaging results. To detect topographic convergence between studies showing positive and, respectively, negative grey matter associations with NE-traits, activation likelihood estimation (ALE) meta-analyses of VBM studies were performed. Individuals scoring high on NE-related traits show consistent morphological differences in a left-lateralized circuit: higher grey matter volume (GMV) in amygdala and anterior parahippocampal gyrus and lower GMV in the orbitofrontal cortex extending into perigenual anterior cingulate cortex. Most DTI studies indicate reduced white matter integrity in various brain regions and tracts, particularly in the uncinate fasciculus and in cingulum bundle. These results show that the behavioural phenotype associated to NE traits is reflected in structural differences within the cortico-limbic system, suggesting alterations in information processing and transmission. The results are discussed from the perspective of neuron-glia interactions. Future directions are outlined based on recent developments in structural imaging techniques. Copyright © 2015 Elsevier Ltd. All rights reserved.

A real-time phenotyping framework using machine learning for plant stress severity rating in soybean.

PubMed

Naik, Hsiang Sing; Zhang, Jiaoping; Lofquist, Alec; Assefa, Teshale; Sarkar, Soumik; Ackerman, David; Singh, Arti; Singh, Asheesh K; Ganapathysubramanian, Baskar

2017-01-01

Phenotyping is a critical component of plant research. Accurate and precise trait collection, when integrated with genetic tools, can greatly accelerate the rate of genetic gain in crop improvement. However, efficient and automatic phenotyping of traits across large populations is a challenge; which is further exacerbated by the necessity of sampling multiple environments and growing replicated trials. A promising approach is to leverage current advances in imaging technology, data analytics and machine learning to enable automated and fast phenotyping and subsequent decision support. In this context, the workflow for phenotyping (image capture → data storage and curation → trait extraction → machine learning/classification → models/apps for decision support) has to be carefully designed and efficiently executed to minimize resource usage and maximize utility. We illustrate such an end-to-end phenotyping workflow for the case of plant stress severity phenotyping in soybean, with a specific focus on the rapid and automatic assessment of iron deficiency chlorosis (IDC) severity on thousands of field plots. We showcase this analytics framework by extracting IDC features from a set of ~4500 unique canopies representing a diverse germplasm base that have different levels of IDC, and subsequently training a variety of classification models to predict plant stress severity. The best classifier is then deployed as a smartphone app for rapid and real time severity rating in the field. We investigated 10 different classification approaches, with the best classifier being a hierarchical classifier with a mean per-class accuracy of ~96%. We construct a phenotypically meaningful 'population canopy graph', connecting the automatically extracted canopy trait features with plant stress severity rating. We incorporated this image capture → image processing → classification workflow into a smartphone app that enables automated real-time evaluation of IDC scores using digital images of the canopy. We expect this high-throughput framework to help increase the rate of genetic gain by providing a robust extendable framework for other abiotic and biotic stresses. We further envision this workflow embedded onto a high throughput phenotyping ground vehicle and unmanned aerial system that will allow real-time, automated stress trait detection and quantification for plant research, breeding and stress scouting applications.

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

amamutdb.no: A relational database for MAN2B1 allelic variants that compiles genotypes, clinical phenotypes, and biochemical and structural data of mutant MAN2B1 in α-mannosidosis.

PubMed

Riise Stensland, Hilde Monica Frostad; Frantzen, Gabrio; Kuokkanen, Elina; Buvang, Elisabeth Kjeldsen; Klenow, Helle Bagterp; Heikinheimo, Pirkko; Malm, Dag; Nilssen, Øivind

2015-06-01

α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding lysosomal α-mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes, and immunodeficiency. Here, we report an α-mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants (http://amamutdb.no). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional, and structural properties. The α-mannosidosis mutation database is comprehensive and relational in the sense that information can be retrieved and compiled across datasets; hence, it will facilitate diagnostics and increase our understanding of the clinical and molecular aspects of α-mannosidosis. We believe that the amamutdb.no structure and architecture will be applicable for the development of databases for any monogenic disorder. © 2015 WILEY PERIODICALS, INC.

Extracellular environment modulates the formation and propagation of particular amyloid structures

PubMed Central

Westergard, Laura; True, Heather L.

2016-01-01

Summary Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [PSI+] prion, endogenous to the yeast Saccharomyces cerevisiae, is a dominantly inherited, epigenetic modifier of phenotypes. [PSI+] formation relies on the coexistence of another prion, [RNQ+]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self-propagating amyloid structures of the Sup35 protein, called [PSI+] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [PSI+] that formed de novo. Additionally, we found that stress also influenced the association between the [PSI+] and [RNQ+] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [PSI+]-inducing capabilities of the [RNQ+] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross-species transmission barriers characteristic of prion diseases. PMID:24628771

The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

PubMed Central

Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

2014-01-01

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

[Phenotypic heterogeneity of chronic obstructive pulmonary disease].

PubMed

Garcia-Aymerich, Judith; Agustí, Alvar; Barberà, Joan A; Belda, José; Farrero, Eva; Ferrer, Antoni; Ferrer, Jaume; Gáldiz, Juan B; Gea, Joaquim; Gómez, Federico P; Monsó, Eduard; Morera, Josep; Roca, Josep; Sauleda, Jaume; Antó, Josep M

2009-03-01

A functional definition of chronic obstructive pulmonary disease (COPD) based on airflow limitation has largely dominated the field. However, a view has emerged that COPD involves a complex array of cellular, organic, functional, and clinical events, with a growing interest in disentangling the phenotypic heterogeneity of COPD. The present review is based on the opinion of the authors, who have extensive research experience in several aspects of COPD. The starting assumption of the review is that current knowledge on the pathophysiology and clinical features of COPD allows us to classify phenotypic information in terms of the following dimensions: respiratory symptoms and health status, acute exacerbations, lung function, structural changes, local and systemic inflammation, and systemic effects. Twenty-six phenotypic traits were identified and assigned to one of the 6 dimensions. For each dimension, a summary is provided of the best evidence on the relationships among phenotypic traits, in particular among those corresponding to different dimensions, and on the relationship between these traits and relevant events in the natural history of COPD. The information has been organized graphically into a phenotypic matrix where each cell representing a pair of phenotypic traits is linked to relevant references. The information provided has the potential to increase our understanding of the heterogeneity of COPD phenotypes and help us plan future studies on aspects that are as yet unexplored.

Essential role for the alpha 1 chain of type VIII collagen in zebrafish notochord formation.

PubMed

Gansner, John M; Gitlin, Jonathan D

2008-12-01

Several zebrafish mutants identified in large-scale forward genetic screens exhibit notochord distortion. We now report the cloning and further characterization of one such mutant, gulliver(m208) (gul(m208)). The notochord defect in gul(m208) mutants is exacerbated under conditions of copper depletion or lysyl oxidase cuproenzyme inhibition that are without a notochord effect on wild-type embryos. The gul(m208) phenotype results from a missense mutation in the gene encoding Col8a1, a lysyl oxidase substrate, and morpholino knockdown of col8a1 recapitulates the notochord distortion observed in gul(m208) mutants. Of interest, the amino acid mutated in gul(m208) Col8a1 is highly conserved, and the equivalent substitution in a closely related human protein, COL10A1, causes Schmid metaphyseal chondrodysplasia. Taken together, the data identify a new protein essential for notochord morphogenesis, extend our understanding of gene-nutrient interactions in early development, and suggest that human mutations in COL8A1 may cause structural birth defects. (c) 2008 Wiley-Liss, Inc.

Phenotypes, genome wide markers and structured genetic populations; a means to understand economically important traits in beta vulgaris and to inform the process of germplasm enhancement

USDA-ARS?s Scientific Manuscript database

Although hybrid seed systems in beet have been widely adopted due to profitability and productivity, the population remains the operational unit of beet improvement and thus characterizing populations in terms of markers and phenotypes is critical for novel trait discovery and eventual deployment of...

Neurophysiology of Drosophila Models of Parkinson's Disease

PubMed Central

West, Ryan J. H.; Furmston, Rebecca; Williams, Charles A. C.; Elliott, Christopher J. H.

2015-01-01

We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson's disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson's disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak's scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing. PMID:25960916

Identifying pleiotropic genes in genome-wide association studies from related subjects using the linear mixed model and Fisher combination function.

PubMed

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

2017-08-24

A multivariate genome-wide association test is proposed for analyzing data on multivariate quantitative phenotypes collected from related subjects. The proposed method is a two-step approach. The first step models the association between the genotype and marginal phenotype using a linear mixed model. The second step uses the correlation between residuals of the linear mixed model to estimate the null distribution of the Fisher combination test statistic. The simulation results show that the proposed method controls the type I error rate and is more powerful than the marginal tests across different population structures (admixed or non-admixed) and relatedness (related or independent). The statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that applying the multivariate association test may facilitate identification of the pleiotropic genes contributing to the risk for alcohol dependence commonly expressed by four correlated phenotypes. This study proposes a multivariate method for identifying pleiotropic genes while adjusting for cryptic relatedness and population structure between subjects. The two-step approach is not only powerful but also computationally efficient even when the number of subjects and the number of phenotypes are both very large.

Next-generation phenotyping: requirements and strategies for enhancing our understanding of genotype-phenotype relationships and its relevance to crop improvement.

PubMed

Cobb, Joshua N; Declerck, Genevieve; Greenberg, Anthony; Clark, Randy; McCouch, Susan

2013-04-01

More accurate and precise phenotyping strategies are necessary to empower high-resolution linkage mapping and genome-wide association studies and for training genomic selection models in plant improvement. Within this framework, the objective of modern phenotyping is to increase the accuracy, precision and throughput of phenotypic estimation at all levels of biological organization while reducing costs and minimizing labor through automation, remote sensing, improved data integration and experimental design. Much like the efforts to optimize genotyping during the 1980s and 1990s, designing effective phenotyping initiatives today requires multi-faceted collaborations between biologists, computer scientists, statisticians and engineers. Robust phenotyping systems are needed to characterize the full suite of genetic factors that contribute to quantitative phenotypic variation across cells, organs and tissues, developmental stages, years, environments, species and research programs. Next-generation phenotyping generates significantly more data than previously and requires novel data management, access and storage systems, increased use of ontologies to facilitate data integration, and new statistical tools for enhancing experimental design and extracting biologically meaningful signal from environmental and experimental noise. To ensure relevance, the implementation of efficient and informative phenotyping experiments also requires familiarity with diverse germplasm resources, population structures, and target populations of environments. Today, phenotyping is quickly emerging as the major operational bottleneck limiting the power of genetic analysis and genomic prediction. The challenge for the next generation of quantitative geneticists and plant breeders is not only to understand the genetic basis of complex trait variation, but also to use that knowledge to efficiently synthesize twenty-first century crop varieties.

Phenotype in girls and women with Turner syndrome: Association between dysmorphic features, karyotype and cardio-aortic malformations.

PubMed

Noordman, Iris; Duijnhouwer, Anthonie; Kapusta, Livia; Kempers, Marlies; Roeleveld, Nel; Schokking, Michiel; Smeets, Dominique; Freriks, Kim; Timmers, Henri; van Alfen-van der Velden, Janiëlle

2018-06-01

Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations. This prospective study investigated 14 dysmorphic features of TS girls and women using a checklist. Three major phenotypic patterns were recognized (severe phenotype, lymphatic phenotype and skeletal phenotype). Patient data including karyotype and cardio-aortic malformations (bicuspid aortic valve (BAV) and aortic coarctation (COA)) were collected. Associations between the prevalence of dysmorphic features, karyotype and cardio-aortic malformations were analysed using chi 2 -test and odds ratios. A total of 202 patients (84 girls and 118 women) were analysed prospectively. Differences in prevalence of dysmorphic features were found between girls and women. A strong association was found between monosomy 45,X and the phenotypic patterns. Furthermore, an association was found between COA and lymphatic phenotype, but no association was found between karyotype and cardio-aortic malformations. This study uncovered a difference in dysmorphic features between girls and women. Monosomy 45,X is associated with a more severe phenotype, lymphatic phenotype and skeletal phenotype. All patients with TS should be screened for cardio-aortic malformations, because in contrast to previous reports, karyotype and cardio-aortic malformations showed no significant association. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

An introduction to niche construction theory.

PubMed

Laland, Kevin; Matthews, Blake; Feldman, Marcus W

Niche construction refers to the modification of selective environments by organisms. Theoretical and empirical studies of niche construction are increasing in importance as foci in evolutionary ecology. This special edition presents theoretical and empirical research that illustrates the significance of niche construction to the field. Here we set the scene for the following papers by (1) discussing the history of niche construction research, (2) providing clear definitions that distinguish niche construction from related concepts such as ecosystem engineering and the extended phenotype, (3) providing a brief summary of the findings of niche construction research, (4) discussing the contribution of niche construction and ecological inheritance to (a) expanded notions of inheritance, and (b) the extended evolutionary synthesis, and (5) briefly touching on some of the issues that underlie the controversies over niche construction.

Development of a Phenotypic Method for Detection of Fecal Carriage of OXA-48-Producing Enterobacteriaceae after Incidental Detection from Clinical Specimen▿

PubMed Central

Ruppé, Etienne; Armand-Lefèvre, Laurence; Lolom, Isabelle; El Mniai, Assiya; Muller-Serieys, Claudette; Ruimy, Raymond; Woerther, Paul-Louis; Bilariki, Kalliopi; Marre, Michel; Massin, Philippe; Andremont, Antoine; Lucet, Jean-Christophe

2011-01-01

We report incidental isolation of an OXA-48-producing Escherichia coli strain in urine of a 62-year-old woman recently returning from a 2-month vacation in Morocco. Commercially available extended-spectrum beta-lactamase (ESBL)-targeting medium failed to detect it in the patient's stools, although a locally developed and easy-to-implement method using ertapenem-supplemented brain heart infusion (BHI) broths could. PMID:21562103

Have studies of the developmental regulation of behavioral phenotypes revealed the mechanisms of gene-environment interactions?

PubMed Central

Hall, F. Scott; Perona, Maria T. G.

2012-01-01

This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that are determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. PMID:22643448

Genetic methods for detection of antibiotic resistance: focus on extended-spectrum β-lactamases.

PubMed

Chroma, Magdalena; Kolar, Milan

2010-12-01

In 1928, the first antibiotic, penicillin, was discovered. That was the beginning of a great era in the development and prescription of antibiotics. However, the introduction of these antimicrobial agents into clinical practice was accompanied by the problem of antibiotic resistance. Currently, bacterial resistance to antibiotics poses a major problem in both hospital and community settings throughout the world. This review provides examples of modern genetic methods and their practical application in the field of extended-spectrum β-lactamase detection. Since extended-spectrum β-lactamases are the main mechanism of Gram-negative bacterial resistance to oxyimino-cephalosporins, rapid and accurate detection is requested in common clinical practice. Currently, the detection of extended-spectrum β-lactamases is primarily based on the determination of bacterial phenotypes rather than genotypes. This is because therapeutic decisions are based on assessing the susceptibility rather than presence of resistance genes. One of the main disadvantages of genetic methods is high costs, including those of laboratory equipment. On the other hand, if these modern methods are introduced into diagnostics, they often help in rapid and accurate detection of certain microorganisms or their resistance and pathogenic determinants.

The evolutionary legacy of size-selective harvesting extends from genes to populations

PubMed Central

Uusi-Heikkilä, Silva; Whiteley, Andrew R; Kuparinen, Anna; Matsumura, Shuichi; Venturelli, Paul A; Wolter, Christian; Slate, Jon; Primmer, Craig R; Meinelt, Thomas; Killen, Shaun S; Bierbach, David; Polverino, Giovanni; Ludwig, Arne; Arlinghaus, Robert

2015-01-01

Size-selective harvesting is assumed to alter life histories of exploited fish populations, thereby negatively affecting population productivity, recovery, and yield. However, demonstrating that fisheries-induced phenotypic changes in the wild are at least partly genetically determined has proved notoriously difficult. Moreover, the population-level consequences of fisheries-induced evolution are still being controversially discussed. Using an experimental approach, we found that five generations of size-selective harvesting altered the life histories and behavior, but not the metabolic rate, of wild-origin zebrafish (Danio rerio). Fish adapted to high positively size selective fishing pressure invested more in reproduction, reached a smaller adult body size, and were less explorative and bold. Phenotypic changes seemed subtle but were accompanied by genetic changes in functional loci. Thus, our results provided unambiguous evidence for rapid, harvest-induced phenotypic and evolutionary change when harvesting is intensive and size selective. According to a life-history model, the observed life-history changes elevated population growth rate in harvested conditions, but slowed population recovery under a simulated moratorium. Hence, the evolutionary legacy of size-selective harvesting includes populations that are productive under exploited conditions, but selectively disadvantaged to cope with natural selection pressures that often favor large body size. PMID:26136825

Genome-wide association study identifies 74 loci associated with educational attainment

PubMed Central

Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

2016-01-01

Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

Co-niche construction between hosts and symbionts: ideas and evidence.

PubMed

Borges, Renee M

2017-07-01

Symbiosis is a process that can generate evolutionary novelties and can extend the phenotypic niche space of organisms. Symbionts can act together with their hosts to co-construct host organs, within which symbionts are housed. Once established within hosts, symbionts can also influence various aspects of host phenotype, such as resource acquisition, protection from predation by acquisition of toxicity, as well as behaviour. Once symbiosis is established, its fidelity between generations must be ensured. Hosts evolve various mechanisms to screen unwanted symbionts and to facilitate faithful transmission of mutualistic partners between generations. Microbes are the most important symbionts that have influenced plant and animal phenotypes; multicellular organisms engage in developmental symbioses with microbes at many stages in ontogeny. The co-construction of niches may result in composite organisms that are physically nested within each other. While it has been advocated that these composite organisms need new evolutionary theories and perspectives to describe their properties and evolutionary trajectories, it appears that standard evolutionary theories are adequate to explore selection pressures on their composite or individual traits. Recent advances in our understanding of composite organisms open up many important questions regarding the stability and transmission of these units.

ASYMMETRY AND POLYMORPHISM OF HYBRID MALE STERILITY DURING THE EARLY STAGES OF SPECIATION IN HOUSE MICE

PubMed Central

Good, Jeffrey M.; Handel, Mary Ann; Nachman, Michael W.

2010-01-01

House mice offer a powerful system for dissecting the genetic basis of phenotypes that isolate species in the early stages of speciation. We used a series of reciprocal crosses between wild-derived strains of Mus musculus and M. domesticus to examine F1 hybrid male sterility, one of the primary phenotypes thought to isolate these species. We report four main results. First, we found significantly smaller testes and fewer sperm in hybrid male progeny of most crosses. Second, in some crosses hybrid male sterility was asymmetric and depended on the species origin of the X chromosome. These observations confirm and extend previous findings, underscoring the central role that the M. musculus X chromosome plays in reproductive isolation. Third, comparisons among reciprocal crosses revealed polymorphism at one or more hybrid incompatibilities within M. musculus. Fourth, the spermatogenic phenotype of this polymorphic interaction appears distinct from previously described hybrid incompatibilities between these species. These data build on previous studies of speciation in house mice and show that the genetic basis of hybrid male sterility is fairly complex, even at this early stage of divergence. PMID:18005156

Genome-wide association study identifies 74 loci associated with educational attainment.

PubMed

Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

2016-05-26

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Aminoacyl-tRNA synthetase deficiencies in search of common themes.

PubMed

Fuchs, Sabine A; Schene, Imre F; Kok, Gautam; Jansen, Jurriaan M; Nikkels, Peter G J; van Gassen, Koen L I; Terheggen-Lagro, Suzanne W J; van der Crabben, Saskia N; Hoeks, Sanne E; Niers, Laetitia E M; Wolf, Nicole I; de Vries, Maaike C; Koolen, David A; Houwen, Roderick H J; Mulder, Margot F; van Hasselt, Peter M

2018-06-06

Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

Multifactorial inheritance with cultural transmission and assortative mating. II. a general model of combined polygenic and cultural inheritance.

PubMed Central

Cloninger, C R; Rice, J; Reich, T

1979-01-01

A general linear model of combined polygenic-cultural inheritance is described. The model allows for phenotypic assortative mating, common environment, maternal and paternal effects, and genic-cultural correlation. General formulae for phenotypic correlation between family members in extended pedigrees are given for both primary and secondary assortative mating. A FORTRAN program BETA, available upon request, is used to provide maximum likelihood estimates of the parameters from reported correlations. American data about IQ and Burks' culture index are analyzed. Both cultural and genetic components of phenotypic variance are observed to make significant and substantial contributions to familial resemblance in IQ. The correlation between the environments of DZ twins is found to equal that of singleton sibs, not that of MZ twins. Burks' culture index is found to be an imperfect measure of midparent IQ rather than an index of home environment as previously assumed. Conditions under which the parameters of the model may be uniquely and precisely estimated are discussed. Interpretation of variance components in the presence of assortative mating and genic-cultural covariance is reviewed. A conservative, but robust, approach to the use of environmental indices is described. PMID:453202

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).

Revisiting Robustness and Evolvability: Evolution in Weighted Genotype Spaces

PubMed Central

Partha, Raghavendran; Raman, Karthik

2014-01-01

Robustness and evolvability are highly intertwined properties of biological systems. The relationship between these properties determines how biological systems are able to withstand mutations and show variation in response to them. Computational studies have explored the relationship between these two properties using neutral networks of RNA sequences (genotype) and their secondary structures (phenotype) as a model system. However, these studies have assumed every mutation to a sequence to be equally likely; the differences in the likelihood of the occurrence of various mutations, and the consequence of probabilistic nature of the mutations in such a system have previously been ignored. Associating probabilities to mutations essentially results in the weighting of genotype space. We here perform a comparative analysis of weighted and unweighted neutral networks of RNA sequences, and subsequently explore the relationship between robustness and evolvability. We show that assuming an equal likelihood for all mutations (as in an unweighted network), underestimates robustness and overestimates evolvability of a system. In spite of discarding this assumption, we observe that a negative correlation between sequence (genotype) robustness and sequence evolvability persists, and also that structure (phenotype) robustness promotes structure evolvability, as observed in earlier studies using unweighted networks. We also study the effects of base composition bias on robustness and evolvability. Particularly, we explore the association between robustness and evolvability in a sequence space that is AU-rich – sequences with an AU content of 80% or higher, compared to a normal (unbiased) sequence space. We find that evolvability of both sequences and structures in an AU-rich space is lesser compared to the normal space, and robustness higher. We also observe that AU-rich populations evolving on neutral networks of phenotypes, can access less phenotypic variation compared to normal populations evolving on neutral networks. PMID:25390641

The Plant Structure Ontology, a Unified Vocabulary of Anatomy and Morphology of a Flowering Plant1[W][OA

PubMed Central

Ilic, Katica; Kellogg, Elizabeth A.; Jaiswal, Pankaj; Zapata, Felipe; Stevens, Peter F.; Vincent, Leszek P.; Avraham, Shulamit; Reiser, Leonore; Pujar, Anuradha; Sachs, Martin M.; Whitman, Noah T.; McCouch, Susan R.; Schaeffer, Mary L.; Ware, Doreen H.; Stein, Lincoln D.; Rhee, Seung Y.

2007-01-01

Formal description of plant phenotypes and standardized annotation of gene expression and protein localization data require uniform terminology that accurately describes plant anatomy and morphology. This facilitates cross species comparative studies and quantitative comparison of phenotypes and expression patterns. A major drawback is variable terminology that is used to describe plant anatomy and morphology in publications and genomic databases for different species. The same terms are sometimes applied to different plant structures in different taxonomic groups. Conversely, similar structures are named by their species-specific terms. To address this problem, we created the Plant Structure Ontology (PSO), the first generic ontological representation of anatomy and morphology of a flowering plant. The PSO is intended for a broad plant research community, including bench scientists, curators in genomic databases, and bioinformaticians. The initial releases of the PSO integrated existing ontologies for Arabidopsis (Arabidopsis thaliana), maize (Zea mays), and rice (Oryza sativa); more recent versions of the ontology encompass terms relevant to Fabaceae, Solanaceae, additional cereal crops, and poplar (Populus spp.). Databases such as The Arabidopsis Information Resource, Nottingham Arabidopsis Stock Centre, Gramene, MaizeGDB, and SOL Genomics Network are using the PSO to describe expression patterns of genes and phenotypes of mutants and natural variants and are regularly contributing new annotations to the Plant Ontology database. The PSO is also used in specialized public databases, such as BRENDA, GENEVESTIGATOR, NASCArrays, and others. Over 10,000 gene annotations and phenotype descriptions from participating databases can be queried and retrieved using the Plant Ontology browser. The PSO, as well as contributed gene associations, can be obtained at www.plantontology.org. PMID:17142475

Most Colorful Example of Genetic Assimilation? Exploring the Evolutionary Destiny of Recurrent Phenotypic Accommodation.

PubMed

Badyaev, Alexander V; Potticary, Ahva L; Morrison, Erin S

2017-08-01

Evolution of adaptation requires both generation of novel phenotypic variation and retention of a locally beneficial subset of this variation. Such retention can be facilitated by genetic assimilation, the accumulation of genetic and molecular mechanisms that stabilize induced phenotypes and assume progressively greater control over their reliable production. A particularly strong inference into genetic assimilation as an evolutionary process requires a system where it is possible to directly evaluate the extent to which an induced phenotype is progressively incorporated into preexisting developmental pathways. Evolution of diet-dependent pigmentation in birds-where external carotenoids are coopted into internal metabolism to a variable degree before being integrated with a feather's developmental processes-provides such an opportunity. Here we combine a metabolic network view of carotenoid evolution with detailed empirical study of feather modifications to show that the effect of physical properties of carotenoids on feather structure depends on their metabolic modification, their environmental recurrence, and biochemical redundancy, as predicted by the genetic assimilation hypothesis. Metabolized carotenoids caused less stochastic variation in feather structure and were more closely integrated with feather growth than were dietary carotenoids of the same molecular weight. These patterns were driven by the recurrence of organism-carotenoid associations: commonly used dietary carotenoids and biochemically redundant derived carotenoids caused less stochastic variation in feather structure than did rarely used or biochemically unique compounds. We discuss implications of genetic assimilation processes for the evolutionary diversification of diet-dependent animal coloration.

Limited plasticity in the phenotypic variance-covariance matrix for male advertisement calls in the black field cricket, Teleogryllus commodus

PubMed Central

Pitchers, W. R.; Brooks, R.; Jennions, M. D.; Tregenza, T.; Dworkin, I.; Hunt, J.

2013-01-01

Phenotypic integration and plasticity are central to our understanding of how complex phenotypic traits evolve. Evolutionary change in complex quantitative traits can be predicted using the multivariate breeders’ equation, but such predictions are only accurate if the matrices involved are stable over evolutionary time. Recent work, however, suggests that these matrices are temporally plastic, spatially variable and themselves evolvable. The data available on phenotypic variance-covariance matrix (P) stability is sparse, and largely focused on morphological traits. Here we compared P for the structure of the complex sexual advertisement call of six divergent allopatric populations of the Australian black field cricket, Teleogryllus commodus. We measured a subset of calls from wild-caught crickets from each of the populations and then a second subset after rearing crickets under common-garden conditions for three generations. In a second experiment, crickets from each population were reared in the laboratory on high- and low-nutrient diets and their calls recorded. In both experiments, we estimated P for call traits and used multiple methods to compare them statistically (Flury hierarchy, geometric subspace comparisons and random skewers). Despite considerable variation in means and variances of individual call traits, the structure of P was largely conserved among populations, across generations and between our rearing diets. Our finding that P remains largely stable, among populations and between environmental conditions, suggests that selection has preserved the structure of call traits in order that they can function as an integrated unit. PMID:23530814

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease☆

PubMed Central

Bunzeck, Nico; Singh-Curry, Victoria; Eckart, Cindy; Weiskopf, Nikolaus; Perry, Richard J.; Bain, Peter G.; Düzel, Emrah; Husain, Masud

2013-01-01

Background In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population. Methods Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals. Results We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus. Conclusions Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease. PMID:24025315

A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data

PubMed Central

Zhu, Yun; Fan, Ruzong; Xiong, Momiao

2017-01-01

Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative internal representation and features from high dimensional genotype and phenotype data. To explore correlation information of genetic variants, effectively reduce data dimensions, and overcome critical barriers in advancing the development of novel statistical methods and computational algorithms for genetic pleiotropic analysis, we proposed a new statistic method referred to as a quadratically regularized functional CCA (QRFCCA) for association analysis which combines three approaches: (1) quadratically regularized matrix factorization, (2) functional data analysis and (3) canonical correlation analysis (CCA). Large-scale simulations show that the QRFCCA has a much higher power than that of the ten competing statistics while retaining the appropriate type 1 errors. To further evaluate performance, the QRFCCA and ten other statistics are applied to the whole genome sequencing dataset from the TwinsUK study. We identify a total of 79 genes with rare variants and 67 genes with common variants significantly associated with the 46 traits using QRFCCA. The results show that the QRFCCA substantially outperforms the ten other statistics. PMID:29040274

Human bony labyrinth is an indicator of population history and dispersal from Africa

PubMed Central

Ponce de León, Marcia S.; Koesbardiati, Toetik; Weissmann, John David; Milella, Marco; Reyna-Blanco, Carlos S.; Suwa, Gen; Kondo, Osamu; Malaspinas, Anna-Sapfo; White, Tim D.; Zollikofer, Christoph P. E.

2018-01-01

The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype–phenotype comparisons. PMID:29610337

Directional selection effects on patterns of phenotypic (co)variation in wild populations.

PubMed

Assis, A P A; Patton, J L; Hubbe, A; Marroig, G

2016-11-30

Phenotypic (co)variation is a prerequisite for evolutionary change, and understanding how (co)variation evolves is of crucial importance to the biological sciences. Theoretical models predict that under directional selection, phenotypic (co)variation should evolve in step with the underlying adaptive landscape, increasing the degree of correlation among co-selected traits as well as the amount of genetic variance in the direction of selection. Whether either of these outcomes occurs in natural populations is an open question and thus an important gap in evolutionary theory. Here, we documented changes in the phenotypic (co)variation structure in two separate natural populations in each of two chipmunk species (Tamias alpinus and T. speciosus) undergoing directional selection. In populations where selection was strongest (those of T. alpinus), we observed changes, at least for one population, in phenotypic (co)variation that matched theoretical expectations, namely an increase of both phenotypic integration and (co)variance in the direction of selection and a re-alignment of the major axis of variation with the selection gradient. © 2016 The Author(s).

Highly designable phenotypes and mutational buffers emerge from a systematic mapping between network topology and dynamic output.

PubMed

Nochomovitz, Yigal D; Li, Hao

2006-03-14

Deciphering the design principles for regulatory networks is fundamental to an understanding of biological systems. We have explored the mapping from the space of network topologies to the space of dynamical phenotypes for small networks. Using exhaustive enumeration of a simple model of three- and four-node networks, we demonstrate that certain dynamical phenotypes can be generated by an atypically broad spectrum of network topologies. Such dynamical outputs are highly designable, much like certain protein structures can be designed by an unusually broad spectrum of sequences. The network topologies that encode a highly designable dynamical phenotype possess two classes of connections: a fully conserved core of dedicated connections that encodes the stable dynamical phenotype and a partially conserved set of variable connections that controls the transient dynamical flow. By comparing the topologies and dynamics of the three- and four-node network ensembles, we observe a large number of instances of the phenomenon of "mutational buffering," whereby addition of a fourth node suppresses phenotypic variation amongst a set of three-node networks.

Predicting disease-related proteins based on clique backbone in protein-protein interaction network.

PubMed

Yang, Lei; Zhao, Xudong; Tang, Xianglong

2014-01-01

Network biology integrates different kinds of data, including physical or functional networks and disease gene sets, to interpret human disease. A clique (maximal complete subgraph) in a protein-protein interaction network is a topological module and possesses inherently biological significance. A disease-related clique possibly associates with complex diseases. Fully identifying disease components in a clique is conductive to uncovering disease mechanisms. This paper proposes an approach of predicting disease proteins based on cliques in a protein-protein interaction network. To tolerate false positive and negative interactions in protein networks, extending cliques and scoring predicted disease proteins with gene ontology terms are introduced to the clique-based method. Precisions of predicted disease proteins are verified by disease phenotypes and steadily keep to more than 95%. The predicted disease proteins associated with cliques can partly complement mapping between genotype and phenotype, and provide clues for understanding the pathogenesis of serious diseases.

Assessing Sociability, Social Memory, and Pup Retrieval in Mice.

PubMed

Zimprich, Annemarie; Niessing, Jörn; Cohen, Lior; Garrett, Lillian; Einicke, Jan; Sperling, Bettina; Schmidt, Mathias V; Hölter, Sabine M

2017-12-20

Adaptive social behavior is important in mammals, both for the well-being of the individual and for the thriving of the species. Dysfunctions in social behavior occur in many neurodevelopmental and psychiatric diseases, and research into the genetic components of disease-relevant social deficits can open up new avenues for understanding the underlying biological mechanisms and therapeutic interventions. Genetically modified mouse models are particularly useful in this respect, and robust experimental protocols are needed to reliably assess relevant social behavior phenotypes. Here we describe in detail three protocols to quantitatively measure sociability, one of the most frequently investigated social behavior phenotypes in mice, using a three-chamber sociability test. These protocols can be extended to also assess social memory. In addition, we provide a detailed protocol on pup retrieval, which is a particularly robust maternal behavior amenable to various scientific questions. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

A library of MiMICs allows tagging of genes and reversible, spatial and temporal knockdown of proteins in Drosophila

DOE PAGES

Nagarkar-Jaiswal, Sonal; Lee, Pei-Tseng; Campbell, Megan E.; ...

2015-03-31

Here, we document a collection of ~7434 MiMIC (Minos Mediated Integration Cassette) insertions of which 2854 are inserted in coding introns. They allowed us to create a library of 400 GFP-tagged genes. We show that 72% of internally tagged proteins are functional, and that more than 90% can be imaged in unfixed tissues. Moreover, the tagged mRNAs can be knocked down by RNAi against GFP (iGFPi), and the tagged proteins can be efficiently knocked down by deGradFP technology. The phenotypes associated with RNA and protein knockdown typically correspond to severe loss of function or null mutant phenotypes. Finally, we demonstratemore » reversible, spatial, and temporal knockdown of tagged proteins in larvae and adult flies. This new strategy and collection of strains allows unprecedented in vivo manipulations in flies for many genes. These strategies will likely extend to vertebrates.« less

Reinventing the ames test as a quantitative lab that connects classical and molecular genetics.

PubMed

Goodson-Gregg, Nathan; De Stasio, Elizabeth A

2009-01-01

While many institutions use a version of the Ames test in the undergraduate genetics laboratory, students typically are not exposed to techniques or procedures beyond qualitative analysis of phenotypic reversion, thereby seriously limiting the scope of learning. We have extended the Ames test to include both quantitative analysis of reversion frequency and molecular analysis of revertant gene sequences. By giving students a role in designing their quantitative methods and analyses, students practice and apply quantitative skills. To help students connect classical and molecular genetic concepts and techniques, we report here procedures for characterizing the molecular lesions that confer a revertant phenotype. We suggest undertaking reversion of both missense and frameshift mutants to allow a more sophisticated molecular genetic analysis. These modifications and additions broaden the educational content of the traditional Ames test teaching laboratory, while simultaneously enhancing students' skills in experimental design, quantitative analysis, and data interpretation.

Memory and modularity in cell-fate decision making

NASA Astrophysics Data System (ADS)

Norman, Thomas M.; Lord, Nathan D.; Paulsson, Johan; Losick, Richard

2013-11-01

Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. By observing thousands of cells for hundreds of consecutive generations under constant conditions, we dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is `memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.

Tumour model with intrusive morphology, progressive phenotypical heterogeneity and memory

NASA Astrophysics Data System (ADS)

Atangana, Abdon; Alqahtani, Rubayyi T.

2018-03-01

The model of a tumour, taking into account invasive morphology, progressive phenotypical heterogeneity and also memory, is developed and analyzed in this paper. Three models are investigated: first we consider the model describing the proliferation concentrates in proximity of tumour boundaries, in which the oxygen levels are pronounced. Then we consider the model where the oxygen around the tumour is considered to be unchanged by the vascular system. Finally, we investigate the model of growth of tumours using the concept of non-local operators with the Mittag-Leffler kernel. We provide the numerical solution using the extended 3/8 Simpson method for the new trends of fractional integration for the proliferation concentrates in the proximity of the tumour model. Then we provide the exact solutions of the Gompertz model with three different fractional differentiations involving power law, exponential decay law and the Mittag-Leffler law.

48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome

PubMed Central

Tartaglia, Nicole; Ayari, Natalie; Howell, Susan; D’Epagnier, Cheryl; Zeitler, Philip

2012-01-01

Sex chromosome tetrasomy and pentasomy conditions occur in 1:18 000–1:100 000 male births. While often compared with 47,XXY/Klinefelter syndrome because of shared features including tall stature and hypergonadotropic hypogonadism, 48,XXYY, 48,XXXY and 49,XXXXY syndromes are associated with additional physical findings, congenital malformations, medical problems and psychological features. While the spectrum of cognitive abilities extends much higher than originally described, developmental delays, cognitive impairments and behavioural disorders are common and require strong treatment plans. Future research should focus on genotype–phenotype relationships and the development of evidence-based treatments. Conclusion The more complex physical, medical and psychological phenotypes of 48,XXYY, 48,XXXY and 49,XXXXY syndromes make distinction from 47,XXY important; however, all of these conditions share features of hypergonadotropic hypogonadism and the need for increased awareness, biomedical research and the development of evidence-based treatments. PMID:21342258

Investigation of the multifunctional gene AOP3 expands the regulatory network fine-tuning glucosinolate production in Arabidopsis

PubMed Central

Jensen, Lea M.; Kliebenstein, Daniel J.; Burow, Meike

2015-01-01

Quantitative trait loci (QTL) mapping studies enable identification of loci that are part of regulatory networks controlling various phenotypes. Detailed investigations of genes within these loci are required to ultimately understand the function of individual genes and how they interact with other players in the network. In this study, we use transgenic plants in combination with natural variation to investigate the regulatory role of the AOP3 gene found in GS-AOP locus previously suggested to contribute to the regulation of glucosinolate defense compounds. Phenotypic analysis and QTL mapping in F2 populations with different AOP3 transgenes support that the enzymatic function and the AOP3 RNA both play a significant role in controlling glucosinolate accumulation. Furthermore, we find different loci interacting with either the enzymatic activity or the RNA of AOP3 and thereby extend the regulatory network controlling glucosinolate accumulation. PMID:26442075

49 CFR 229.5 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... of the end structures of a rail vehicle that extend vertically from the underframe to which they are... body structure of a locomotive. Fuel tank, internal means a fuel containment vessel that does not extend outside the car body structure of a locomotive. High voltage means an electrical potential of more...

PHENOstruct: Prediction of human phenotype ontology terms using heterogeneous data sources.

PubMed

Kahanda, Indika; Funk, Christopher; Verspoor, Karin; Ben-Hur, Asa

2015-01-01

The human phenotype ontology (HPO) was recently developed as a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. At present, only a small fraction of human protein coding genes have HPO annotations. But, researchers believe that a large portion of currently unannotated genes are related to disease phenotypes. Therefore, it is important to predict gene-HPO term associations using accurate computational methods. In this work we demonstrate the performance advantage of the structured SVM approach which was shown to be highly effective for Gene Ontology term prediction in comparison to several baseline methods. Furthermore, we highlight a collection of informative data sources suitable for the problem of predicting gene-HPO associations, including large scale literature mining data.

Preparation of Desirable Porous Cell Structure Polylactide/Wood Flour Composite Foams Assisted by Chain Extender

PubMed Central

Wang, Youyong; Song, Yongming; Du, Jun; Xi, Zhenhao; Wang, Qingwen

2017-01-01

Polylactide (PLA)/wood flour composite foam were prepared through a batch foaming process. The effect of the chain extender on the crystallization behavior and dynamic rheological properties of the PLA/wood flour composites were investigated as well as the crystal structure and cell morphology of the composite foams. The incorporation of the chain extender enhanced the complex viscosity and storage modulus of PLA/wood flour composites, indicating the improved melt elasticity. The chain extender also led to a decreased crystallization rate and final crystallinity of PLA/wood flour composites. With an increasing chain extender content, a finer and more uniform cell structure was formed, and the expansion ratio of PLA/wood flour composite foams was much higher than without the chain extender. Compared to the unfoamed composites, the crystallinity of the foamed PLA/wood flour composites was improved and the crystal was loosely packed. However, the new crystalline form was not evident. PMID:28846604

Performance of Extended Local Clustering Organization (LCO) for Large Scale Job-Shop Scheduling Problem (JSP)

NASA Astrophysics Data System (ADS)

Konno, Yohko; Suzuki, Keiji

This paper describes an approach to development of a solution algorithm of a general-purpose for large scale problems using “Local Clustering Organization (LCO)” as a new solution for Job-shop scheduling problem (JSP). Using a performance effective large scale scheduling in the study of usual LCO, a solving JSP keep stability induced better solution is examined. In this study for an improvement of a performance of a solution for JSP, processes to a optimization by LCO is examined, and a scheduling solution-structure is extended to a new solution-structure based on machine-division. A solving method introduced into effective local clustering for the solution-structure is proposed as an extended LCO. An extended LCO has an algorithm which improves scheduling evaluation efficiently by clustering of parallel search which extends over plural machines. A result verified by an application of extended LCO on various scale of problems proved to conduce to minimizing make-span and improving on the stable performance.

Tether mutations that restore function and suppress pleiotropic phenotypes of the C. elegans isp-1(qm150) Rieske iron–sulfur protein

PubMed Central

Jafari, Gholamali; Wasko, Brian M.; Tonge, Ashley; Schurman, Nathan; Dong, Cindy; Li, Zhongyu; Peters, Rebecca; Kayser, Ernst-Bernhard; Pitt, Jason N.; Morgan, Phil G.; Sedensky, Margaret M.; Crofts, Antony R.; Kaeberlein, Matt

2015-01-01

Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron–sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron–sulfur protein Rip1, revealing remarkable conservation of the structure–function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a “spring-loaded” model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity. PMID:26504246

Nonlinear Dynamics in Gene Regulation Promote Robustness and Evolvability of Gene Expression Levels.

PubMed

Steinacher, Arno; Bates, Declan G; Akman, Ozgur E; Soyer, Orkun S

2016-01-01

Cellular phenotypes underpinned by regulatory networks need to respond to evolutionary pressures to allow adaptation, but at the same time be robust to perturbations. This creates a conflict in which mutations affecting regulatory networks must both generate variance but also be tolerated at the phenotype level. Here, we perform mathematical analyses and simulations of regulatory networks to better understand the potential trade-off between robustness and evolvability. Examining the phenotypic effects of mutations, we find an inverse correlation between robustness and evolvability that breaks only with nonlinearity in the network dynamics, through the creation of regions presenting sudden changes in phenotype with small changes in genotype. For genotypes embedding low levels of nonlinearity, robustness and evolvability correlate negatively and almost perfectly. By contrast, genotypes embedding nonlinear dynamics allow expression levels to be robust to small perturbations, while generating high diversity (evolvability) under larger perturbations. Thus, nonlinearity breaks the robustness-evolvability trade-off in gene expression levels by allowing disparate responses to different mutations. Using analytical derivations of robustness and system sensitivity, we show that these findings extend to a large class of gene regulatory network architectures and also hold for experimentally observed parameter regimes. Further, the effect of nonlinearity on the robustness-evolvability trade-off is ensured as long as key parameters of the system display specific relations irrespective of their absolute values. We find that within this parameter regime genotypes display low and noisy expression levels. Examining the phenotypic effects of mutations, we find an inverse correlation between robustness and evolvability that breaks only with nonlinearity in the network dynamics. Our results provide a possible solution to the robustness-evolvability trade-off, suggest an explanation for the ubiquity of nonlinear dynamics in gene expression networks, and generate useful guidelines for the design of synthetic gene circuits.

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

PubMed Central

Kelly, Scott A.; Bell, Timothy A.; Selitsky, Sara R.; Buus, Ryan J.; Hua, Kunjie; Weinstock, George M.; Garland, Theodore; Pardo-Manuel de Villena, Fernando; Pomp, Daniel

2013-01-01

Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ∼100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4Minimsc. Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics. PMID:24056412

A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice.

PubMed

Kelly, Scott A; Bell, Timothy A; Selitsky, Sara R; Buus, Ryan J; Hua, Kunjie; Weinstock, George M; Garland, Theodore; Pardo-Manuel de Villena, Fernando; Pomp, Daniel

2013-12-01

Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ∼100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4(Minimsc). Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics.

Dissociation between sensitization and learning-related neuromodulation in an aplysiid species.

PubMed

Erixon, N J; Demartini, L J; Wright, W G

1999-06-14

Previous phylogenetic analyses of learning and memory in an opisthobranch lineage uncovered a correlation between two learning-related neuromodulatory traits and their associated behavioral phenotypes. In particular, serotonin-induced increases in sensory neuron spike duration and excitability, which are thought to underlie several facilitatory forms of learning in Aplysia, appear to have been lost over the course of evolution in a distantly related aplysiid, Dolabrifera dolabrifera. This deficit is paralleled by a behavioral deficit: individuals of Dolabrifera do not express generalized sensitization (reflex enhancement of an unhabituated response after a noxious stimulus is applied outside of the reflex receptive field) or dishabituation (reflex enhancement of a habituated reflex). The goal of the present study was to confirm and extend this correlation by testing for the neuromodulatory traits and generalized sensitization in an additional species, Phyllaplysia taylori, which is closely related to Dolabrifera. Instead, our results indicated a lack of correlation between the neuromodulatory and behavioral phenotypes. In particular, sensory neuron homologues in Phyllaplysia showed the ancestral neuromodulatory phenotype typified by Aplysia. Bath-applied 10 microM serotonin significantly increased homologue spike duration and excitability. However, when trained with the identical apparatus and protocols that produced generalized sensitization in Aplysia, individuals of Phyllaplysia showed no evidence of sensitization. Thus, this species expresses the neuromodulatory phenotype of its ancestors while appearing to express the behavioral phenotype of its near relative. These results suggests that generalized sensitization can be lost during the course of evolution in the absence of a deficit in these two neuromodulatory traits, and raises the possibility that the two traits may support some other form of behavioral plasticity in Phyllaplysia. The results also raise the question of the mechanistic basis of the behavioral deficit in Phyllaplysia.

Phenotypic Tests for the Detection of β-Lactamase-Producing Enterobacteriaceae Isolated from Different Environments.

PubMed

de Oliveira, Daniele V; Van Der Sand, Sueli T

2016-07-01

Some bacteria from the Enterobacteriaceae family are showing a significant capability to disseminate β-lactams resistance mechanisms among them, and these same mechanisms can be carried out from the hospital environment to superficial water. The aim of this study was to evaluate different phenotypic methods for the detection β-lactamases production by enterobacteria isolated from the anthropogenic environment: hospital wastewater and from a stream that cross the city of Porto Alegre. The applied tests were the modified Hodge test (MHT) and phenotypic tests with the following inhibitors: carbapenemase-phenylboronic acid (APB), metallo-β-lactamase-EDTA, AmpC β-lactamase-cloxacillin, and the confirmatory test for extended-spectrum β-lactamase (ESBL)-clavulanic acid. For this evaluation, 131 isolates were initially subjected to antibiogram using the following antimicrobials: cefotaxime (30 µg), cefpodoxime (10 μg), ceftazidime (30 µg), ertapenem (10 μg), meropenem (10 μg), and aztreonam (30 μg). After this first screening, 62 isolates showed a profile resistance for at least one antimicrobial. These isolates were subjected to all phenotypic tests. Of those, 40 isolates were positive for at least one phenotypic test. In MHT test, one isolate was positive and five were with inconclusive results. The results achieved with the inhibitors are as follows: APB 25/40 positive strains; EDTA 8/40 positive strains; and with CLOXA 2/40 positive strains. ESBL production was observed for 34/40 strains. This assessment shows a high level of bacteria which can produce enzymes that inactivate β-lactams present in the different environment like the stream waters and from the hospital settings.

Comparison of Molecular and Phenotypic Methods for the Detection and Characterization of Carbapenem Resistant Enterobacteriaceae.

PubMed

Somily, Ali M; Garaween, Ghada A; Abukhalid, Norah; Absar, Muhammad M; Senok, Abiola C

2016-03-01

In recent years, there has been a rapid dissemination of carbapenem resistant Enterobacteriaceae (CRE). This study aimed to compare phenotypic and molecular methods for detection and characterization of CRE isolates at a large tertiary care hospital in Saudi Arabia. This study was carried out between January 2011 and November 2013 at the King Khalid University Hospital (KKUH) in Saudi Arabia. Determination of presence of extended-spectrum beta-lactamases (ESBL) and carbapenem resistance was in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines. Phenotypic classification was done by the MASTDISCS(TM) ID inhibitor combination disk method. Genotypic characterization of ESBL and carbapenemase genes was performed by the Check-MDR CT102. Diversilab rep-PCR was used for the determination of clonal relationship. Of the 883 ESBL-positive Enterobacteriaceae detected during the study period, 14 (1.6%) isolates were carbapenem resistant. Both the molecular genotypic characterization and phenotypic testing were in agreement in the detection of all 8 metalo-beta-lactamases (MBL) producing isolates. Of these 8 MBL-producers, 5 were positive for blaNDM gene and 3 were positive for blaVIM gene. Molecular method identified additional blaOXA gene isolates while MASTDISCS(TM) ID detected one AmpC producer isolate. Both methods agreed in identifying 2 carbapenem resistant isolates which were negative for carbapenemase genes. Diversilab rep-PCR analysis of the 9 Klebsiella pneumoniae isolates revealed polyclonal distribution into eight clusters. MASTDISCS(TM) ID is a reliable simple cheap phenotypic method for detection of majority of carbapenemase genes with the exception of the blaOXA gene. We recommend to use such method in the clinical laboratory.

Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy.

PubMed

Schmied, Julie; Rupa, Prithy; Garvie, Sarah; Wilkie, Bruce

2013-07-15

The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use. Copyright © 2013 Elsevier B.V. All rights reserved.

Heritability of Measures of Kidney Disease Among Zuni Indians: The Zuni Kidney Project

PubMed Central

MacCluer, Jean W.; Scavini, Marina; Shah, Vallabh O.; Cole, Shelley A.; Laston, Sandra L.; Voruganti, V. Saroja; Paine, Susan S.; Eaton, Alfred J.; Comuzzie, Anthony G.; Tentori, Francesca; Pathak, Dorothy R.; Bobelu, Arlene; Bobelu, Jeanette; Ghahate, Donica; Waikaniwa, Mildred; Zager, Philip G.

2010-01-01

Background The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes. Study Design A community-based participatory research approach was used to recruit family members of individuals with kidney disease. Setting & Participants The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. Predictor Outcomes & Measurements Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was ≥0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria. Results Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes. Limitations Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions. Conclusions Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations. PMID:20646805

Predictable Phenotypes of Antibiotic Resistance Mutations.

PubMed

Knopp, M; Andersson, D I

2018-05-15

Antibiotic-resistant bacteria represent a major threat to our ability to treat bacterial infections. Two factors that determine the evolutionary success of antibiotic resistance mutations are their impact on resistance level and the fitness cost. Recent studies suggest that resistance mutations commonly show epistatic interactions, which would complicate predictions of their stability in bacterial populations. We analyzed 13 different chromosomal resistance mutations and 10 host strains of Salmonella enterica and Escherichia coli to address two main questions. (i) Are there epistatic interactions between different chromosomal resistance mutations? (ii) How does the strain background and genetic distance influence the effect of chromosomal resistance mutations on resistance and fitness? Our results show that the effects of combined resistance mutations on resistance and fitness are largely predictable and that epistasis remains rare even when up to four mutations were combined. Furthermore, a majority of the mutations, especially target alteration mutations, demonstrate strain-independent phenotypes across different species. This study extends our understanding of epistasis among resistance mutations and shows that interactions between different resistance mutations are often predictable from the characteristics of the individual mutations. IMPORTANCE The spread of antibiotic-resistant bacteria imposes an urgent threat to public health. The ability to forecast the evolutionary success of resistant mutants would help to combat dissemination of antibiotic resistance. Previous studies have shown that the phenotypic effects (fitness and resistance level) of resistance mutations can vary substantially depending on the genetic context in which they occur. We conducted a broad screen using many different resistance mutations and host strains to identify potential epistatic interactions between various types of resistance mutations and to determine the effect of strain background on resistance phenotypes. Combinations of several different mutations showed a large amount of phenotypic predictability, and the majority of the mutations displayed strain-independent phenotypes. However, we also identified a few outliers from these patterns, illustrating that the choice of host organism can be critically important when studying antibiotic resistance mutations. Copyright © 2018 Knopp and Andersson.

External validity of a hierarchical dimensional model of child and adolescent psychopathology: Tests using confirmatory factor analyses and multivariate behavior genetic analyses.

PubMed

Waldman, Irwin D; Poore, Holly E; van Hulle, Carol; Rathouz, Paul J; Lahey, Benjamin B

2016-11-01

Several recent studies of the hierarchical phenotypic structure of psychopathology have identified a General psychopathology factor in addition to the more expected specific Externalizing and Internalizing dimensions in both youth and adult samples and some have found relevant unique external correlates of this General factor. We used data from 1,568 twin pairs (599 MZ & 969 DZ) age 9 to 17 to test hypotheses for the underlying structure of youth psychopathology and the external validity of the higher-order factors. Psychopathology symptoms were assessed via structured interviews of caretakers and youth. We conducted phenotypic analyses of competing structural models using Confirmatory Factor Analysis and used Structural Equation Modeling and multivariate behavior genetic analyses to understand the etiology of the higher-order factors and their external validity. We found that both a General factor and specific Externalizing and Internalizing dimensions are necessary for characterizing youth psychopathology at both the phenotypic and etiologic levels, and that the 3 higher-order factors differed substantially in the magnitudes of their underlying genetic and environmental influences. Phenotypically, the specific Externalizing and Internalizing dimensions were slightly negatively correlated when a General factor was included, which reflected a significant inverse correlation between the nonshared environmental (but not genetic) influences on Internalizing and Externalizing. We estimated heritability of the general factor of psychopathology for the first time. Its moderate heritability suggests that it is not merely an artifact of measurement error but a valid construct. The General, Externalizing, and Internalizing factors differed in their relations with 3 external validity criteria: mother's smoking during pregnancy, parent's harsh discipline, and the youth's association with delinquent peers. Multivariate behavior genetic analyses supported the external validity of the 3 higher-order factors by suggesting that the General, Externalizing, and Internalizing factors were correlated with peer delinquency and parent's harsh discipline for different etiologic reasons. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof-of-concept and roadmap for future studies

PubMed Central

Anttila, Verneri; Hibar, Derrek P; van Hulzen, Kimm J E; Arias-Vasquez, Alejandro; Smoller, Jordan W; Nichols, Thomas E; Neale, Michael C; McIntosh, Andrew M; Lee, Phil; McMahon, Francis J; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A; Gruber, Oliver; Sachdev, Perminder S; Roiz-Santiañez, Roberto; Saykin, Andrew J; Ehrlich, Stefan; Mather, Karen A; Turner, Jessica A; Schwarz, Emanuel; Thalamuthu, Anbupalam; Shugart, Yin Yao; Ho, Yvonne YW; Martin, Nicholas G; Wright, Margaret J

2016-01-01

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between schizophrenia cases and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. The current study provides proof-of-concept (albeit based on a limited set of structural brain measures), and defines a roadmap for future studies investigating the genetic covariance between structural/functional brain phenotypes and risk for psychiatric disorders. PMID:26854805

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept.

PubMed

Franke, Barbara; Stein, Jason L; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P; van Hulzen, Kimm J E; Arias-Vasquez, Alejandro; Smoller, Jordan W; Nichols, Thomas E; Neale, Michael C; McIntosh, Andrew M; Lee, Phil; McMahon, Francis J; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A; Gruber, Oliver; Sachdev, Perminder S; Roiz-Santiañez, Roberto; Saykin, Andrew J; Ehrlich, Stefan; Mather, Karen A; Turner, Jessica A; Schwarz, Emanuel; Thalamuthu, Anbupalam; Shugart, Yin Yao; Ho, Yvonne Yw; Martin, Nicholas G; Wright, Margaret J; O'Donovan, Michael C; Thompson, Paul M; Neale, Benjamin M; Medland, Sarah E; Sullivan, Patrick F

2016-03-01

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs.

PubMed

Liu, Mei; Wu, Yonghui; Chen, Yukun; Sun, Jingchun; Zhao, Zhongming; Chen, Xue-wen; Matheny, Michael Edwin; Xu, Hua

2012-06-01

Adverse drug reaction (ADR) is one of the major causes of failure in drug development. Severe ADRs that go undetected until the post-marketing phase of a drug often lead to patient morbidity. Accurate prediction of potential ADRs is required in the entire life cycle of a drug, including early stages of drug design, different phases of clinical trials, and post-marketing surveillance. Many studies have utilized either chemical structures or molecular pathways of the drugs to predict ADRs. Here, the authors propose a machine-learning-based approach for ADR prediction by integrating the phenotypic characteristics of a drug, including indications and other known ADRs, with the drug's chemical structures and biological properties, including protein targets and pathway information. A large-scale study was conducted to predict 1385 known ADRs of 832 approved drugs, and five machine-learning algorithms for this task were compared. This evaluation, based on a fivefold cross-validation, showed that the support vector machine algorithm outperformed the others. Of the three types of information, phenotypic data were the most informative for ADR prediction. When biological and phenotypic features were added to the baseline chemical information, the ADR prediction model achieved significant improvements in area under the curve (from 0.9054 to 0.9524), precision (from 43.37% to 66.17%), and recall (from 49.25% to 63.06%). Most importantly, the proposed model successfully predicted the ADRs associated with withdrawal of rofecoxib and cerivastatin. The results suggest that phenotypic information on drugs is valuable for ADR prediction. Moreover, they demonstrate that different models that combine chemical, biological, or phenotypic information can be built from approved drugs, and they have the potential to detect clinically important ADRs in both preclinical and post-marketing phases.

Complex small-molecule architectures regulate phenotypic plasticity in a nematode.

PubMed

Bose, Neelanjan; Ogawa, Akira; von Reuss, Stephan H; Yim, Joshua J; Ragsdale, Erik J; Sommer, Ralf J; Schroeder, Frank C

2012-12-07

Chemistry the worm's way: The nematode Pristionchus pacificus constructs elaborate small molecules from modified building blocks of primary metabolism, including an unusual xylopyranose-based nucleoside (see scheme). These compounds act as signaling molecules to control adult phenotypic plasticity and dauer development and provide examples of modular generation of structural diversity in metazoans. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Are the Most Plastic Species the Most Abundant Ones? An Assessment Using a Fish Assemblage

PubMed Central

Vidal, Nicolás; Zaldúa, Natalia; D'Anatro, Alejandro; Naya, Daniel E.

2014-01-01

Few studies have evaluated phenotypic plasticity at the community level, considering, for example, plastic responses in an entire species assemblage. In addition, none of these studies have addressed the relationship between phenotypic plasticity and community structure. Within this context, here we assessed the magnitude of seasonal changes in digestive traits (seasonal flexibility), and of changes during short-term fasting (flexibility during fasting), occurring in an entire fish assemblage, comprising ten species, four trophic levels, and a 37-fold range in body mass. In addition, we analyzed the relationship between estimates of digestive flexibility and three basic assemblage structure attributes, i.e., species trophic position, body size, and relative abundance. We found that: (1) Seasonal digestive flexibility was not related with species trophic position or with body size; (2) Digestive flexibility during fasting tended to be inversely correlated with body size, as expected from scaling relationships; (3) Digestive flexibility, both seasonal and during fasting, was positively correlated with species relative abundance. In conclusion, the present study identified two trends in digestive flexibility in relation to assemblage structure, which represents an encouraging departure point in the search of general patterns in phenotypic plasticity at the local community scale. PMID:24651865

An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster.

PubMed

Bauer, Johannes H; Goupil, Stephan; Garber, Graham B; Helfand, Stephen L

2004-08-31

Recent advances in aging research have uncovered genes and genetic pathways that influence lifespan in such diverse organisms as yeast, nematodes, flies, and mice. The discovery of genes and drugs that affect lifespan has been delayed by the absence of a phenotype other than survivorship, which depends on the measurement of age at death of individuals in a population. The use of survivorship to identify genetic and pharmacological interventions that prolong life is time-consuming and requires a large number of homogeneous animals. Here, we report the development of an assay in Drosophila melanogaster using the expression of molecular biomarkers that accelerates the ability to evaluate potential lifespan-altering interventions. Coupling the expression of an age-dependent molecular biomarker to a lethal toxin reduces the time needed to perform lifespan studies by 80%. The assay recapitulates the effect of the three best known environmental life-span-extending interventions in the fly: ambient temperature, reproductive status, and calorie reduction. Single gene mutations known to extend lifespan in the fly such as Indy and rpd3 also extend lifespan in this assay. We used this assay as a screen to identify drugs that extend lifespan in flies. Lipoic acid and resveratrol were identified as being beneficial in our assay and shown to extend lifespan under normal laboratory conditions. We propose that this assay can be used to screen pharmacological as well as genetic interventions more rapidly for positive effects on lifespan. Copyright 2004 The National Academy of Sciencs of the USA

An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster

PubMed Central

Bauer, Johannes H.; Goupil, Stephan; Garber, Graham B.; Helfand, Stephen L.

2004-01-01

Recent advances in aging research have uncovered genes and genetic pathways that influence lifespan in such diverse organisms as yeast, nematodes, flies, and mice. The discovery of genes and drugs that affect lifespan has been delayed by the absence of a phenotype other than survivorship, which depends on the measurement of age at death of individuals in a population. The use of survivorship to identify genetic and pharmacological interventions that prolong life is time-consuming and requires a large number of homogeneous animals. Here, we report the development of an assay in Drosophila melanogaster using the expression of molecular biomarkers that accelerates the ability to evaluate potential lifespan-altering interventions. Coupling the expression of an age-dependent molecular biomarker to a lethal toxin reduces the time needed to perform lifespan studies by 80%. The assay recapitulates the effect of the three best known environmental life-span-extending interventions in the fly: ambient temperature, reproductive status, and calorie reduction. Single gene mutations known to extend lifespan in the fly such as Indy and rpd3 also extend lifespan in this assay. We used this assay as a screen to identify drugs that extend lifespan in flies. Lipoic acid and resveratrol were identified as being beneficial in our assay and shown to extend lifespan under normal laboratory conditions. We propose that this assay can be used to screen pharmacological as well as genetic interventions more rapidly for positive effects on lifespan. PMID:15328413

Comparing Mycobacterium tuberculosis genomes using genome topology networks.

PubMed

Jiang, Jianping; Gu, Jianlei; Zhang, Liang; Zhang, Chenyi; Deng, Xiao; Dou, Tonghai; Zhao, Guoping; Zhou, Yan

2015-02-14

Over the last decade, emerging research methods, such as comparative genomic analysis and phylogenetic study, have yielded new insights into genotypes and phenotypes of closely related bacterial strains. Several findings have revealed that genomic structural variations (SVs), including gene gain/loss, gene duplication and genome rearrangement, can lead to different phenotypes among strains, and an investigation of genes affected by SVs may extend our knowledge of the relationships between SVs and phenotypes in microbes, especially in pathogenic bacteria. In this work, we introduce a 'Genome Topology Network' (GTN) method based on gene homology and gene locations to analyze genomic SVs and perform phylogenetic analysis. Furthermore, the concept of 'unfixed ortholog' has been proposed, whose members are affected by SVs in genome topology among close species. To improve the precision of 'unfixed ortholog' recognition, a strategy to detect annotation differences and complete gene annotation was applied. To assess the GTN method, a set of thirteen complete M. tuberculosis genomes was analyzed as a case study. GTNs with two different gene homology-assigning methods were built, the Clusters of Orthologous Groups (COG) method and the orthoMCL clustering method, and two phylogenetic trees were constructed accordingly, which may provide additional insights into whole genome-based phylogenetic analysis. We obtained 24 unfixable COG groups, of which most members were related to immunogenicity and drug resistance, such as PPE-repeat proteins (COG5651) and transcriptional regulator TetR gene family members (COG1309). The GTN method has been implemented in PERL and released on our website. The tool can be downloaded from http://homepage.fudan.edu.cn/zhouyan/gtn/ , and allows re-annotating the 'lost' genes among closely related genomes, analyzing genes affected by SVs, and performing phylogenetic analysis. With this tool, many immunogenic-related and drug resistance-related genes were found to be affected by SVs in M. tuberculosis genomes. We believe that the GTN method will be suitable for the exploration of genomic SVs in connection with biological features of bacterial strains, and that GTN-based phylogenetic analysis will provide additional insights into whole genome-based phylogenetic analysis.

Cold-Adapted Viral Attenuation (CAVA): Highly Temperature Sensitive Polioviruses as Novel Vaccine Strains for a Next Generation Inactivated Poliovirus Vaccine

PubMed Central

Sanders, Barbara P.; de los Rios Oakes, Isabel; van Hoek, Vladimir; Bockstal, Viki; Kamphuis, Tobias; Uil, Taco G.; Song, Yutong; Cooper, Gillian; Crawt, Laura E.; Martín, Javier; Zahn, Roland; Lewis, John; Wimmer, Eckard; Custers, Jerome H. H. V.; Schuitemaker, Hanneke; Cello, Jeronimo; Edo-Matas, Diana

2016-01-01

The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4–9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive PER.C6 cell culture platform, the stably attenuated CAVA strains may serve as an attractive low-cost and (bio)safe option for the production of a novel next generation IPV. PMID:27032093

Cold-Adapted Viral Attenuation (CAVA): Highly Temperature Sensitive Polioviruses as Novel Vaccine Strains for a Next Generation Inactivated Poliovirus Vaccine.

PubMed

Sanders, Barbara P; de Los Rios Oakes, Isabel; van Hoek, Vladimir; Bockstal, Viki; Kamphuis, Tobias; Uil, Taco G; Song, Yutong; Cooper, Gillian; Crawt, Laura E; Martín, Javier; Zahn, Roland; Lewis, John; Wimmer, Eckard; Custers, Jerome H H V; Schuitemaker, Hanneke; Cello, Jeronimo; Edo-Matas, Diana

2016-03-01

The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4-9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive PER.C6 cell culture platform, the stably attenuated CAVA strains may serve as an attractive low-cost and (bio)safe option for the production of a novel next generation IPV.

A quantitative study of shape descriptors from glioblastoma multiforme phenotypes for predicting survival outcome

PubMed Central

Desrosiers, Christian; Hassan, Lama; Tanougast, Camel

2016-01-01

Objective: Predicting the survival outcome of patients with glioblastoma multiforme (GBM) is of key importance to clinicians for selecting the optimal course of treatment. The goal of this study was to evaluate the usefulness of geometric shape features, extracted from MR images, as a potential non-invasive way to characterize GBM tumours and predict the overall survival times of patients with GBM. Methods: The data of 40 patients with GBM were obtained from the Cancer Genome Atlas and Cancer Imaging Archive. The T1 weighted post-contrast and fluid-attenuated inversion-recovery volumes of patients were co-registered and segmented into delineate regions corresponding to three GBM phenotypes: necrosis, active tumour and oedema/invasion. A set of two-dimensional shape features were then extracted slicewise from each phenotype region and combined over slices to describe the three-dimensional shape of these phenotypes. Thereafter, a Kruskal–Wallis test was employed to identify shape features with significantly different distributions across phenotypes. Moreover, a Kaplan–Meier analysis was performed to find features strongly associated with GBM survival. Finally, a multivariate analysis based on the random forest model was used for predicting the survival group of patients with GBM. Results: Our analysis using the Kruskal–Wallis test showed that all but one shape feature had statistically significant differences across phenotypes, with p-value < 0.05, following Holm–Bonferroni correction, justifying the analysis of GBM tumour shapes on a per-phenotype basis. Furthermore, the survival analysis based on the Kaplan–Meier estimator identified three features derived from necrotic regions (i.e. Eccentricity, Extent and Solidity) that were significantly correlated with overall survival (corrected p-value < 0.05; hazard ratios between 1.68 and 1.87). In the multivariate analysis, features from necrotic regions gave the highest accuracy in predicting the survival group of patients, with a mean area under the receiver-operating characteristic curve (AUC) of 63.85%. Combining the features of all three phenotypes increased the mean AUC to 66.99%, suggesting that shape features from different phenotypes can be used in a synergic manner to predict GBM survival. Conclusion: Results show that shape features, in particular those extracted from necrotic regions, can be used effectively to characterize GBM tumours and predict the overall survival of patients with GBM. Advances in knowledge: Simple volumetric features have been largely used to characterize the different phenotypes of a GBM tumour (i.e. active tumour, oedema and necrosis). This study extends previous work by considering a wide range of shape features, extracted in different phenotypes, for the prediction of survival in patients with GBM. PMID:27781499

Uniparental disomy and prenatal phenotype

PubMed Central

Li, Xiaofei; Liu, Yan; Yue, Song; Wang, Li; Zhang, Tiejuan; Guo, Cuixia; Hu, Wenjie; Kagan, Karl-Oliver; Wu, Qingqing

2017-01-01

Abstract Rationale: Uniparental disomy (UPD) gives a description of the inheritance of both homologues of a chromosome pair from the same parent. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin. Patient concerns: We report prenatal phenotypes of 2 rare cases of UPD. Diagnoses: The prenatal phenotype of case 1 included sonographic markers such as enlarged nuchal translucency (NT), absent nasal bone, short femur and humerus length, and several structural malformations involving Dandy–Walker malformation and congenital heart defects. The prenatal phenotype of Case 2 are sonographic markers, including enlarged NT, thickened nuchal fold, ascites, and polyhydramnios without apparent structural malformations. Interventions: Conventional G-band karyotype appears normal in case 1, while it shows normal chromosomes with a small supernumerary marker chromosome (sSMC) in case 2. Genetic etiology was left unknown until single-nucleotide polymorphism-based array (SNP-array) was performed, and segmental paternal UPD 22 was identified in case 1 and segmental paternal UPD 14 was found in case 2. Outcomes: The parents of case 1 chose termination of pregnancy. The neonate of case 2 was born prematurely with a bellshaped small thorax and died within a day. Lessons: UPD cases are rare and the phenotypes are different, which depend on the origin and affected chromosomal part. If a fetus shows multiple anomalies that cannot be attributed to a common aneuploidy or a genetic syndrome, or manifests some features possibly related to an UPD syndrome, such as detection of sSMC, SNP-array should be considered. PMID:29137034

Uniparental disomy and prenatal phenotype: Two case reports and review.

PubMed

Li, Xiaofei; Liu, Yan; Yue, Song; Wang, Li; Zhang, Tiejuan; Guo, Cuixia; Hu, Wenjie; Kagan, Karl-Oliver; Wu, Qingqing

2017-11-01

Uniparental disomy (UPD) gives a description of the inheritance of both homologues of a chromosome pair from the same parent. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin. We report prenatal phenotypes of 2 rare cases of UPD. The prenatal phenotype of case 1 included sonographic markers such as enlarged nuchal translucency (NT), absent nasal bone, short femur and humerus length, and several structural malformations involving Dandy-Walker malformation and congenital heart defects. The prenatal phenotype of Case 2 are sonographic markers, including enlarged NT, thickened nuchal fold, ascites, and polyhydramnios without apparent structural malformations. Conventional G-band karyotype appears normal in case 1, while it shows normal chromosomes with a small supernumerary marker chromosome (sSMC) in case 2. Genetic etiology was left unknown until single-nucleotide polymorphism-based array (SNP-array) was performed, and segmental paternal UPD 22 was identified in case 1 and segmental paternal UPD 14 was found in case 2. The parents of case 1 chose termination of pregnancy. The neonate of case 2 was born prematurely with a bellshaped small thorax and died within a day. UPD cases are rare and the phenotypes are different, which depend on the origin and affected chromosomal part. If a fetus shows multiple anomalies that cannot be attributed to a common aneuploidy or a genetic syndrome, or manifests some features possibly related to an UPD syndrome, such as detection of sSMC, SNP-array should be considered.

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

PubMed Central

Schutzman, Jennifer L.; Borland, Christina Z.; Newman, John C.; Robinson, Matthew K.; Kokel, Michelle; Stern, Michael J.

2001-01-01

EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15. PMID:11689700

Comparative study of the organisation and phenotypes of bladder interstitial cells in human, mouse and rat.

PubMed

Gevaert, Thomas; Neuhaus, Jochen; Vanstreels, Els; Daelemans, Dirk; Everaerts, Wouter; Der Aa, Frank Van; Timmermans, Jean-Pierre; Roskams, Tania; Steiner, Clara; Pintelon, Isabel; De Ridder, Dirk

2017-12-01

With most research on interstitial cells (IC) in the bladder being conducted on animal models, it remains unclear whether all structural and functional data on IC from animal models can be translated to the human context. This prompted us to compare the structural and immunohistochemical properties of IC in bladders from mouse, rat and human. Tissue samples were obtained from the bladder dome and subsequently processed for immunohistochemistry and electron microscopy. The ultrastructural properties of IC were compared by means of electron microscopy and IC were additionally characterized with single/double immunohistochemistry/immunofluorescence. Our results reveal a similar organization of the IC network in the upper lamina propria (ULP), the deep lamina propria (DLP) and the detrusor muscle in human, rat and mouse bladders. Furthermore, despite several similarities in IC phenotypes, we also found several obvious inter-species differences in IC, especially in the ULP. Most remarkably in this respect, ULP IC in human bladder predominantly displayed a myoid phenotype with abundant presence of contractile micro-filaments, while those in rat and mouse bladders showed a fibroblast phenotype. In conclusion, the organization of ULP IC, DLP IC and detrusor IC is comparable in human, rat and mouse bladders, although several obvious inter-species differences in IC phenotypes were found. The present data show that translating research data on IC in laboratory animals to the human setting should be carried out with caution.

Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population

PubMed Central

2006-01-01

Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988ΔA = 352stop), otoancorin (1067A >T = D356V) and pendrin (716T > A = V239D and 1001G > T = 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide. PMID:16460646

New Real-Time PCR Assays for Detection of Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Group.

PubMed

Shallom, Shamira J; Moura, Natalia S; Olivier, Kenneth N; Sampaio, Elizabeth P; Holland, Steven M; Zelazny, Adrian M

2015-11-01

Members of the Mycobacterium abscessus group (MAG) cause lung, soft tissue, and disseminated infections. The oral macrolides clarithromycin and azithromycin are commonly used for treatment. MAG can display clarithromycin resistance through the inducible erm(41) gene or via acquired mutations in the rrl (23S rRNA) gene. Strains harboring a truncation or a T28C substitution in erm(41) lose the inducible resistance trait. Phenotypic detection of clarithromycin resistance requires extended incubation (14 days), highlighting the need for faster methods to detect resistance. Two real-time PCR-based assays were developed to assess inducible and acquired clarithromycin resistance and tested on a total of 90 clinical and reference strains. A SYBR green assay was designed to distinguish between a full-length and truncated erm(41) gene by temperature shift in melting curve analysis. Single nucleotide polymorphism (SNP) allele discrimination assays were developed to distinguish T or C at position 28 of erm(41) and 23S rRNA rrl gene mutations at position 2058 and/or 2059. Truncated and full-size erm(41) genes were detected in 21/90 and 69/90 strains, respectively, with 64/69 displaying T at nucleotide position 28 and 5/69 containing C at that position. Fifteen isolates showed rrl mutations conferring clarithromycin resistance, including A2058G (11 isolates), A2058C (3 isolates), and A2059G (1 isolate). Targeted sequencing and phenotypic assessment of resistance concurred with molecular assay results. Interestingly, we also noted cooccurring strains harboring an active erm(41), inactive erm(41), and/or acquired mutational resistance, as well as slowly growing MAG strains and also strains displaying an inducible resistance phenotype within 5 days, long before the recommended 14-day extended incubation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease.

PubMed

Ertekin-Taner, Nilüfer; Allen, Mariet; Fadale, Daniel; Scanlin, Leah; Younkin, Linda; Petersen, Ronald C; Graff-Radford, Neill; Younkin, Steven G

2004-04-01

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p=0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p=0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD. Copyright 2004 Wiley-Liss, Inc.

Nanoscale Morphology of Type I Collagen is Altered in the Brtl Mouse Model of Osteogenesis Imperfecta

PubMed Central

Wallace, Joseph M.; Orr, Bradford G.; Marini, Joan C.; Banaszak Holl, Mark M.

2010-01-01

Bone has a complex hierarchical structure that has evolved to serve structural and metabolic roles in the body. Due to the complexity of bone structure and the number of diseases which affect the ultrastructural constituents of bone, it is important to develop quantitative methods to assess bone nanoscale properties. Autosomal dominant Osteogenesis Imperfecta results predominantly from glycine substitutions (80%) and splice site mutations (20%) in the genes encoding the α1 or α2 chains of Type I collagen. Genotype-phenotype correlations using over 830 collagen mutations have revealed that lethal mutations are located in regions crucial for collagen-ligand binding in the matrix. However, few of these correlations have been extended to collagen structure in bone. Here, an atomic force microscopy-based approach was used to image and quantitatively analyze the D-periodic spacing of Type I collagen fibrils in femora from heterozygous (Brtl/+) mice (α1(I)G349C), compared to wild type (WT) littermates. This disease system has a well-defined change in the col1α1 allele, leading to a well characterized alteration in collagen protein structure, which are directly related to altered Type I collagen nanoscale morphology, as measured by the D-periodic spacing. In Brtl/+ bone, the D-periodic spacing shows significantly greater variability on average and along the length of the bone compared to WT, although the average spacing was unchanged. Brtl/+ bone also had a significant difference in the population distribution of collagen D-period spacings. These changes may be due to the mutant collagen structure, or to the heterogeneity of collagen monomers in the Brtl/+ matrix. These observations at the nanoscale level provide insight into the structural basis for changes present in bone composition, geometry and mechanical integrity in Brtl/+ bones. Further studies are necessary to link these morphological observations to nanoscale mechanical integrity. PMID:20696252

Thermal shields for gas turbine rotor

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

Ross, Christopher W.; Acar, Bulent

A turbomachine including a rotor having an axis and a plurality of disks positioned adjacent to each other in the axial direction, each disk including opposing axially facing surfaces and a circumferentially extending radially facing surface located between the axially facing surfaces. At least one row of blades is positioned on each of the disks, and the blades include an airfoil extending radially outward from the disk A non-segmented circumferentially continuous ring structure includes an outer rim defining a thermal barrier extending axially in overlapping relation over a portion of the radially facing surface of at least one disk, andmore » extending to a location adjacent to a blade on the disk A compliant element is located between a radially inner circumferential portion of the ring structure and a flange structure that extends axially from an axially facing surface of the disk.« less

Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi–Goutières and Singleton–Merten syndromes

PubMed Central

Bursztejn, A.-C.; Briggs, T.A.; del Toro Duany, Y.; Anderson, B.H.; O’Sullivan, J.; Williams, S.G.; Bodemer, C.; Fraitag, S.; Gebhard, F.; Leheup, B.; Lemelle, I.; Oojageer, A.; Raffo, E.; Schmitt, E.; Rice, G.I.; Hur, S.; Crow, Y.J.

2016-01-01

Summary Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi–Goutières syndrome. To date, seven genes related to Aicardi–Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi–Goutières syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi–Goutières syndrome and Singleton–Merten syndrome. PMID:26284909

Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency

PubMed Central

Bone, William P.; Washington, Nicole L.; Buske, Orion J.; Adams, David R.; Davis, Joie; Draper, David; Flynn, Elise D.; Girdea, Marta; Godfrey, Rena; Golas, Gretchen; Groden, Catherine; Jacobsen, Julius; Köhler, Sebastian; Lee, Elizabeth M. J.; Links, Amanda E.; Markello, Thomas C.; Mungall, Christopher J.; Nehrebecky, Michele; Robinson, Peter N.; Sincan, Murat; Soldatos, Ariane G.; Tifft, Cynthia J.; Toro, Camilo; Trang, Heather; Valkanas, Elise; Vasilevsky, Nicole; Wahl, Colleen; Wolfe, Lynne A.; Boerkoel, Cornelius F.; Brudno, Michael; Haendel, Melissa A.; Gahl, William A.; Smedley, Damian

2016-01-01

Purpose: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles. Genet Med 18 6, 608–617. Methods: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease–gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein–protein association neighbors. Genet Med 18 6, 608–617. Results: Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease–gene associations and ranked the correct seeded variant in up to 87% when detectable disease–gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation. Genet Med 18 6, 608–617. Conclusion: Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders. Genet Med 18 6, 608–617. PMID:26562225

The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype

PubMed Central

Thayer, Patrick; Balachandran, Kartik; Rathan, Swetha; Yap, Choon Hwai; Arjunon, Sivakkumar; Jo, Hanjoong; Yoganathan, Ajit P.

2017-01-01

Aortic valve interstitial cells (VIC) can exhibit phenotypic characteristics of fibroblasts, myofibroblasts, and smooth muscle cells. Others have proposed that valve cells become activated and exhibit myofibroblast or fibroblast characteristics during disease initiation and progression; however, the cues that modulate this phenotypic change remain unclear. We hypothesize that the mechanical forces experienced by the valve play a role in regulating the native phenotype of the valve and that altered mechanical forces result in an activated phenotype. Using a novel ex vivo cyclic stretch and pressure bioreactor, we subjected porcine aortic valve (AV) leaflets to combinations of normal and pathological stretch and pressure magnitudes. The myofibroblast markers α-SMA and Vimentin, along with the smooth muscle markers Calponin and Caldesmon, were analyzed using immunohistochemistry and immunoblotting. Tissue structure was analyzed using Movat’s pentachrome staining. We report that pathological stretch and pressure inhibited the contractile and possibly myofibroblast phenotypes as indicated by downregulation of the proteins α-SMA, Vimentin, and Calponin. In particular, Calponin downregulation implies depolymerization of actin filaments and possible conversion to a more synthetic (non-contractile) phenotype. This agreed well with the increase in spongiosa and fibrosa thickness observed under elevated pressure and stretch that are typically indicative of increased matrix synthesis. Our study therefore demonstrates how cyclic stretch and pressure may possibly act together to modulate the AVIC phenotype. PMID:21347552

Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping

PubMed Central

Wu, Yijen L.; Lo, Cecilia W.

2017-01-01

Small animal models, particularly mouse models, of human diseases are becoming an indispensable tool for biomedical research. Studies in animal models have provided important insights into the etiology of diseases and accelerated the development of therapeutic strategies. Detailed phenotypic characterization is essential, both for the development of such animal models and mechanistic studies into disease pathogenesis and testing the efficacy of experimental therapeutics. Magnetic Resonance Imaging (MRI) is a versatile and non-invasive imaging modality with excellent penetration depth, tissue coverage, and soft tissue contrast. MRI, being a multi-modal imaging modality, together with proven imaging protocols and availability of good contrast agents, is ideally suited for phenotyping mutant mouse models. Here we describe the applications of MRI for phenotyping structural birth defects involving the brain, heart, and kidney in mice. The versatility of MRI and its ease of use are well suited to meet the rapidly increasing demands for mouse phenotyping in the coming age of functional genomics. PMID:28544650

Neopolyploidy and diversification in Heuchera grossulariifolia.

PubMed

Oswald, Benjamin P; Nuismer, Scott L

2011-06-01

Newly formed polyploid lineages must contend with several obstacles to avoid extinction, including minority cytotype exclusion, competition, and inbreeding depression. If polyploidization results in immediate divergence of phenotypic characters these hurdles may be reduced and establishment made more likely. In addition, if polyploidization alters the phenotypic and genotypic associations between traits, that is, the P and G matrices, polyploids may be able to explore novel evolutionary paths, facilitating their divergence and successful establishment. Here, we report results from a study of the perennial plant Heuchera grossulariifolia in which the phenotypic divergence and changes in phenotypic and genotypic covariance matrices caused by neopolyploidization have been estimated. Our results reveal that polyploidization causes immediate divergence for traits relevant to establishment and results in significant changes in the structure of the phenotypic covariance matrix. In contrast, our results do not provide evidence that polyploidization results in immediate and substantial shifts in the genetic covariance matrix. © 2010 The Author(s). Evolution© 2010 The Society for the Study of Evolution.

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.

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

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms.

PubMed

Woodcock, K A; Oliver, C; Humphreys, G W

2009-06-01

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes. Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics. The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage. We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Emerging therapies for hemophilia: controversies and unanswered questions

PubMed Central

Arruda, Valder R.; Doshi, Bhavya S.; Samelson-Jones, Benjamin J.

2018-01-01

Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life factor replacement products and non-factor options with improved pharmacokinetic profiles to gene therapy aiming for phenotypic cure. While these products have the potential to change hemophilia care dramatically, several challenges and questions remain regarding broader applicability, long-term safety, and which option to pursue for each patient. Here, we review these emerging therapies with a focus on controversies and unanswered questions in each category. PMID:29770199

Cancer Imaging Phenomics Toolkit (CaPTk) | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

CaPTk is a software toolkit to facilitate translation of quantitative image analysis methods that help us obtain rich imaging phenotypic signatures of oncologic images and relate them to precision diagnostics and prediction of clinical outcomes, as well as to underlying molecular characteristics of cancer. The stand-alone graphical user interface of CaPTk brings analysis methods from the realm of medical imaging research to the clinic, and will be extended to use web-based services for computationally-demanding pipelines.

Host manipulation by an ichneumonid spider ectoparasitoid that takes advantage of preprogrammed web-building behaviour for its cocoon protection.

PubMed

Takasuka, Keizo; Yasui, Tomoki; Ishigami, Toru; Nakata, Kensuke; Matsumoto, Rikio; Ikeda, Kenichi; Maeto, Kaoru

2015-08-01

Host manipulation by parasites and parasitoids is a fascinating phenomenon within evolutionary ecology, representing an example of extended phenotypes. To elucidate the mechanism of host manipulation, revealing the origin and function of the invoked actions is essential. Our study focused on the ichneumonid spider ectoparasitoid Reclinervellus nielseni, which turns its host spider (Cyclosa argenteoalba) into a drugged navvy, to modify the web structure into a more persistent cocoon web so that the wasp can pupate safely on this web after the spider's death. We focused on whether the cocoon web originated from the resting web that an unparasitized spider builds before moulting, by comparing web structures, building behaviour and silk spectral/tensile properties. We found that both resting and cocoon webs have reduced numbers of radii decorated by numerous fibrous threads and specific decorating behaviour was identical, suggesting that the cocoon web in this system has roots in the innate resting web and ecdysteroid-related components may be responsible for the manipulation. We also show that these decorations reflect UV light, possibly to prevent damage by flying web-destroyers such as birds or large insects. Furthermore, the tensile test revealed that the spider is induced to repeat certain behavioural steps in addition to resting web construction so that many more threads are laid down for web reinforcement. © 2015. Published by The Company of Biologists Ltd.

Multilevel regularized regression for simultaneous taxa selection and network construction with metagenomic count data.

PubMed

Liu, Zhenqiu; Sun, Fengzhu; Braun, Jonathan; McGovern, Dermot P B; Piantadosi, Steven

2015-04-01

Identifying disease associated taxa and constructing networks for bacteria interactions are two important tasks usually studied separately. In reality, differentiation of disease associated taxa and correlation among taxa may affect each other. One genus can be differentiated because it is highly correlated with another highly differentiated one. In addition, network structures may vary under different clinical conditions. Permutation tests are commonly used to detect differences between networks in distinct phenotypes, and they are time-consuming. In this manuscript, we propose a multilevel regularized regression method to simultaneously identify taxa and construct networks. We also extend the framework to allow construction of a common network and differentiated network together. An efficient algorithm with dual formulation is developed to deal with the large-scale n ≪ m problem with a large number of taxa (m) and a small number of samples (n) efficiently. The proposed method is regularized with a general Lp (p ∈ [0, 2]) penalty and models the effects of taxa abundance differentiation and correlation jointly. We demonstrate that it can identify both true and biologically significant genera and network structures. Software MLRR in MATLAB is available at http://biostatistics.csmc.edu/mlrr/. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

Admixture in Latin America: Geographic Structure, Phenotypic Diversity and Self-Perception of Ancestry Based on 7,342 Individuals

PubMed Central

Ruiz-Linares, Andrés; Adhikari, Kaustubh; Acuña-Alonzo, Victor; Quinto-Sanchez, Mirsha; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Everardo, Paola; de Avila, Francisco; Gómez-Valdés, Jorge; León-Mimila, Paola; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C.; Burley, Mari-Wyn; Konca, Esra; de Oliveira, Marcelo Zagonel; Veronez, Mauricio Roberto; Rubio-Codina, Marta; Attanasio, Orazio; Gibbon, Sahra; Ray, Nicolas; Gallo, Carla; Poletti, Giovanni; Rosique, Javier; Schuler-Faccini, Lavinia; Salzano, Francisco M.; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Balding, David; Gonzalez-José, Rolando

2014-01-01

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry. PMID:25254375

Phage phenomics: Physiological approaches to characterize novel viral proteins

ScienceCinema

Sanchez, Savannah E. [San Diego State Univ., San Diego, CA (United States); Cuevas, Daniel A. [San Diego State Univ., San Diego, CA (United States); Rostron, Jason E. [San Diego State Univ., San Diego, CA (United States); Liang, Tiffany Y. [San Diego State Univ., San Diego, CA (United States); Pivaroff, Cullen G. [San Diego State Univ., San Diego, CA (United States); Haynes, Matthew R. [San Diego State Univ., San Diego, CA (United States); Nulton, Jim [San Diego State Univ., San Diego, CA (United States); Felts, Ben [San Diego State Univ., San Diego, CA (United States); Bailey, Barbara A. [San Diego State Univ., San Diego, CA (United States); Salamon, Peter [San Diego State Univ., San Diego, CA (United States); Edwards, Robert A. [San Diego State Univ., San Diego, CA (United States); Argonne National Lab. (ANL), Argonne, IL (United States); Burgin, Alex B. [Broad Institute, Cambridge, MA (United States); Segall, Anca M. [San Diego State Univ., San Diego, CA (United States); Rohwer, Forest [San Diego State Univ., San Diego, CA (United States)

2018-06-21

Current investigations into phage-host interactions are dependent on extrapolating knowledge from (meta)genomes. Interestingly, 60 - 95% of all phage sequences share no homology to current annotated proteins. As a result, a large proportion of phage genes are annotated as hypothetical. This reality heavily affects the annotation of both structural and auxiliary metabolic genes. Here we present phenomic methods designed to capture the physiological response(s) of a selected host during expression of one of these unknown phage genes. Multi-phenotype Assay Plates (MAPs) are used to monitor the diversity of host substrate utilization and subsequent biomass formation, while metabolomics provides bi-product analysis by monitoring metabolite abundance and diversity. Both tools are used simultaneously to provide a phenotypic profile associated with expression of a single putative phage open reading frame (ORF). Thus, representative results for both methods are compared, highlighting the phenotypic profile differences of a host carrying either putative structural or metabolic phage genes. In addition, the visualization techniques and high throughput computational pipelines that facilitated experimental analysis are presented.

Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals.

PubMed

Ruiz-Linares, Andrés; Adhikari, Kaustubh; Acuña-Alonzo, Victor; Quinto-Sanchez, Mirsha; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Everardo, Paola; de Avila, Francisco; Gómez-Valdés, Jorge; León-Mimila, Paola; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Burley, Mari-Wyn; Konca, Esra; de Oliveira, Marcelo Zagonel; Veronez, Mauricio Roberto; Rubio-Codina, Marta; Attanasio, Orazio; Gibbon, Sahra; Ray, Nicolas; Gallo, Carla; Poletti, Giovanni; Rosique, Javier; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Balding, David; Gonzalez-José, Rolando

2014-09-01

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry.

Genotype-phenotype association study via new multi-task learning model

PubMed Central

Huo, Zhouyuan; Shen, Dinggang

2018-01-01

Research on the associations between genetic variations and imaging phenotypes is developing with the advance in high-throughput genotype and brain image techniques. Regression analysis of single nucleotide polymorphisms (SNPs) and imaging measures as quantitative traits (QTs) has been proposed to identify the quantitative trait loci (QTL) via multi-task learning models. Recent studies consider the interlinked structures within SNPs and imaging QTs through group lasso, e.g. ℓ2,1-norm, leading to better predictive results and insights of SNPs. However, group sparsity is not enough for representing the correlation between multiple tasks and ℓ2,1-norm regularization is not robust either. In this paper, we propose a new multi-task learning model to analyze the associations between SNPs and QTs. We suppose that low-rank structure is also beneficial to uncover the correlation between genetic variations and imaging phenotypes. Finally, we conduct regression analysis of SNPs and QTs. Experimental results show that our model is more accurate in prediction than compared methods and presents new insights of SNPs. PMID:29218896

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

Sanchez, Savannah E.; Cuevas, Daniel A.; Rostron, Jason E.

Current investigations into phage-host interactions are dependent on extrapolating knowledge from (meta)genomes. Interestingly, 60 - 95% of all phage sequences share no homology to current annotated proteins. As a result, a large proportion of phage genes are annotated as hypothetical. This reality heavily affects the annotation of both structural and auxiliary metabolic genes. Here we present phenomic methods designed to capture the physiological response(s) of a selected host during expression of one of these unknown phage genes. Multi-phenotype Assay Plates (MAPs) are used to monitor the diversity of host substrate utilization and subsequent biomass formation, while metabolomics provides bi-product analysismore » by monitoring metabolite abundance and diversity. Both tools are used simultaneously to provide a phenotypic profile associated with expression of a single putative phage open reading frame (ORF). Thus, representative results for both methods are compared, highlighting the phenotypic profile differences of a host carrying either putative structural or metabolic phage genes. In addition, the visualization techniques and high throughput computational pipelines that facilitated experimental analysis are presented.« less