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Sample records for genetic phenotypic information

  1. On genetic information uncertainty and the mutator phenotype in cancer.

    PubMed

    Chan, Jason Yongsheng

    2012-01-01

    Recent evidence supports the existence of a mutator phenotype in cancer cells, although the mechanistic basis remains unknown. In this paper, it is shown that this enhanced genetic instability is generated by an amplified measurement uncertainty on genetic information during DNA replication. At baseline, an inherent measurement uncertainty implies an imprecision of the recognition, replication and transfer genetic information, and forms the basis for an intrinsic genetic instability in all biological cells. Genetic information is contained in the sequence of DNA bases, each existing due to proton tunnelling, as a coherent superposition of quantum states composed of both the canonical and rare tautomeric forms until decoherence by interaction with DNA polymerase. The result of such a quantum measurement process may be interpreted classically as akin to a Bernoulli trial, whose outcome X is random and can be either of two possibilities, depending on whether the proton is tunnelled (X=1) or not (X=0). This inherent quantum uncertainty is represented by a binary entropy function and quantified in terms of Shannon information entropy H(X)=-P(X=1)log(2)P(X=1)-P(X=0)log(2)P(X=0). Enhanced genetic instability may either be directly derived from amplified uncertainty induced by increases in quantum and thermodynamic fluctuation, or indirectly arise from the loss of natural uncertainty reduction mechanisms.

  2. Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis

    PubMed Central

    Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

    2009-01-01

    Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed. PMID:19015126

  3. Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis.

    PubMed

    Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

    2009-01-01

    Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed.

  4. Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

    PubMed Central

    2010-01-01

    Background The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease. PMID:20092628

  5. GERMINATE. a generic database for integrating genotypic and phenotypic information for plant genetic resource collections.

    PubMed

    Lee, Jennifer M; Davenport, Guy F; Marshall, David; Ellis, T H Noel; Ambrose, Michael J; Dicks, Jo; van Hintum, Theo J L; Flavell, Andrew J

    2005-10-01

    The extensive germplasm resource collections that are now available for major crop plants and their wild relatives will increasingly provide valuable biological and bioinformatics resources for plant physiologists and geneticists to dissect the molecular basis of key traits and to develop highly adapted plant material to sustain future breeding programs. A key to the efficient deployment of these resources is the development of information systems that will enable the collection and storage of biological information for these plant lines to be integrated with the molecular information that is now becoming available through the use of high-throughput genomics and post-genomics technologies. The GERMINATE database has been designed to hold a diverse variety of data types, ranging from molecular to phenotypic, and to allow querying between such data for any plant species. Data are stored in GERMINATE in a technology-independent manner, such that new technologies can be accommodated in the database as they emerge, without modification of the underlying schema. Users can access data in GERMINATE databases either via a lightweight Perl-CGI Web interface or by the more complex Genomic Diversity and Phenotype Connection software. GERMINATE is released under the GNU General Public License and is available at http://germinate.scri.sari.ac.uk/germinate/.

  6. Quantifying Phenotypic Plasticity Using Genetic Information for Simulating Plant Height in Winter Wheat

    USDA-ARS?s Scientific Manuscript database

    A challenge for crop simulation modeling is to incorporate existing and rapidly emerging genomic information into models to develop new and improved algorithms. The objective of this effort was to simulate plant height in winter wheat (Triticum aestivum L.) across a range of environments in Nebraska...

  7. Hot topic: a unified approach to utilize phenotypic, full pedigree, and genomic information for genetic evaluation of Holstein final score.

    PubMed

    Aguilar, I; Misztal, I; Johnson, D L; Legarra, A; Tsuruta, S; Lawlor, T J

    2010-02-01

    The first national single-step, full-information (phenotype, pedigree, and marker genotype) genetic evaluation was developed for final score of US Holsteins. Data included final scores recorded from 1955 to 2009 for 6,232,548 Holsteins cows. BovineSNP50 (Illumina, San Diego, CA) genotypes from the Cooperative Dairy DNA Repository (Beltsville, MD) were available for 6,508 bulls. Three analyses used a repeatability animal model as currently used for the national US evaluation. The first 2 analyses used final scores recorded up to 2004. The first analysis used only a pedigree-based relationship matrix. The second analysis used a relationship matrix based on both pedigree and genomic information (single-step approach). The third analysis used the complete data set and only the pedigree-based relationship matrix. The fourth analysis used predictions from the first analysis (final scores up to 2004 and only a pedigree-based relationship matrix) and prediction using a genomic based matrix to obtain genetic evaluation (multiple-step approach). Different allele frequencies were tested in construction of the genomic relationship matrix. Coefficients of determination between predictions of young bulls from parent average, single-step, and multiple-step approaches and their 2009 daughter deviations were 0.24, 0.37 to 0.41, and 0.40, respectively. The highest coefficient of determination for a single-step approach was observed when using a genomic relationship matrix with assumed allele frequencies of 0.5. Coefficients for regression of 2009 daughter deviations on parent-average, single-step, and multiple-step predictions were 0.76, 0.68 to 0.79, and 0.86, respectively, which indicated some inflation of predictions. The single-step regression coefficient could be increased up to 0.92 by scaling differences between the genomic and pedigree-based relationship matrices with little loss in accuracy of prediction. One complete evaluation took about 2h of computing time and 2

  8. Molecular Genetic Studies of Complex Phenotypes

    PubMed Central

    Marian, A.J.

    2012-01-01

    The approach to molecular genetic studies of complex phenotypes has evolved considerably during the recent years. The candidate gene approach, restricted to analysis of a few single nucleotide polymorphisms (SNPs) in a modest number of cases and controls, has been supplanted by the unbiased approach of Genome-Wide Association Studies (GWAS), wherein a large number of tagger SNPs are typed in a large number of individuals. GWAS, which are designed upon the common disease- common variant hypothesis (CD-CV), have identified a large number of SNPs and loci for complex phenotypes. However, alleles identified through GWAS are typically not causative but rather in linkage disequilibrium (LD) with the true causal variants. The common alleles, which may not capture the uncommon and rare variants, account only for a fraction of heritability of the complex traits. Hence, the focus is being shifted to rare variants – common disease (RV-CD) hypothesis, surmising that rare variants exert large effect sizes on the phenotype. In conjunctional with this conceptual shift technological advances in DNA sequencing techniques have dramatically enhanced whole genome or whole exome sequencing capacity. The sequencing approach affords identification of not only the rare but also the common variants. The approach – whether used in complementation with GWAS or as a stand-alone approach - could define the genetic architecture of the complex phenotypes. Robust phenotyping and large-scale sequencing studies are essential to extract the information content of the vast number of DNA sequence variants (DSVs) in the genome. To garner meaningful clinical information and link the genotype to a phenotype, identification and characterization of a very large number of causal fields beyond the information content of DNA sequence variants would be necessary. This review provides an update on the current progress and limitations in identifying DSVs that are associated with phenotypic effects. PMID

  9. Polydactyly: phenotypes, genetics and classification.

    PubMed

    Malik, S

    2014-03-01

    Polydactyly is one of the most common hereditary limb malformations featuring additional digits in hands and/or feet. It constituted the highest proportion among the congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting as an additional pre-axial or post-axial digit of autopod, is a highly heterogeneous condition and depicts broad inter- and intra-familial clinical variability. There is a plethora of polydactyly classification methods reported in the medical literature which approach the heterogeneity in polydactyly in various ways. In this communication, well-characterized, non-syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic variability and molecular advances of each type have been presented. Polydactyly at cellular and developmental levels is mainly a failure in the control of digit number. Interestingly, GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit number and identity during development, have also been implicated in polydactyly. Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting shared molecular cascades in the etiology of additional digits, and thus suggesting the lumping of at least six distinct polydactyly entities. However, owing to the extreme phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic heterogeneity is expected across different populations and ethnic groups.

  10. Probing genetic overlap among complex human phenotypes.

    PubMed

    Rzhetsky, Andrey; Wajngurt, David; Park, Naeun; Zheng, Tian

    2007-07-10

    Geneticists and epidemiologists often observe that certain hereditary disorders cooccur in individual patients significantly more (or significantly less) frequently than expected, suggesting there is a genetic variation that predisposes its bearer to multiple disorders, or that protects against some disorders while predisposing to others. We suggest that, by using a large number of phenotypic observations about multiple disorders and an appropriate statistical model, we can infer genetic overlaps between phenotypes. Our proof-of-concept analysis of 1.5 million patient records and 161 disorders indicates that disease phenotypes form a highly connected network of strong pairwise correlations. Our modeling approach, under appropriate assumptions, allows us to estimate from these correlations the size of putative genetic overlaps. For example, we suggest that autism, bipolar disorder, and schizophrenia share significant genetic overlaps. Our disease network hypothesis can be immediately exploited in the design of genetic mapping approaches that involve joint linkage or association analyses of multiple seemingly disparate phenotypes.

  11. A phenotypic null hypothesis for the genetics of personality.

    PubMed

    Turkheimer, Eric; Pettersson, Erik; Horn, Erin E

    2014-01-01

    We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level.

  12. Characterizing the ADHD Phenotype for Genetic Studies

    ERIC Educational Resources Information Center

    Stevenson, Jim; Asherson, Phil; Hay, David; Levy, Florence; Swanson, Jim; Thapar, Anita; Willcutt, Erik

    2005-01-01

    The genetic study of ADHD has made considerable progress. Further developments in the field will be reliant in part on identifying the most appropriate phenotypes for genetic analysis. The use of both categorical and dimensional measures of symptoms related to ADHD has been productive. The use of multiple reporters is a valuable feature of the…

  13. Phenotypic plasticity and evolution by genetic assimilation.

    PubMed

    Pigliucci, Massimo; Murren, Courtney J; Schlichting, Carl D

    2006-06-01

    In addition to considerable debate in the recent evolutionary literature about the limits of the Modern Synthesis of the 1930s and 1940s, there has also been theoretical and empirical interest in a variety of new and not so new concepts such as phenotypic plasticity, genetic assimilation and phenotypic accommodation. Here we consider examples of the arguments and counter-arguments that have shaped this discussion. We suggest that much of the controversy hinges on several misunderstandings, including unwarranted fears of a general attempt at overthrowing the Modern Synthesis paradigm, and some fundamental conceptual confusion about the proper roles of phenotypic plasticity and natural selection within evolutionary theory.

  14. Environmental change, phenotypic plasticity, and genetic compensation.

    PubMed

    Grether, Gregory F

    2005-10-01

    When a species encounters novel environmental conditions, some phenotypic characters may develop differently than in the ancestral environment. Most environmental perturbations of development are likely to reduce fitness, and thus selection would usually be expected to favor genetic changes that restore the ancestral phenotype. I propose the term "genetic compensation" to refer to this form of adaptive evolution. Genetic compensation is a subset of genetic accommodation and the reverse of genetic assimilation. When genetic compensation has occurred along a spatial environmental gradient, the mean trait values of populations in different environments may be more similar in the field than when representatives of the same populations are raised in a common environment (i.e., countergradient variation). If compensation is complete, genetic divergence between populations may be cryptic, that is, not detectable in the field. Here I apply the concept of genetic compensation to three examples involving carotenoid-based sexual coloration and then use these and other examples to discuss the concept in a broader context. I show that genetic compensation may lead to a cryptic form of reproductive isolation between populations evolving in different environments, may explain some puzzling cases in which heritable traits exposed to strong directional selection fail to show the expected evolutionary response, and may complicate efforts to monitor populations for signs of environmental deterioration.

  15. Elucidation of the full genetic information of Japanese rubella vaccines and the genetic changes associated with in vitro and in vivo vaccine virus phenotypes.

    PubMed

    Otsuki, Noriyuki; Abo, Hitoshi; Kubota, Toru; Mori, Yoshio; Umino, Yukiko; Okamoto, Kiyoko; Takeda, Makoto; Komase, Katsuhiro

    2011-02-24

    Rubella is a mild disease characterized by low-grade fever, and a morbilliform rash, but causes congenital defects in neonates born from mothers who suffered from rubella during the pregnancy. After many passages of wild-type rubella virus strains in various types of cultured cells, five live attenuated rubella vaccines were developed in Japan. An inability to elicit anti-rubella virus antibodies in experimentally infected animals was used as an in vivo marker phenotype of Japanese rubella vaccines. All Japanese rubella vaccine viruses exhibit a temperature-sensitive (ts) phenotype, and replicate very poorly at a high temperature. We determined the entire genome sequences of three Japanese rubella vaccines (Matsuba, TCRB19, and Matsuura), thereby completing the sequencing of all five Japanese rubella vaccines. In addition, the entire genome sequences of three vaccine progenitors were determined. Comparative nucleotide sequence analyses revealed mutations that were introduced into the genomes of the TO-336 and Matsuura vaccines during their production by laboratory passaging. Analyses involving cellular expression of viral P150 nonstructural protein-derived peptides revealed that the N1159S mutation conferred the ts phenotype on the TO-336 vaccine, and that reduced thermal stability of the P150 protease domain was a cause of the ts phenotype of some rubella vaccine viruses. The ts phenotype of vaccine viruses was not necessarily correlated with their inability to elicit humoral immune responses in animals. Therefore, the molecular mechanisms underlying the inability of these vaccines to elicit humoral responses in animals are more complicated than the previously considered mechanism involving the ts phenotype as the major cause.

  16. Genetics of alcoholism using intermediate phenotypes.

    PubMed

    Enoch, Mary-Anne; Schuckit, Marc A; Johnson, Bankole A; Goldman, David

    2003-02-01

    This article represents the proceedings of a symposium at the 2002 meeting of the Research Society on Alcoholism in San Francisco, CA. It was organized by Mary-Anne Enoch and David Goldman and chaired by David Goldman. The presentations were (1) Two functional polymorphisms and their intermediate phenotypes in complex behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and anxiety disorders, by Mary-Anne Enoch; (3) The response to alcohol as an intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4) Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by Bankole A. Johnson.

  17. Behavioral phenotypes in genetic syndromes: genetic clues to human behavior.

    PubMed

    Cassidy, Suzanne B; Morris, Colleen A

    2002-01-01

    A behavioral phenotype is the characteristic cognitive, personality, behavioral, and psychiatric pattern that typifies a disorder. A number of genetic syndromes have been identified as having this type of distinctive and consistent behavior pattern. It may act as an important diagnostic sign, like a malformation or characteristic facial appearance. Such patterns are also useful for the physician's anticipatory guidance from an educational, rehabilitative, and parenting perspective. In addition, because they are the consequences of known genetic alterations, behavioral phenotypes can be potentially highly valuable clues to the identification of genes in the population that are important to determination of cognitive skills or deficits, personality determinants, behavioral abnormalities, or psychiatric disorders. The nature of a behavioral phenotype and its potential for genetic insight can be appreciated through the examples of Williams syndrome, Prader-Willi syndrome, and Angelman syndrome. The cognitive and behavioral characteristics of these disorders are distinctive. Williams syndrome is known for its association with remarkable conversational verbal abilities and excessive empathy, whereas Prader-Willi syndrome is known for temper tantrums and obsessive-compulsive features, and Angelman syndrome is associated with a constantly happy affect and hyperactivity. The genetic basis for each of these disorders is known, and the pathophysiology and genotype-phenotype correlations are beginning to provide insight into genes responsible for personality characteristics and behavioral abnormalities.

  18. Recovery of native genetic background in admixed populations using haplotypes, phenotypes, and pedigree information--using Cika cattle as a case breed.

    PubMed

    Simčič, Mojca; Smetko, Anamarija; Sölkner, Johann; Seichter, Doris; Gorjanc, Gregor; Kompan, Dragomir; Medugorac, Ivica

    2015-01-01

    The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had

  19. Recovery of Native Genetic Background in Admixed Populations Using Haplotypes, Phenotypes, and Pedigree Information – Using Cika Cattle as a Case Breed

    PubMed Central

    Simčič, Mojca; Smetko, Anamarija; Sölkner, Johann; Seichter, Doris; Gorjanc, Gregor; Kompan, Dragomir; Medugorac, Ivica

    2015-01-01

    The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had

  20. Genetic ancestry affects the phenotype of normogonadotropic anovulatory (WHOII) subfertility.

    PubMed

    Valkenburg, O; Lao, O; Schipper, I; Louwers, Y; Uitterlinden, A G; Kayser, M; Laven, J S E

    2011-07-01

    Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio-geographic ancestry and predict the phenotype of individual patients. A standardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structure on a continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility.

  1. Syndactyly: phenotypes, genetics and current classification.

    PubMed

    Malik, Sajid

    2012-08-01

    Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes. It may occur as an isolated entity or a component of more than 300 syndromic anomalies. Syndactylies exhibit great inter- and intra-familial clinical variability. Even within a subject, phenotype can be unilateral or bilateral and symmetrical or asymmetrical. At least nine non-syndromic syndactylies with additional sub-types have been characterized. Most of the syndactyly types are inherited as autosomal dominant but two autosomal recessive and an X-linked recessive entity have also been described. Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the etiology and molecular basis of the other syndactyly types remain unknown. In this communication, based on an overview of well-characterized isolated syndactylies, their cardinal phenotypes, inheritance patterns, and clinical and genetic heterogeneities, a 'current classification scheme' is presented. Despite considerable progress in the understanding of syndactyly at clinical and molecular levels, fundamental questions regarding the disturbed developmental mechanisms leading to fused digits, remain to be answered.

  2. Mouse Genetic Background Influences the Dental Phenotype

    PubMed Central

    Li, Yong; Konicki, William S.; Wright, J. Timothy; Suggs, Cynthia; Xue, Hui; Kuehl, Melissa A.; Kulkarni, Ashok B.; Gibson, Carolyn W.

    2014-01-01

    Dental enamel covers the crown of the vertebrate tooth and is considered to be the hardest tissue in the body. Enamel develops during secretion of an extracellular matrix by ameloblast cells in the tooth germ, prior to eruption of the tooth into the oral cavity. Secreted enamel proteins direct mineralization patterns during the maturation stage of amelogenesis as the tooth prepares to erupt. The amelogenins are the most abundant enamel proteins, and are required for normal enamel development. Phenotypic differences were observed between incisors from individual Amelx (Amelogenin) null mice that had a mixed 129xC57BL/6J genetic background, and between inbred wld-type (WT) mice with different genetic backgrounds (C57BL/6J, C3H/HEJ, FVB/NJ). We hypothesized this could be due to modifier genes, as human patients with a mutation in an enamel protein gene causing the enamel defect amelogenesis imperfecta (AI) also can have varied appearance of dentitions within a kindred. Enamel density measurements varied for all WT inbred strains midway during incisor development. Enamel thickness varied between some WT strains and, unexpectedly, dentin density varied extensively between incisors and molars of all WT and Amelx null strains studied. WT FVB/NJ incisors were more similar to Amelx null than to the other WT strains in incisor height/weight ratio and pattern of enamel mineralization. Strain-specific differences led to the conclusion that modifier genes may be implicated in determining both normal development and severity of enamel appearance in AI mouse models and may in future studies be related to phenotypic heterogeneity within human AI kindreds reported in the literature. PMID:24732779

  3. Phenotypic categorization of genetic skin diseases reveals new relations between phenotypes, genes and pathways

    PubMed Central

    Sadreyev, Ruslan I.; Feramisco, Jamison D.; Tsao, Hensin; Grishin, Nick V.

    2009-01-01

    Motivation: Systematic analysis of connection between proteins, their cellular function and phenotypic manifestations in disease is a central problem of biological and clinical research. The solution to this problem requires the development of new approaches to link the rapidly growing dataset of gene–disease associations with the many complex and overlapping phenotypes of human disease. Results: We analyze genetic skin disorders and suggest a manually designed set of elementary phenotypes whose combinations define diseases as points in a multidimensional space, providing a basis for phenotypic disease clustering. Placing the known gene–disease associations in the context of this space reveals new patterns that suggest previously unknown functional links between proteins, signaling pathways and disease phenotypes. For example, analysis of telangiectasias (spider vein diseases) reveals a previously unrecognized interplay between the TGF-β signaling pathway and pentose phosphate pathway. This interaction may mediate glucose-dependent regulation of TGF-β signaling, providing a clue to the known association between angiopathies and diabetes and implying new gene candidates for mutational analysis and drug targeting. Contact: grishin@chop.swmed.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19744994

  4. Phenotype databases for genetic screens in human cells.

    PubMed

    Rauscher, Benedikt; Valentini, Erica; Hardeland, Ulrike; Boutros, Michael

    2017-11-10

    Genetic screens are powerful tools to identify components that make up biological systems. Perturbations introduced by methods such as RNA interference (RNAi) or CRISPR/Cas9-mediated genome editing lead to biological phenotypes that can be examined to understand the molecular function of genes in the cell. Over the years, many of such experiments have been conducted providing a wealth of knowledge about genotype-to-phenotype relationships. These data are a rich source of information and it is in a common interest to make them available in a simplified and integrated format. Thus, an important challenge is that genetic screening data can be stored in databases in standardized ways, allowing users to gain new biological insights through data mining and integrated analyses. Here, we provide an overview of available phenotype databases for human cells. We review in detail two databases for high-throughput screens, GenomeRNAi and GenomeCRISPR, and describe how these resources are integrated into the German Network for Bioinformatics Infrastructure de.NBI as part of the European infrastructure for life-science information ELIXIR. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  5. Genetic architecture and phenotypic plasticity of thermally-regulated traits in an eruptive species, Dendroctonus ponderosae

    Treesearch

    Barbara J. Bentz; Ryan B. Bracewell; Karen E. Mock; Michael E. Pfrender

    2011-01-01

    Phenotypic plasticity in thermally-regulated traits enables close tracking of changing environmental conditions, and can thereby enhance the potential for rapid population increase, a hallmark of outbreak insect species. In a changing climate, exposure to conditions that exceed the capacity of existing phenotypic plasticity may occur. Combining information on genetic...

  6. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations.

    PubMed

    Shah, Sonia; Bonder, Marc J; Marioni, Riccardo E; Zhu, Zhihong; McRae, Allan F; Zhernakova, Alexandra; Harris, Sarah E; Liewald, Dave; Henders, Anjali K; Mendelson, Michael M; Liu, Chunyu; Joehanes, Roby; Liang, Liming; Levy, Daniel; Martin, Nicholas G; Starr, John M; Wijmenga, Cisca; Wray, Naomi R; Yang, Jian; Montgomery, Grant W; Franke, Lude; Deary, Ian J; Visscher, Peter M

    2015-07-02

    We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Phenotype Information Retrieval for Existing GWAS Studies.

    PubMed

    Alipanah, Neda; Lin, Ko-Wei; Venkatesh, Vinay; Farzaneh, Seena; Kim, Hyeon-Eui

    2013-01-01

    The database of Genotypes and Phenotypes (dbGaP) is archiving the results of different Genome Wide Association Studies (GWAS). dbGaP has a multitude of phenotype variables, but they are not harmonized across studies. We proposed a method to standardize phenotype variables by classifying similar variables based on semantic distances. We first extracted variables description, enriched them using domain knowledge, and computed the distances among them. We used clustering techniques to classify the most similar variables. We used domain experts to audit clusters, annotated the clusters with appropriate labels, and used re-clustering to build a semantically-driven Genotypes and Phenotypes (sdGaP) ontology using the UMLS semantic network and metathesaurus. The sdGaP ontology allowed us to expand user queries and retrieve information using a semantic metric called density measure (DM). We illustrated the potential improvement of information retrieval using the sdGaP ontology in one search scenario using the variables from the Cleveland Family Study.

  8. Legal aspects of genetic information.

    PubMed Central

    Andrews, L. B.

    1991-01-01

    The federally funded Human Genome Initiative will lead to the development of new capabilities to learn about an individual's genetic status. Legal issues are raised concerning patients' and other parties' access to that information. This article discusses the effect of existing statutes and case law on three pivotal questions: To what sort of information are people entitled? What control should people have over their genetic information? Do people have a right to refuse genetic information? The article emphasizes that the law protects a patient's right to obtain or refuse genetic information about oneself, as well as the right to control the dissemination of that information to others. PMID:1897258

  9. Estimation of Genetic Effects and Genotype-Phenotype Maps

    PubMed Central

    Le Rouzic, Arnaud; Álvarez-Castro, José M.

    2008-01-01

    Determining the genetic architecture of complex traits is a necessary step to understand phenotypic changes in natural, experimental and domestic populations. However, this is still a major challenge for modern genetics, since the estimation of genetic effects tends to be complicated by genetic interactions, which lead to changes in the effect of allelic substitutions depending on the genetic background. Recent progress in statistical tools aiming to describe and quantify genetic effects meaningfully improves the efficiency and the availability of genotype-to-phenotype mapping methods. In this contribution, we facilitate the practical use of the recently published ‘NOIA’ quantitative framework by providing an implementation of linear and multilinear regressions, change of reference operation and genotype-to-phenotype mapping in a package (‘noia’) for the software R, and we discuss theoretical and practical benefits evolutionary and quantitative geneticists may find in using proper modeling strategies to quantify the effects of genes. PMID:19204820

  10. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism.

    PubMed

    Bonomi, M; Rochira, V; Pasquali, D; Balercia, G; Jannini, E A; Ferlin, A

    2017-02-01

    Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.

  11. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth

    PubMed Central

    Yadav, Anupama; Dhole, Kaustubh

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it’s evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with the environment specific regulators is not well understood. Saccharomyces cerevisiae is highly sensitive to the environment, which acts as not just external stimulus but also as signalling cue for this unicellular, sessile organism. We used a previously published dataset of a biparental yeast population grown in 34 diverse environments and mapped genetic loci regulating variation in phenotypic plasticity, plasticity QTL, and compared them with environment-specific QTL. Plasticity QTL is one whose one allele exhibits high plasticity whereas the other shows a relatively canalised behaviour. We mapped phenotypic plasticity using two parameters–environmental variance, an environmental order-independent parameter and reaction norm (slope), an environmental order-dependent parameter. Our results show a partial overlap between pleiotropic QTL and plasticity QTL such that while some plasticity QTL are also pleiotropic, others have a significant effect on phenotypic plasticity without being significant in any environment independently. Furthermore, while some plasticity QTL are revealed only in specific environmental orders, we identify large effect plasticity QTL, which are order-independent such that whatever the order of the environments, one allele is always plastic and the other is canalised. Finally, we show that the environments can be divided into two categories based on the phenotypic diversity of the population within them and the two categories have differential

  12. The Genetics of Phenotypic Plasticity. XIV. Coevolution.

    PubMed

    Scheiner, Samuel M; Gomulkiewicz, Richard; Holt, Robert D

    2015-05-01

    Plastic changes in organisms' phenotypes can result from either abiotic or biotic effectors. Biotic effectors create the potential for a coevolutionary dynamic. Through the use of individual-based simulations, we examined the coevolutionary dynamic of two species that are phenotypically plastic. We explored two modes of biotic and abiotic interactions: ecological interactions that determine the form of natural selection and developmental interactions that determine phenotypes. Overall, coevolution had a larger effect on the evolution of phenotypic plasticity than plasticity had on the outcome of coevolution. Effects on the evolution of plasticity were greater when the fitness-maximizing coevolutionary outcomes were antagonistic between the species pair (predator-prey interactions) than when those outcomes were augmenting (competitive or mutualistic). Overall, evolution in the context of biotic interactions reduced selection for plasticity even when trait development was responding to just the abiotic environment. Thus, the evolution of phenotypic plasticity must always be interpreted in the full context of a species' ecology. Our results show how the merging of two theory domains--coevolution and phenotypic plasticity--can deepen our understanding of both and point to new empirical research.

  13. 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...

  14. [Genotype/phenotype correlation in autism: genetic models and phenotypic characterization].

    PubMed

    Bonnet-Brilhault, F

    2011-02-01

    Autism spectrum disorders are a class of conditions categorized by communication problems, ritualistic behaviors, and deficits in social behaviors. This class of disorders merges a heterogeneous group of neurodevelopmental disorders regarding some phenotypic and probably physiopathological aspects. Genetic basis is well admitted, however, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be established. To better identify such correspondences, genetic models have to be identified and phenotypic markers have to be characterized. Recent insights show that a variety of genetic mechanisms may be involved in autism spectrum disorders, i.e. single gene disorders, copy number variations and polygenic mechanisms. These current genetic models are described. Regarding clinical aspects, several approaches can be used in genetic studies. Nosographical approach, especially with the concept of autism spectrum disorders, merges a large group of disorders with clinical heterogeneity and may fail to identify clear genotype/phenotype correlations. Dimensional approach referred in genetic studies to the notion of "Broad Autism Phenotype" related to a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype may provide a potentially important complementary approach for detecting the genes involved in these domains. However, control population used in those studies need to be well characterized too. Identification of endophenotypes seems to offer more promising results. Endophenotypes, which are supposed to be more proximal markers of gene action in the same biological pathway, linking genes and complex clinical symptoms, are thought to be less genetically complex than the broader disease phenotype, indexing a limited aspect of genetic risk for the disorder as a whole. However

  15. The phenotypic and genetic covariance structure of drosphilid wings.

    PubMed

    McGuigan, Katrina; Blows, Mark W

    2007-04-01

    Evolutionary constraint results from the interaction between the distribution of available genetic variation and the position of selective optima. The availability of genetic variance in multitrait systems, as described by the additive genetic variance-covariance matrix (G), has been the subject of recent attempts to assess the prevalence of genetic constraints. However, evolutionary constraints have not yet been considered from the perspective of the phenotypes available to multivariate selection, and whether genetic variance is present in all phenotypes potentially under selection. Determining the rank of the phenotypic variance-covariance matrix (P) to characterize the phenotypes available to selection, and contrasting it with the rank of G, may provide a general approach to determining the prevalence of genetic constraints. In a study of a laboratory population of Drosophila bunnanda from northern Australia we applied factor-analytic modeling to repeated measures of individual wing phenotypes to determine the dimensionality of the phenotypic space described by P. The phenotypic space spanned by the 10 wing traits had 10 statistically supported dimensions. In contrast, factor-analytic modeling of G estimated for the same 10 traits from a paternal half-sibling breeding design suggested G had fewer dimensions than traits. Statistical support was found for only five and two genetic dimensions, describing a total of 99% and 72% of genetic variance in wing morphology in females and males, respectively. The observed mismatch in dimensionality between P and G suggests that although selection might act to shift the intragenerational population mean toward any trait combination, evolution may be restricted to fewer dimensions.

  16. Environmental and genetic modulation of the phenotypic expression of antibiotic resistance.

    PubMed

    Hughes, Diarmaid; Andersson, Dan I

    2017-03-08

    Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype. This dissociation of genotype and phenotype has important consequences for clinical bacteriology and for our ability to predict resistance phenotypes from genetics and DNA sequences. A related problem concerns the degree to which the genes/mutations currently identified in vitro can fully explain the in vivo resistance phenotype, or whether there is a significant additional amount of presently unknown mutations/genes (genetic 'dark matter') that could contribute to resistance in clinical isolates. Finally, a very important question is whether/how we can identify the genetic features that contribute to making a successful pathogen, and predict why some resistant clones are very successful and spread globally? In this review, we describe different environmental and genetic factors that influence phenotypic expression of antibiotic resistance genes/mutations and how this information is needed to understand why particular resistant clones spread worldwide and to what extent we can use DNA sequences to predict evolutionary success.

  17. Environmental and genetic modulation of the phenotypic expression of antibiotic resistance

    PubMed Central

    Andersson, Dan I

    2017-01-01

    Abstract Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype. This dissociation of genotype and phenotype has important consequences for clinical bacteriology and for our ability to predict resistance phenotypes from genetics and DNA sequences. A related problem concerns the degree to which the genes/mutations currently identified in vitro can fully explain the in vivo resistance phenotype, or whether there is a significant additional amount of presently unknown mutations/genes (genetic ‘dark matter’) that could contribute to resistance in clinical isolates. Finally, a very important question is whether/how we can identify the genetic features that contribute to making a successful pathogen, and predict why some resistant clones are very successful and spread globally? In this review, we describe different environmental and genetic factors that influence phenotypic expression of antibiotic resistance genes/mutations and how this information is needed to understand why particular resistant clones spread worldwide and to what extent we can use DNA sequences to predict evolutionary success. PMID:28333270

  18. Behavioral idiosyncrasy reveals genetic control of phenotypic variability

    PubMed Central

    Ayroles, Julien F.; Buchanan, Sean M.; O’Leary, Chelsea; Skutt-Kakaria, Kyobi; Grenier, Jennifer K.; Clark, Andrew G.; Hartl, Daniel L.; de Bivort, Benjamin L.

    2015-01-01

    Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype. PMID:25953335

  19. Property rights in genetic information.

    PubMed

    Spinello, Richard A

    2004-01-01

    The primary theme of this paper is the normative case against ownership of one's genetic information along with the source of that information (usually human tissues samples). The argument presented here against such "upstream" property rights is based primarily on utilitarian grounds. This issue has new salience thanks to the Human Genome Project and "bio-prospecting" initiatives based on the aggregation of genetic information, such as the one being managed by deCODE Genetics in Iceland. The rationale for ownership is twofold: ownership will protect the basic human rights of privacy and autonomy and it will enable the data subjects to share in the tangible benefits of the genetic research. Proponents of this viewpoint often cite the principle of genetic exceptionalism, which asserts that genetic information needs a higher level of protection than other kinds of personal information such as financial data. We argue, however, that the recognition of such ownership rights would lead to inefficiency along with the disutility of genetic discoveries. Biomedical research will be hampered if property rights in genes and genetic material are too extensive. We contend that other mechanisms such as informed consent and strict confidentiality rules can accomplish the same result as a property right without the liabilities of an exclusive entitlement.

  20. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities

    PubMed Central

    Chong, Jessica X.; Buckingham, Kati J.; Jhangiani, Shalini N.; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D.; Harrell, Tanya M.; McMillin, Margaret J.; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H.; Doheny, Kimberly; Scott, Alan F.; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P. Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E.; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V. Reid; Tabor, Holly K.; Leal, Suzanne M.; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A.; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R.; Lifton, Richard P.; Valle, David; Nickerson, Deborah A.; Bamshad, Michael J.

    2015-01-01

    Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families. PMID:26166479

  1. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

    PubMed

    Chong, Jessica X; Buckingham, Kati J; Jhangiani, Shalini N; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D; Harrell, Tanya M; McMillin, Margaret J; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H; Doheny, Kimberly; Scott, Alan F; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V Reid; Tabor, Holly K; Leal, Suzanne M; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R; Lifton, Richard P; Valle, David; Nickerson, Deborah A; Bamshad, Michael J

    2015-08-06

    Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

  2. Testing evolutionary hypotheses for phenotypic divergence using landscape genetics.

    PubMed

    Funk, W Chris; Murphy, Melanie A

    2010-02-01

    Understanding the evolutionary causes of phenotypic variation among populations has long been a central theme in evolutionary biology. Several factors can influence phenotypic divergence, including geographic isolation, genetic drift, divergent natural or sexual selection, and phenotypic plasticity. But the relative importance of these factors in generating phenotypic divergence in nature is still a tantalizing and unresolved problem in evolutionary biology. The origin and maintenance of phenotypic divergence is also at the root of many ongoing debates in evolutionary biology, such as the extent to which gene flow constrains adaptive divergence (Garant et al. 2007) and the relative importance of genetic drift, natural selection, and sexual selection in initiating reproductive isolation and speciation (Coyne & Orr 2004). In this issue, Wang & Summers (2010) test the causes of one of the most fantastic examples of phenotypic divergence in nature: colour pattern divergence among populations of the strawberry poison frog (Dendrobates pumilio) in Panama and Costa Rica (Fig. 1). This study provides a beautiful example of the use of the emerging field of landscape genetics to differentiate among hypotheses for phenotypic divergence. Using landscape genetic analyses, Wang & Summers were able to reject the hypotheses that colour pattern divergence is due to isolation-by-distance (IBD) or landscape resistance. Instead, the hypothesis left standing is that colour divergence is due to divergent selection, in turn driving reproductive isolation among populations with different colour morphs. More generally, this study provides a wonderful example of how the emerging field of landscape genetics, which has primarily been applied to questions in conservation and ecology, now plays an essential role in evolutionary research.

  3. The genetics of phenotypic plasticity in nematode feeding structures

    PubMed Central

    Dardiry, Mohannad; Lenuzzi, Masa; Namdeo, Suryesh; Renahan, Tess; Sieriebriennikov, Bogdan; Werner, Michael S.

    2017-01-01

    Phenotypic plasticity has been proposed as an ecological and evolutionary concept. Ecologically, it can help study how genes and the environment interact to produce robust phenotypes. Evolutionarily, as a facilitator it might contribute to phenotypic novelty and diversification. However, the discussion of phenotypic plasticity remains contentious in parts due to the absence of model systems and rigorous genetic studies. Here, we summarize recent work on the nematode Pristionchus pacificus, which exhibits a feeding plasticity allowing predatory or bacteriovorous feeding. We show feeding plasticity to be controlled by developmental switch genes that are themselves under epigenetic control. Phylogenetic and comparative studies support phenotypic plasticity and its role as a facilitator of morphological novelty and diversity. PMID:28298309

  4. Discordant patterns of genetic and phenotypic differentiation in five grasshopper species codistributed across a microreserve network.

    PubMed

    Ortego, Joaquín; García-Navas, Vicente; Noguerales, Víctor; Cordero, Pedro J

    2015-12-01

    Conservation plans can be greatly improved when information on the evolutionary and demographic consequences of habitat fragmentation is available for several codistributed species. Here, we study spatial patterns of phenotypic and genetic variation among five grasshopper species that are codistributed across a network of microreserves but show remarkable differences in dispersal-related morphology (body size and wing length), degree of habitat specialization and extent of fragmentation of their respective habitats in the study region. In particular, we tested the hypothesis that species with preferences for highly fragmented microhabitats show stronger genetic and phenotypic structure than codistributed generalist taxa inhabiting a continuous matrix of suitable habitat. We also hypothesized a higher resemblance of spatial patterns of genetic and phenotypic variability among species that have experienced a higher degree of habitat fragmentation due to their more similar responses to the parallel large-scale destruction of their natural habitats. In partial agreement with our first hypothesis, we found that genetic structure, but not phenotypic differentiation, was higher in species linked to highly fragmented habitats. We did not find support for congruent patterns of phenotypic and genetic variability among any studied species, indicating that they show idiosyncratic evolutionary trajectories and distinctive demographic responses to habitat fragmentation across a common landscape. This suggests that conservation practices in networks of protected areas require detailed ecological and evolutionary information on target species to focus management efforts on those taxa that are more sensitive to the effects of habitat fragmentation. © 2015 John Wiley & Sons Ltd.

  5. The contribution of selection and genetic constraints to phenotypic divergence.

    PubMed

    Chenoweth, Stephen F; Rundle, Howard D; Blows, Mark W

    2010-02-01

    Although divergent natural selection is common in nature, the extent to which genetic constraints bias evolutionary trajectories in its presence remains largely unknown. Here we develop a general framework to integrate estimates of divergent selection and genetic constraints to estimate their contributions to phenotypic divergence among natural populations. We apply these methods to estimates of phenotypic selection and genetic covariance from sexually selected traits that have undergone adaptive divergence among nine natural populations of the fly Drosophila serrata. Despite ongoing sexual selection within populations, differences in its direction among them, and genetic variance for all traits in all populations, divergent sexual selection only weakly resembled the observed pattern of divergence. Accounting for the influence of genetic covariance among the traits significantly improved the alignment between observed and predicted divergence. Our results suggest that the direction in which sexual selection generates divergence may depend on the pattern of genetic constraint in individual populations, ultimately restricting how sexually selected traits may diversify. More generally, we show how evolution is likely to proceed in the direction of major axes of genetic variance, rather than the direction of selection itself, when genetic variance-covariance matrices are ill conditioned and genetic variance is low in the direction of selection.

  6. [Challenging behavior: behavioral phenotypes of some genetic syndromes].

    PubMed

    2014-01-01

    Challenging behavior in individuals with mental retardation (MR) is relatively frequent, and represents a significant obstacle to adaptive skills. The frequency of specific forms and manifestations of challenging behavior can depend on a variety of personal and environmental factors. There are several prominent theoretical models regarding the etiology of challenging behavior and psychopathology in persons with MR: behavioral, developmental, socio-cultural and biological.The biological model emphasizes the physiological, biochemical and genetic factors as the potential source of challenging behavior. The progress in the field of genetics and neuroscience has opened the opportunity to study and discover the neurobiological basis of phenotypic characteristics. Genetic syndromes associated with MR can be followed by a specific set of problems and disorders which constitutes their behavioral phenotype. The aim of this paper was to present challenging behaviors that manifest in the most frequently studied syndromes: Down syndrome, Fragile X syndrome, Williams syndrome, Prader-Willi syndrome and Angelman syndrome. The concept of behavioral phenotype implies a higher probability of manifesting specific developmental characteristics and specific behaviors in individuals with a certain genetic syndrome. Although the specific set of (possible) problems and disorders is distinctive for the described genetic syndromes, the connection between genetics and behavior should be viewed through probabilistic dimension. The probabilistic concept takes into consideration the possibility of intra-syndrome variability in the occurrence, intensity and time onset of behavioral characteristics, at which the higher variability the lower is the specificity of the genetic syndrome. Identifying the specific pattern of behavior can be most important for the process of early diagnosis and prognosis. In addition, having knowledge about behavioral phenotype can be a landmark in the creation of

  7. Estimation of Odds Ratios of Genetic Variants for the Secondary Phenotypes Associated with Primary Diseases

    PubMed Central

    Wang, Jian; Shete, Sanjay

    2011-01-01

    Genetic association studies for binary diseases are designed as case-control studies: the cases are those affected with the primary disease and the controls are free of the disease. At the time of case-control collection, information about secondary phenotypes is also collected. Association studies of secondary phenotype and genetic variants have received a great deal of interest recently. To study the secondary phenotypes, investigators use standard regression approaches, where individuals with secondary phenotypes are coded as cases and those without secondary phenotypes are coded as controls. However, using the secondary phenotype as an outcome variable in a case-control study might lead to a biased estimate of odds ratios (ORs) for genetic variants. The secondary phenotype is associated with the primary disease; therefore, individuals with and without the secondary phenotype are not sampled following the principles of a case-control study. In this article, we demonstrate that such analyses will lead to a biased estimate of OR and propose new approaches to provide more accurate OR estimates of genetic variants associated with the secondary phenotype for both unmatched and frequency-matched (with respect to the secondary phenotype) case-control studies. We also propose a bootstrapping method to estimate the empirical confidence intervals for the corrected ORs. Using simulation studies and analysis of lung cancer data for single-nucleotide polymorphism associated with smoking quantity, we compared our new approaches to standard logistic regression and to an extended version of the inverse-probability-of-sampling-weighted regression. The proposed approaches provide more accurate estimation of the true OR. PMID:21308766

  8. Genetic Mechanisms Involved in the Phenotype of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA…

  9. Genetic Mechanisms Involved in the Phenotype of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA…

  10. Behavioral Genetic Toolkits: Toward the Evolutionary Origins of Complex Phenotypes.

    PubMed

    Rittschof, C C; Robinson, G E

    2016-01-01

    The discovery of toolkit genes, which are highly conserved genes that consistently regulate the development of similar morphological phenotypes across diverse species, is one of the most well-known observations in the field of evolutionary developmental biology. Surprisingly, this phenomenon is also relevant for a wide array of behavioral phenotypes, despite the fact that these phenotypes are highly complex and regulated by many genes operating in diverse tissues. In this chapter, we review the use of the toolkit concept in the context of behavior, noting the challenges of comparing behaviors and genes across diverse species, but emphasizing the successes in identifying genetic toolkits for behavior; these successes are largely attributable to the creative research approaches fueled by advances in behavioral genomics. We have two general goals: (1) to acknowledge the groundbreaking progress in this field, which offers new approaches to the difficult but exciting challenge of understanding the evolutionary genetic basis of behaviors, some of the most complex phenotypes known, and (2) to provide a theoretical framework that encompasses the scope of behavioral genetic toolkit studies in order to clearly articulate the research questions relevant to the toolkit concept. We emphasize areas for growth and highlight the emerging approaches that are being used to drive the field forward. Behavioral genetic toolkit research has elevated the use of integrative and comparative approaches in the study of behavior, with potentially broad implications for evolutionary biologists and behavioral ecologists alike.

  11. Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

    ERIC Educational Resources Information Center

    Losh, Molly; Piven, Joseph

    2007-01-01

    Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

  12. Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

    ERIC Educational Resources Information Center

    Losh, Molly; Piven, Joseph

    2007-01-01

    Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

  13. Disease-Phenotype Deconvolution in Genetic Eye Diseases Using Online Mendelian Inheritance in Man.

    PubMed

    Pandey, Priyanka; Acharya, Moulinath

    2016-05-01

    Capturing organ-specific phenomes in genetic diseases is an uphill task for the eye as it comprises tissue types derived from all three germinal layers. We attempted to deconstruct genetic eye diseases (GEDs) into primary phenotypic features, to understand the complex genome-phenome relationship in GEDs. Using phenotype, molecular basis, and gene description features in OMIM as a primary resource, we analyzed gene-phenotype information. All ocular and systemic phenotypes were categorized and ranked based on occurrence. Clustering was performed on shared ocular features to identify genetic interactions and the largest cluster of each phenotype was used for functional analyses. We collected 527 GEDs associated with 440 unique protein-coding genes. We indexed 787 ocular and 3094 systemic features, for an average of 2.17 ocular and 8.14 systemic features, respectively, per disease unit. The most common ocular features included nystagmus, hypertelorism, and myopia, while neurological and skeletal are the most common systemic groups associated with GEDs. Functional analyses revealed pathways relevant to GEDs (e.g., extracellular matrix organization in ONH3 [glaucoma]) and protein metabolism in EOM35 (nystagmus) phenotype clusters. Our work imparts a structure in dissecting GEDs into unique phenotypes to study the relationship between genes and diseases involving the eye.

  14. Genetic heterogeneity of asthma phenotypes identified by a clustering approach.

    PubMed

    Siroux, Valérie; González, Juan R; Bouzigon, Emmanuelle; Curjuric, Ivan; Boudier, Anne; Imboden, Medea; Anto, Josep Maria; Gut, Ivo; Jarvis, Deborah; Lathrop, Mark; Omenaas, Ernst Reidar; Pin, Isabelle; Wjst, Mathias; Demenais, Florence; Probst-Hensch, Nicole; Kogevinas, Manolis; Kauffmann, Francine

    2014-02-01

    The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account. Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474). The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p<1.25 × 10(-7)) were observed between "active adult-onset nonallergic asthma" and rs9851461 flanking CD200 (3q13.2) and between "inactive/mild nonallergic asthma" and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5 × 10(-7) < p <8.2 × 10(-7)) were observed between three single nucleotide polymorphisms (SNPs) in the ALCAM region (3q13.11) and "active adult-onset nonallergic asthma". These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the "active allergic asthma" phenotype. Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.

  15. A multiple-phenotype imputation method for genetic studies.

    PubMed

    Dahl, Andrew; Iotchkova, Valentina; Baud, Amelie; Johansson, Åsa; Gyllensten, Ulf; Soranzo, Nicole; Mott, Richard; Kranis, Andreas; Marchini, Jonathan

    2016-04-01

    Genetic association studies have yielded a wealth of biological discoveries. However, these studies have mostly analyzed one trait and one SNP at a time, thus failing to capture the underlying complexity of the data sets. Joint genotype-phenotype analyses of complex, high-dimensional data sets represent an important way to move beyond simple genome-wide association studies (GWAS) with great potential. The move to high-dimensional phenotypes will raise many new statistical problems. Here we address the central issue of missing phenotypes in studies with any level of relatedness between samples. We propose a multiple-phenotype mixed model and use a computationally efficient variational Bayesian algorithm to fit the model. On a variety of simulated and real data sets from a range of organisms and trait types, we show that our method outperforms existing state-of-the-art methods from the statistics and machine learning literature and can boost signals of association.

  16. A multiple phenotype imputation method for genetic studies

    PubMed Central

    Dahl, Andrew; Iotchkova, Valentina; Baud, Amelie; Johansson, Åsa; Gyllensten, Ulf; Soranzo, Nicole; Mott, Richard; Kranis, Andreas; Marchini, Jonathan

    2016-01-01

    Genetic association studies have yielded a wealth of biologic discoveries. However, these have mostly analyzed one trait and one SNP at a time, thus failing to capture the underlying complexity of these datasets. Joint genotype-phenotype analyses of complex, high-dimensional datasets represent an important way to move beyond simple GWAS with great potential. The move to high-dimensional phenotypes will raise many new statistical problems. In this paper we address the central issue of missing phenotypes in studies with any level of relatedness between samples. We propose a multiple phenotype mixed model and use a computationally efficient variational Bayesian algorithm to fit the model. On a variety of simulated and real datasets from a range of organisms and trait types, we show that our method outperforms existing state-of-the-art methods from the statistics and machine learning literature and can boost signals of association. PMID:26901065

  17. The Genetics of Reading Disabilities: From Phenotypes to Candidate Genes

    PubMed Central

    Raskind, Wendy H.; Peter, Beate; Richards, Todd; Eckert, Mark M.; Berninger, Virginia W.

    2013-01-01

    This article provides an overview of (a) issues in definition and diagnosis of specific reading disabilities at the behavioral level that may occur in different constellations of developmental and phenotypic profiles (patterns); (b) rapidly expanding research on genetic heterogeneity and gene candidates for dyslexia and other reading disabilities; (c) emerging research on gene-brain relationships; and (d) current understanding of epigenetic mechanisms whereby environmental events may alter behavioral expression of genetic variations. A glossary of genetic terms (denoted by bold font) is provided for readers not familiar with the technical terms. PMID:23308072

  18. The evolution of human genetic and phenotypic variation in Africa.

    PubMed

    Campbell, Michael C; Tishkoff, Sarah A

    2010-02-23

    Africa is the birthplace of modern humans, and is the source of the geographic expansion of ancestral populations into other regions of the world. Indigenous Africans are characterized by high levels of genetic diversity within and between populations. The pattern of genetic variation in these populations has been shaped by demographic events occurring over the last 200,000 years. The dramatic variation in climate, diet, and exposure to infectious disease across the continent has also resulted in novel genetic and phenotypic adaptations in extant Africans. This review summarizes some recent advances in our understanding of the demographic history and selective pressures that have influenced levels and patterns of diversity in African populations.

  19. Genetic mapping of quantitative phenotypic traits in Saccharomyces cerevisiae.

    PubMed

    Swinnen, Steve; Thevelein, Johan M; Nevoigt, Elke

    2012-03-01

    Saccharomyces cerevisiae has become a favorite production organism in industrial biotechnology presenting new challenges to yeast engineers in terms of introducing advantageous traits such as stress tolerances. Exploring subspecies diversity of S. cerevisiae has identified strains that bear industrially relevant phenotypic traits. Provided that the genetic basis of such phenotypic traits can be identified inverse engineering allows the targeted modification of production strains. Most phenotypic traits of interest in S. cerevisiae strains are quantitative, meaning that they are controlled by multiple genetic loci referred to as quantitative trait loci (QTL). A straightforward approach to identify the genetic basis of quantitative traits is QTL mapping which aims at the allocation of the genetic determinants to regions in the genome. The application of high-density oligonucleotide arrays and whole-genome re-sequencing to detect genetic variations between strains has facilitated the detection of large numbers of molecular markers thus allowing high-resolution QTL mapping over the entire genome. This review focuses on the basic principle and state of the art of QTL mapping in S. cerevisiae. Furthermore we discuss several approaches developed during the last decade that allow down-scaling of the regions identified by QTL mapping to the gene level. We also emphasize the particular challenges of QTL mapping in nonlaboratory strains of S. cerevisiae.

  20. Phenotypic, genetic, and environmental properties of the portrait values questionnaire.

    PubMed

    Schermer, Julie Aitken; Feather, N T; Zhu, Gu; Martin, Nicholas G

    2008-10-01

    The purpose of the present study was to examine the 10 value types from the Portrait Values Questionnaire (PVQ; Schwartz et al., 2001) both at the phenotypic (observed) level as well as the genetic and environmental level. Australian twins (N = 695) completed the PVQ as part of a larger questionnaire battery. Nine of the value types were found to have a genetic component with heritability estimates ranging from 10.8% for power to 38% for conformity. The achievement scale was best explained by environmental factors. The interscale correlations were found to range from -.02 to .70 at the phenotypic level. Of these 45 correlations, 16 were found to be explained by overlapping genetic factors and almost all (41) were found to have significant unique environment correlations.

  1. Genetic neurological channelopathies: molecular genetics and clinical phenotypes.

    PubMed

    Spillane, J; Kullmann, D M; Hanna, M G

    2016-01-01

    Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies.

  2. Genetic neurological channelopathies: molecular genetics and clinical phenotypes

    PubMed Central

    Spillane, J; Kullmann, D M; Hanna, M G

    2016-01-01

    Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies. PMID:26558925

  3. Psychiatric features in children with genetic syndromes: toward functional phenotypes.

    PubMed

    Siegel, Matthew S; Smith, Wendy E

    2010-04-01

    Neurodevelopmental disorders with identified genetic etiologies present a unique opportunity to study gene-brain-behavior connections in child psychiatry. Parsing complex human behavior into dissociable components is facilitated by examining a relatively homogenous genetic population. As children with developmental delay carry a greater burden of mental illness than the general population, familiarity with the most common genetic disorders will serve practitioners seeing a general child population. In this article basic genetic testing and 11 of the most common genetic disorders are reviewed, including the evidence base for treatment. Based on their training in child development, family systems, and multimodal treatment, child psychiatrists are well positioned to integrate cognitive, behavioral, social, psychiatric, and physical phenotypes, with a focus on functional impairment.

  4. Evolution of phenotype-environment associations by genetic responses to selection and phenotypic plasticity in a temporally autocorrelated environment.

    PubMed

    Michel, Matt J; Chevin, Luis-Miguel; Knouft, Jason H

    2014-05-01

    Covariation between population-mean phenotypes and environmental variables, sometimes termed a "phenotype-environment association" (PEA), can result from phenotypic plasticity, genetic responses to natural selection, or both. PEAs can potentially provide information on the evolutionary dynamics of a particular set of populations, but this requires a full theoretical characterization of PEAs and their evolution. Here, we derive formulas for the expected PEA in a temporally fluctuating environment for a quantitative trait with a linear reaction norm. We compare several biologically relevant scenarios, including constant versus evolving plasticity, and the situation in which an environment affects both development and selection but at different time periods. We find that PEAs are determined not only by biological factors (e.g., magnitude of plasticity, genetic variation), but also environmental factors, such as the association between the environments of development and of selection, and in some cases the level of temporal autocorrelation. We also describe how a PEA can be used to estimate the relationship between an optimum phenotype and an environmental variable (i.e., the environmental sensitivity of selection), an important parameter for determining the extinction risk of populations experiencing environmental change. We illustrate this ability using published data on the predator-induced morphological responses of tadpoles to predation risk.

  5. A New Method to Infer Causal Phenotype Networks Using QTL and Phenotypic Information

    PubMed Central

    Wang, Huange; van Eeuwijk, Fred A.

    2014-01-01

    In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs) to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO) algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the-art approach, the QTL-directed dependency graph (QDG) algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request. PMID:25144184

  6. A new method to infer causal phenotype networks using QTL and phenotypic information.

    PubMed

    Wang, Huange; van Eeuwijk, Fred A

    2014-01-01

    In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs) to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO) algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the-art approach, the QTL-directed dependency graph (QDG) algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request.

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

    PubMed Central

    Weatherall, D

    1999-01-01

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

  8. [Research progress on the phenotype informative SNP in forensic science].

    PubMed

    Liu, Yu-Xuan; Hu, Qing-Qing; Ma, Hong-Du; Huang, Dai-Xin

    2014-10-01

    Single nucleotide polymorphism (SNP) refers to the single base sequence variation in specific location of the human genome. Phenotype informative SNP has gradually become one of the research hot spots in forensic science. In this paper, the forensic research situation and application prospect of phenotype informative SNP in the characteristics of hair, eye and skin color, height, and facial feature are reviewed.

  9. Genetic dynamics underlying phenotypic development of biomass yield in triticale.

    PubMed

    Liu, Wenxin; Gowda, Manje; Reif, Jochen C; Hahn, Volker; Ruckelshausen, Arno; Weissmann, Elmar A; Maurer, Hans Peter; Würschum, Tobias

    2014-06-10

    The nature of dynamic traits with their phenotypic plasticity suggests that they are under the control of a dynamic genetic regulation. We employed a precision phenotyping platform to non-invasively assess biomass yield in a large mapping population of triticale at three developmental stages. Using multiple-line cross QTL mapping we identified QTL for each of these developmental stages which explained a considerable proportion of the genotypic variance. Some QTL were identified at each developmental stage and thus contribute to biomass yield throughout the studied developmental phases. Interestingly, we also observed QTL that were only identified for one or two of the developmental stages illustrating a temporal contribution of these QTL to the trait. In addition, epistatic QTL were detected and the epistatic interaction landscape was shown to dynamically change with developmental progression. In summary, our results reveal the temporal dynamics of the genetic architecture underlying biomass accumulation in triticale and emphasize the need for a temporal assessment of dynamic traits.

  10. Genetic and phenotypic diversity in breast tumor metastases.

    PubMed

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-03-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease. ©2014 AACR

  11. Sex differences in genetic architecture of complex phenotypes?

    PubMed

    Vink, Jacqueline M; Bartels, Meike; van Beijsterveldt, Toos C E M; van Dongen, Jenny; van Beek, Jenny H D A; Distel, Marijn A; de Moor, Marleen H M; Smit, Dirk J A; Minica, Camelia C; Ligthart, Lannie; Geels, Lot M; Abdellaoui, Abdel; Middeldorp, Christel M; Hottenga, Jouke Jan; Willemsen, Gonneke; de Geus, Eco J C; Boomsma, Dorret I

    2012-01-01

    We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.

  12. Genetic and phenotypic variation along an ecological gradient in lake trout Salvelinus namaycush

    USGS Publications Warehouse

    Baillie, Shauna M.; Muir, Andrew M.; Hansen, Michael J.; Krueger, Charles Conrad; Bentzen, Paul

    2016-01-01

    BackgroundAdaptive radiation involving a colonizing phenotype that rapidly evolves into at least one other ecological variant, or ecotype, has been observed in a variety of freshwater fishes in post-glacial environments. However, few studies consider how phenotypic traits vary with regard to neutral genetic partitioning along ecological gradients. Here, we present the first detailed investigation of lake trout Salvelinus namaycushthat considers variation as a cline rather than discriminatory among ecotypes. Genetic and phenotypic traits organized along common ecological gradients of water depth and geographic distance provide important insights into diversification processes in a lake with high levels of human disturbance from over-fishing.ResultsFour putative lake trout ecotypes could not be distinguished using population genetic methods, despite morphological differences. Neutral genetic partitioning in lake trout was stronger along a gradient of water depth, than by locality or ecotype. Contemporary genetic migration patterns were consistent with isolation-by-depth. Historical gene flow patterns indicated colonization from shallow to deep water. Comparison of phenotypic (Pst) and neutral genetic variation (Fst) revealed that morphological traits related to swimming performance (e.g., buoyancy, pelvic fin length) departed more strongly from neutral expectations along a depth gradient than craniofacial feeding traits. Elevated phenotypic variance with increasing water depth in pelvic fin length indicated possible ongoing character release and diversification. Finally, differences in early growth rate and asymptotic fish length across depth strata may be associated with limiting factors attributable to cold deep-water environments.ConclusionWe provide evidence of reductions in gene flow and divergent natural selection associated with water depth in Lake Superior. Such information is relevant for documenting intraspecific biodiversity in the largest freshwater lake

  13. Genetic and phenotypic variation along an ecological gradient in lake trout Salvelinus namaycush.

    PubMed

    Baillie, Shauna M; Muir, Andrew M; Hansen, Michael J; Krueger, Charles C; Bentzen, Paul

    2016-10-19

    Adaptive radiation involving a colonizing phenotype that rapidly evolves into at least one other ecological variant, or ecotype, has been observed in a variety of freshwater fishes in post-glacial environments. However, few studies consider how phenotypic traits vary with regard to neutral genetic partitioning along ecological gradients. Here, we present the first detailed investigation of lake trout Salvelinus namaycush that considers variation as a cline rather than discriminatory among ecotypes. Genetic and phenotypic traits organized along common ecological gradients of water depth and geographic distance provide important insights into diversification processes in a lake with high levels of human disturbance from over-fishing. Four putative lake trout ecotypes could not be distinguished using population genetic methods, despite morphological differences. Neutral genetic partitioning in lake trout was stronger along a gradient of water depth, than by locality or ecotype. Contemporary genetic migration patterns were consistent with isolation-by-depth. Historical gene flow patterns indicated colonization from shallow to deep water. Comparison of phenotypic (Pst) and neutral genetic variation (Fst) revealed that morphological traits related to swimming performance (e.g., buoyancy, pelvic fin length) departed more strongly from neutral expectations along a depth gradient than craniofacial feeding traits. Elevated phenotypic variance with increasing water depth in pelvic fin length indicated possible ongoing character release and diversification. Finally, differences in early growth rate and asymptotic fish length across depth strata may be associated with limiting factors attributable to cold deep-water environments. We provide evidence of reductions in gene flow and divergent natural selection associated with water depth in Lake Superior. Such information is relevant for documenting intraspecific biodiversity in the largest freshwater lake in the world for a

  14. [Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases].

    PubMed

    Humbertclaude, V; Hamroun, D; Picot, M-C; Bezzou, K; Bérard, C; Boespflug-Tanguy, O; Bommelaer, C; Campana-Salort, E; Cances, C; Chabrol, B; Commare, M-C; Cuisset, J-M; de Lattre, C; Desnuelle, C; Echenne, B; Halbert, C; Jonquet, O; Labarre-Vila, A; N'guyen-Morel, M-A; Pages, M; Pepin, J-L; Petitjean, T; Pouget, J; Ollagnon-Roman, E; Richelme, C; Rivier, F; Sacconi, S; Tiffreau, V; Vuillerot, C; Béroud, C; Tuffery-Giraud, S; Claustres, M

    2013-01-01

    The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

  15. Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

    PubMed Central

    Jelcick, Austin S.; Yuan, Yang; Leehy, Barrett D.; Cox, Lakeisha C.; Silveira, Alexandra C.; Qiu, Fang; Schenk, Sarah; Sachs, Andrew J.; Morrison, Margaux A.; Nystuen, Arne M.; DeAngelis, Margaret M.; Haider, Neena B.

    2011-01-01

    Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2-nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases. PMID:21779340

  16. Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network

    PubMed Central

    Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Robert D.; Chapman, Sherita N.; Cole, John W.; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P.; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J.; Kleindorfer, Dawn O.; Labovitz, Daniel L.; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S.; McArdle, Patrick F.; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M.; Rhodes, David; Rich, Stephen S.; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M.; Rundek, Tatjana; Sacco, Ralph L.; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B.; Meschia, James F.

    2014-01-01

    Background and Purpose NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of etiologic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause) and causative ischemic stroke subtypes in 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Results The distribution of etiologic categories varied by study, age, sex, and race (p<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0.72, 95%CI:0.69-0.75) and phenotypic classifications (kappa 0.73, 95%CI:0.70-0.75). Conclusions This study demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke. PMID:25378430

  17. The Evolution of Human Genetic and Phenotypic Variation in Africa

    PubMed Central

    Campbell, Michael C.

    2010-01-01

    Africa is the birthplace of modern humans, and is the source of the geographic expansion of ancestral populations into other regions of the world. Indigenous Africans are characterized by high levels of genetic diversity within and between populations. The pattern of genetic variation in these populations has been shaped by demographic events occurring over the last 200,000 years. The dramatic variation in climate, diet, and exposure to infectious disease across the continent has also resulted in novel genetic and phenotypic adaptations in extant Africans. This review summarizes some recent advances in our understanding of the demographic history and selective pressures that have influenced levels and patterns of diversity in African populations. PMID:20178763

  18. Genetics of resistant hypertension: a novel pharmacogenomics phenotype.

    PubMed

    El Rouby, Nihal; Cooper-DeHoff, Rhonda M

    2015-09-01

    Resistant hypertension (RHTN), defined as an uncontrolled blood pressure despite the use of multiple antihypertensive medications, is an increasing clinical problem associated with increased cardiovascular (CV) risk, including stroke and target organ damage. Genetic variability in blood pressure (BP)-regulating genes and pathways may, in part, account for the variability in BP response to antihypertensive agents, when taken alone or in combination, and may contribute to the RHTN phenotype. Pharmacogenomics focuses on the identification of genetic factors responsible for inter-individual variability in drug response. Expanding pharmacogenomics research to include patients with RHTN taking multiple BP-lowering medications may identify genetic markers associated with RHTN. To date, the available evidence surrounding pharmacogenomics in RHTN is limited and primarily focused on candidate genes. In this review, we summarize the most current data in RHTN pharmacogenomics and offer some recommendations on how to advance the field.

  19. Genetically determined phenotype covariation networks control bone strength.

    PubMed

    Jepsen, Karl J; Courtland, Hayden-William; Nadeau, Joseph H

    2010-07-01

    To identify genes affecting bone strength, we studied how genetic variants regulate components of a phenotypic covariation network that was previously shown to accurately characterize the compensatory trait interactions involved in functional adaptation during growth. Quantitative trait loci (QTLs) regulating femoral robustness, morphologic compensation, and mineralization (tissue quality) were mapped at three ages during growth using AXB/BXA Recombinant Inbred (RI) mouse strains and adult B6-i(A) Chromosome Substitution Strains (CSS). QTLs for robustness were identified on chromosomes 8, 12, 18, and 19 and confirmed at all three ages, indicating that genetic variants established robustness postnatally without further modification. A QTL for morphologic compensation, which was measured as the relationship between cortical area and body weight, was identified on chromosome 8. This QTL limited the amount of bone formed during growth and thus acted as a setpoint for diaphyseal bone mass. Additional QTLs were identified from the CSS analysis. QTLs for robustness and morphologic compensation regulated bone structure independently (ie, in a nonpleiotropic manner), indicating that each trait may be targeted separately to individualize treatments aiming to improve strength. Multiple regression analyses showed that variation in morphologic compensation and tissue quality, not bone size, determined femoral strength relative to body weight. Thus an individual inheriting slender bones will not necessarily inherit weak bones unless the individual also inherits a gene that impairs compensation. This systems genetic analysis showed that genetically determined phenotype covariation networks control bone strength, suggesting that incorporating functional adaptation into genetic analyses will advance our understanding of the genetic basis of bone strength.

  20. A molecular genetic study of autism and related phenotypes in extended pedigrees

    PubMed Central

    2013-01-01

    Background Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. Methods We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. Results Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. Conclusions These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears

  1. Using genetic networks and homology to understand the evolution of phenotypic traits.

    PubMed

    McCune, Amy R; Schimenti, John C

    2012-03-01

    Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, "biological homology" emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as "the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features." Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its "essential identity" (a Character Identity Network or "ChIN") must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits.

  2. Difference in MSA phenotype distribution between populations: genetics or environment?

    PubMed

    Ozawa, Tetsutaro; Revesz, Tamas; Paviour, Dominic; Lees, Andrew J; Quinn, Niall; Tada, Mari; Kakita, Akiyoshi; Onodera, Osamu; Wakabayashi, Koichi; Takahashi, Hitoshi; Nishizawa, Masatoyo; Holton, Janice L

    2012-01-01

    The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA-P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations.

  3. Behavioral phenotypes of genetic mouse models of autism.

    PubMed

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  4. The phenotypic and genetic signatures of common musculoskeletal pain conditions

    PubMed Central

    Diatchenko, Luda; Fillingim, Roger B.; Smith, Shad B.; Maixner, William

    2014-01-01

    Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and ‘psychological’ measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine. PMID:23545734

  5. The genetic basis of hair whorl, handedness, and other phenotypes

    USGS Publications Warehouse

    Hatfield, J.S.

    2006-01-01

    Evidence is presented that RHO, RHCE, and other RH genes, may be interesting candidates to consider when searching for the genetic basis of hair whorl rotation (i.e., clockwise or counterclockwise), handedness (i.e., right handed, left handed or ambidextrous), speech laterality (i.e., right brained or left brained), speech dyslexia (e.g., stuttering), sexual orientation (i.e., heterosexual, homosexual, bisexual, or transsexual), schizophrenia, bipolar disorder, and autism spectrum disorder. Such evidence involves the need for a genetic model that includes maternal immunization to explain some of the empirical results reported in the literature. The complex polymorphisms present among the maternally immunizing RH genes can then be used to explain other empirical results. Easily tested hypotheses are suggested, based upon genotypic (but not phenotypic) frequencies of the RH genes. In particular, homozygous dominant individuals are expected to be less common or lacking entirely among the alternative phenotypes. If it is proven that RH genes are involved in brain architecture, it will have a profound effect upon our understanding of the development and organization of the asymmetrical vertebrate brain and may eventually lead to a better understanding of the developmental processes which occur to produce the various alternative phenotypes discussed here. In addition, if RH genes are shown to be involved in the production of these phenotypes, then the evolutionary studies can be performed to demonstrate the beneficial effect of the recessive alleles of RHO and RHCE, and why human evolution appears to be selecting for the recessive alleles even though an increase in the frequency of such alleles may imply lower average fecundity among some individuals possessing them.

  6. Genetic and phenotypic differentiation of an Andean intermediate altitude population

    PubMed Central

    Eichstaedt, Christina A; Antão, Tiago; Cardona, Alexia; Pagani, Luca; Kivisild, Toomas; Mormina, Maru

    2015-01-01

    Highland populations living permanently under hypobaric hypoxia have been subject of extensive research because of the relevance of their physiological adaptations for the understanding of human health and disease. In this context, what is considered high altitude is a matter of interpretation and while the adaptive processes at high altitude (above 3000 m) are well documented, the effects of moderate altitude (below 3000 m) on the phenotype are less well established. In this study, we compare physiological and anthropometric characteristics as well as genetic variations in two Andean populations: the Calchaquíes (2300 m) and neighboring Collas (3500 m). We compare their phenotype and genotype to the sea-level Wichí population. We measured physiological (heart rate, oxygen saturation, respiration rate, and lung function) as well as anthropometric traits (height, sitting height, weight, forearm, and tibia length). We conducted genome-wide genotyping on a subset of the sample (n = 74) and performed various scans for positive selection. At the phenotypic level (n = 179), increased lung capacity stood out in both Andean groups, whereas a growth reduction in distal limbs was only observed at high altitude. At the genome level, Calchaquíes revealed strong signals around PRKG1, suggesting that the nitric oxide pathway may be a target of selection. PRKG1 was highlighted by one of four selection tests among the top five genes using the population branch statistic. Selection tests results of Collas were reported previously. Overall, our study shows that some phenotypic and genetic differentiation occurs at intermediate altitude in response to moderate lifelong selection pressures. PMID:25948820

  7. AudioGene: Predicting Hearing Loss Genotypes from Phenotypes to Guide Genetic Screening

    PubMed Central

    Taylor, Kyle R.; DeLuca, Adam P.; Shearer, A. Eliot; Hildebrand, Michael S.; Black-Ziegelbein, E. Ann; Anand, V. Nikhil; Sloan, Christina M.; Eppsteiner, Robert W.; Scheetz, Todd E.; Huygen, Patrick L. M.; Smith, Richard J. H.; Braun, Terry A.; Casavant, Thomas L.

    2013-01-01

    Autosomal Dominant Nonsyndromic Hearing Loss (ADNSHL) is a common and often progressive sensory deficit. ADNSHL displays a high degree of genetic heterogeneity, and varying rates of progression. Accurate, comprehensive and cost-effective genetic testing facilitates genetic counseling and provides valuable prognostic information to affected individuals. In this paper, we describe the algorithm underlying AudioGene, a software system employing machine-learning techniques that utilizes phenotypic information derived from audiograms to predict the genetic cause of hearing loss in persons segregating ADNSHL. Our data show that AudioGene has an accuracy of 68% in predicting the causative gene within its top three predictions, as compared to 44% for a Majority classifier. We also show that AudioGene remains effective for audiograms with high levels of clinical measurement noise. We identify audiometric outliers for each genetic locus and hypothesize that outliers may reflect modifying genetic effects. As personalized genomic medicine becomes more common, AudioGene will be increasingly useful as a phenotypic filter to assess pathogenicity of variants identified by massively parallel sequencing. PMID:23280582

  8. Phenotypic and Genetic Effects of Contrasting Ethanol Environments on Physiological and Developmental Traits in Drosophila melanogaster

    PubMed Central

    Castañeda, Luis E.; Nespolo, Roberto F.

    2013-01-01

    A central problem in evolutionary physiology is to understand the relationship between energy metabolism and fitness-related traits. Most attempts to do so have been based on phenotypic correlations that are not informative for the evolutionary potential of natural populations. Here, we explored the effect of contrasting ethanol environments on physiological and developmental traits, their genetic (co)variances and genetic architecture in Drosophila melanogaster. Phenotypic and genetic parameters were estimated in two populations (San Fernando and Valdivia, Chile), using a half-sib family design where broods were split into ethanol-free and ethanol-supplemented conditions. Our findings show that metabolic rate, body mass and development times were sensitive (i.e., phenotypic plasticity) to ethanol conditions and dependent on population origin. Significant heritabilities were found for all traits, while significant genetic correlations were only found between larval and total development time and between development time and metabolic rate for flies of the San Fernando population developed in ethanol-free conditions. Posterior analyses indicated that the G matrices differed between ethanol conditions for the San Fernando population (mainly explained by differences in genetic (co)variances of developmental traits), whereas the Valdivia population exhibited similar G matrices between ethanol conditions. Our findings suggest that ethanol-free environment increases the energy available to reduce development time. Therefore, our results indicate that environmental ethanol could modify the process of energy allocation, which could have consequences on the evolutionary response of natural populations of D. melanogaster. PMID:23505567

  9. Phenotype profile of a genetic mouse model for Muenke syndrome

    PubMed Central

    Koyama, Eiki; Agochukwu, Nneamaka B.; Bartlett, Scott P.; Muenke, Maximilian

    2014-01-01

    Purpose The Muenke syndrome mutation (FGFR3P250R), which was discovered 15 years ago, represents the single most common craniosynostosis mutation. Muenke syndrome is characterized by coronal suture synostosis, mid-face hypoplasia, subtle limb anomalies, and hearing loss. However, the spectrum of clinical presentation continues to expand. To better understand the pathophysiology of the Muenke syndrome, we present collective findings from several recent studies that have characterized a genetically equivalent mouse model for Muenke syndrome (FgfR3P244R) and compare them with human phenotypes. Conclusions FgfR3P244R mutant mice show premature fusion of facial sutures, premaxillary and/or zygomatic sutures, but rarely the coronal suture. The mice also lack the typical limb phenotype. On the other hand, the mutant mice display maxillary retrusion in association with a shortening of the anterior cranial base and a premature closure of intersphenoidal and spheno-occipital synchondroses, resembling human midface hypoplasia. In addition, sensorineural hearing loss is detected in all FgfR3P244R mutant mice as in the majority of Muenke syndrome patients. It is caused by a defect in the mechanism of cell fate determination in the organ of Corti. The mice also express phenotypes that have not been previously described in humans, such as reduced cortical bone thickness, hypoplastic trabecular bone, and defective temporomandibular joint structure. Therefore, the FgfR3P244R mouse provides an excellent opportunity to study disease mechanisms of some classical phenotypes of Muenke syndrome and to test novel therapeutic strategies. The mouse model can also be further explored to discover previously unreported yet potentially significant phenotypes of Muenke syndrome. PMID:22872265

  10. Phenotype with a side of genotype, please: Patients, parents and priorities in rare genetic disease

    PubMed Central

    Collins, Christy

    2016-01-01

    As the parent and caregiver of a child with an ultra-rare disease and advocate for others with the same condition, I discuss the importance of phenotyping in rare disease research. I emphasize the need for more clinical geneticists, deeper and more intentional integration of clinical genetics in complex patient care, and a greater appreciation of patients and families as an informational resource. PMID:27047761

  11. New genetic model for predicting phenotype traits in sports.

    PubMed

    Massidda, Myosotis; Scorcu, Marco; Calò, Carla M

    2014-05-01

    The aim of the current study was to construct a genetic model with a new algorithm for predicting athletic-performance variability based on genetic variations. The influence of 6 polymorphisms (ACE, ACTN-3, BDKRB2, VDR-ApaI, VDR-BsmI, and VDR-FokI) on vertical jump was studied in top-level male Italian soccer players (n = 90). First, the authors calculated the traditional total genotype score and then determined the total weighting genotype score (TWGS), which accounts for the proportion of significant phenotypic variance predicted by the polymorphisms. Genomic DNA was extracted from saliva samples using a standard protocol. Genotyping was performed using polymerase chain reaction (PCR). The results obtained from the new genetic model (TWGS) showed that only 3 polymorphisms entered the regression equation (ACTN-3, ACE, and BDKRB2), and these polymorphisms explained 17.68-24.24% of the vertical-jump variance. With the weighting given to each polymorphism, it may be possible to identify a polygenic profile that more accurately explains, at least in part, the individual variance of athletic-performance traits. This model may be used to create individualized training programs based on a player's genetic predispositions, as well as to identify athletes who need an adapted training routine to account for individual susceptibility to injury.

  12. Genetic and phenotypic intra-species variation in Candida albicans

    PubMed Central

    Hirakawa, Matthew P.; Martinez, Diego A.; Sakthikumar, Sharadha; Anderson, Matthew Z.; Berlin, Aaron; Gujja, Sharvari; Zeng, Qiandong; Zisson, Ethan; Wang, Joshua M.; Greenberg, Joshua M.; Berman, Judith

    2015-01-01

    Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity. PMID:25504520

  13. Behavioral phenotypes of genetic mouse models of autism

    PubMed Central

    Kazdoba, T. M.; Leach, P. T.; Crawley, J. N.

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. PMID:26403076

  14. Genetic and phenotypic intra-species variation in Candida albicans.

    PubMed

    Hirakawa, Matthew P; Martinez, Diego A; Sakthikumar, Sharadha; Anderson, Matthew Z; Berlin, Aaron; Gujja, Sharvari; Zeng, Qiandong; Zisson, Ethan; Wang, Joshua M; Greenberg, Joshua M; Berman, Judith; Bennett, Richard J; Cuomo, Christina A

    2015-03-01

    Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity.

  15. [Genetic analysis of an individual with para-Bombay phenotype].

    PubMed

    Lin, Jia-jin; Huang, Ying; Zhu, Sui-yong

    2013-04-01

    To study genetic characteristics of an individual with para-Bombay phenotype and her family members. ABO and H antigens were detected with routine serological techniques.The entire coding region of FUT1 gene was amplified by polymerase chain reaction (PCR). PCR products was purified with enzymes digestion and directly sequenced. The RBCs of the proband did not agglutinate with H antibody. The proband therefore has a para-Bombay phenotype (Bmh). Direct sequencing indicated the FUT1 sequence of the proband contained a homozygous 547-552 del AG and heterozygous 814A>G mutation, which gave rise to two haplotypes of 547-552delAG, 547-552delAG and 814A>G. The ABO blood type of the proband' s mother and sisters were all B.Sequencing of the FUT1 gene has found heterozygous 547-552 del AG, 814A>G mutations in the mother and elder sister, and heterozygous 547-552 del AG mutation in her younger sister. The FUT1 547-552 del AG and 814 A>G mutations of the proband were inherited from her mother. A complex mutation of the FUT1 gene consisting of 547-55 del AG and 814 A>G has been identified in an individual with para-Bombay phenotype.

  16. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection

    PubMed Central

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-01

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. DOI: http://dx.doi.org/10.7554/eLife.04494.001 PMID:25599590

  17. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.

    PubMed

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-20

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies.

  18. Pangenesis as a source of new genetic information. The history of a now disproven theory.

    PubMed

    Bergman, Gerald

    2006-01-01

    Evolution is based on natural selection of existing biological phenotypic traits. Natural selection can only eliminate traits. It cannot create new ones, requiring a theory to explain the origin of new genetic information. The theory of pangenesis was a major attempt to explain the source of new genetic information required to produce phenotypic variety. This theory, advocated by Darwin as the main source of genetic variety, has now been empirically disproved. It is currently a theory mainly of interest to science historians.

  19. Toward conservation of genetic and phenotypic diversity in Japanese sticklebacks.

    PubMed

    Kitano, Jun; Mori, Seiichi

    2016-10-13

    Stickleback fishes have been established as a leading model system for studying the genetic mechanisms that underlie naturally occurring phenotypic diversification. Because of the tremendous diversification achieved by stickleback species in various environments, different geographical populations have unique phenotypes and genotypes, which provide us with unique opportunities for evolutionary genetic research. Among sticklebacks, Japanese species have several unique characteristics that have not been found in other populations. The sympatric marine threespine stickleback species Gasterosteus aculeatus and G. nipponicus (Japan Sea stickleback) are a good system for speciation research. Gasterosteus nipponicus also has several unique characteristics, such as neo-sex chromosomes and courtship behaviors, that differ from those of G. aculeatus. Several freshwater populations derived from G. aculeatus (Hariyo threespine stickleback) inhabit spring-fed ponds and streams in central Honshu and exhibit year-round reproduction, which has never been observed in other stickleback populations. Four species of ninespine stickleback, including Pungitius tymensis and the freshwater, brackish water and Omono types of the P. pungitius-P. sinensis complex, are also excellent model systems for speciation research. Anthropogenic alteration of environments, however, has exposed several Japanese stickleback populations to the risk of extinction and has actually led to extinction of several populations and species. Pungitius kaibarae, which is endemic to East Asia, used to inhabit Kyoto and Hyogo prefectures, but is now extinct. Causes of extinction include depletion of spring water, landfill of habitats, and construction of river-mouth weirs. Here, we review the importance of Japanese sticklebacks as genetic resources, the status of several endangered stickleback populations and species, and the factors putting these populations at risk.

  20. The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families

    PubMed Central

    Keser, Vafa; Khan, Ayesha; Siddiqui, Sorath; Lopez, Irma; Ren, Huanan; Qamar, Raheel; Nadaf, Javad; Majewski, Jacek; Chen, Rui; Koenekoop, Robert K.

    2017-01-01

    Purpose To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). Methods We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing. Results We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes. Conclusions Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families. PMID:28192794

  1. Deep phenotyping unveils hidden traits and genetic relations in subtle mutants

    PubMed Central

    San-Miguel, Adriana; Kurshan, Peri T.; Crane, Matthew M.; Zhao, Yuehui; McGrath, Patrick T.; Shen, Kang; Lu, Hang

    2016-01-01

    Discovering mechanistic insights from phenotypic information is critical for the understanding of biological processes. For model organisms, unlike in cell culture, this is currently bottlenecked by the non-quantitative nature and perceptive biases of human observations, and the limited number of reporters that can be simultaneously incorporated in live animals. An additional challenge is that isogenic populations exhibit significant phenotypic heterogeneity. These difficulties limit genetic approaches to many biological questions. To overcome these bottlenecks, we developed tools to extract complex phenotypic traits from images of fluorescently labelled subcellular landmarks, using C. elegans synapses as a test case. By population-wide comparisons, we identified subtle but relevant differences inaccessible to subjective conceptualization. Furthermore, the models generated testable hypotheses of how individual alleles relate to known mechanisms or belong to new pathways. We show that our model not only recapitulates current knowledge in synaptic patterning but also identifies novel alleles overlooked by traditional methods. PMID:27876787

  2. Deep phenotyping unveils hidden traits and genetic relations in subtle mutants

    NASA Astrophysics Data System (ADS)

    San-Miguel, Adriana; Kurshan, Peri T.; Crane, Matthew M.; Zhao, Yuehui; McGrath, Patrick T.; Shen, Kang; Lu, Hang

    2016-11-01

    Discovering mechanistic insights from phenotypic information is critical for the understanding of biological processes. For model organisms, unlike in cell culture, this is currently bottlenecked by the non-quantitative nature and perceptive biases of human observations, and the limited number of reporters that can be simultaneously incorporated in live animals. An additional challenge is that isogenic populations exhibit significant phenotypic heterogeneity. These difficulties limit genetic approaches to many biological questions. To overcome these bottlenecks, we developed tools to extract complex phenotypic traits from images of fluorescently labelled subcellular landmarks, using C. elegans synapses as a test case. By population-wide comparisons, we identified subtle but relevant differences inaccessible to subjective conceptualization. Furthermore, the models generated testable hypotheses of how individual alleles relate to known mechanisms or belong to new pathways. We show that our model not only recapitulates current knowledge in synaptic patterning but also identifies novel alleles overlooked by traditional methods.

  3. Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes.

    PubMed

    Amberger, Joanna S; Hamosh, Ada

    2017-06-27

    Online Mendelian Inheritance in Man (OMIM) at OMIM.org is the primary repository of comprehensive, curated information on genes and genetic phenotypes and the relationships between them. This unit provides an overview of the types of information in OMIM and optimal strategies for searching and retrieving the information. OMIM.org has links to many related and complementary databases, providing easy access to more information on a topic. The relationship between genes and genetic disorders is highlighted in this unit. The basic protocol explains searching OMIM both from a gene perspective and a clinical features perspective. Two alternate protocols provide strategies for viewing gene-phenotype relationships: a gene map table and Quick View or Side-by-Side format for clinical features. OMIM.org is updated nightly, and the MIMmatch service, described in the support protocol, provides a convenient way to follow updates to entries, gene-phenotype relationships, and collaborate with other researchers. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  4. The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses.

    PubMed

    Buxbaum, Joseph D; Bolshakova, Nadia; Brownfeld, Jessica M; Anney, Richard Jl; Bender, Patrick; Bernier, Raphael; Cook, Edwin H; Coon, Hilary; Cuccaro, Michael; Freitag, Christine M; Hallmayer, Joachim; Geschwind, Daniel; Klauck, Sabine M; Nurnberger, John I; Oliveira, Guiomar; Pinto, Dalila; Poustka, Fritz; Scherer, Stephen W; Shih, Andy; Sutcliffe, James S; Szatmari, Peter; Vicente, Astrid M; Vieland, Veronica; Gallagher, Louise

    2014-01-01

    There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete

  5. The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

    PubMed Central

    2014-01-01

    Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the

  6. Sequential phenotypic constraints on social information use in wild baboons.

    PubMed

    Carter, Alecia J; Torrents Ticó, Miquel; Cowlishaw, Guy

    2016-04-12

    Social information allows the rapid dissemination of novel information among individuals. However, an individual's ability to use information is likely to be dependent on phenotypic constraints operating at three successive steps: acquisition, application, and exploitation. We tested this novel framework by quantifying the sequential process of social information use with experimental food patches in wild baboons (Papio ursinus). We identified phenotypic constraints at each step of the information use sequence: peripheral individuals in the proximity network were less likely to acquire and apply social information, while subordinate females were less likely to exploit it successfully. Social bonds and personality also played a limiting role along the sequence. As a result of these constraints, the average individual only acquired and exploited social information on.

  7. B lymphocyte immune response gene phenotype is genetically determined

    SciTech Connect

    Tse, H.Y.; Mond, J.J.; Longo, D.L.

    1982-04-01

    We examined the effects of the developmental milieu on the capacity of B cells to undergo immune response gene-controlled, T cell-dependent polyclonal proliferation. Although I-Aq poly(Glu60 Ala30 Tyr10)n (GAT)-nonresponder T cells developing in a responder environment become phenotypic GAT-responders, I-Aq B cells remain unresponsive to GAT, even after maturation in a GAT-responder animal. Conversely, (B10.A x B10.Q)F1 ((GAT responder x GAT nonresponder)F1) T cells developing in a B10.Q GAT nonresponder host fail to respond to GAT, but F1 B cells from the same F1 leads to parent chimeras make excellent proliferative responses in the presence of GAT and responder T cells. Thus, by this assay, B cell immune response gene function is genetically determined and is not affected by the developmental milieu.

  8. Smallpox virus plaque phenotypes: genetic, geographical and case fatality relationships.

    PubMed

    Olson, Victoria A; Karem, Kevin L; Smith, Scott K; Hughes, Christine M; Damon, Inger K

    2009-04-01

    Smallpox (infection with Orthopoxvirus variola) remains a feared illness more than 25 years after its eradication. Historically, case-fatality rates (CFRs) varied between outbreaks (<1 to approximately 40 %), the reasons for which are incompletely understood. The extracellular enveloped virus (EEV) form of orthopoxvirus progeny is hypothesized to disseminate infection. Investigations with the closely related Orthopoxvirus vaccinia have associated increased comet formation (EEV production) with increased mouse mortality (pathogenicity). Other vaccinia virus genetic manipulations which affect EEV production inconsistently support this association. However, antisera against vaccinia virus envelope protect mice from lethal challenge, further supporting a critical role for EEV in pathogenicity. Here, we show that the increased comet formation phenotypes of a diverse collection of variola viruses associate with strain phylogeny and geographical origin, but not with increased outbreak-related CFRs; within clades, there may be an association of plaque size with CFR. The mechanisms for variola virus pathogenicity probably involves multiple host and pathogen factors.

  9. Simple Phenotypic Sweeps Hide Complex Genetic Changes in Populations

    PubMed Central

    Maharjan, Ram P.; Liu, Bin; Feng, Lu; Ferenci, Thomas; Wang, Lei

    2015-01-01

    Changes in allele frequencies and the fixation of beneficial mutations are central to evolution. The precise relationship between mutational and phenotypic sweeps is poorly described however, especially when multiple alleles are involved. Here, we investigate these relationships in a bacterial population over 60 days in a glucose-limited chemostat in a large population. High coverage metagenomic analysis revealed a disconnection between smooth phenotypic sweeps and the complexity of genetic changes in the population. Phenotypic adaptation was due to convergent evolution and involved soft sweeps by 7–26 highly represented alleles of several genes in different combinations. Allele combinations spread from undetectably low baselines, indicating that minor subpopulations provide the basis of most innovations. A hard sweep was also observed, involving a single combination of rpoS, mglD, malE, sdhC, and malT mutations sweeping to greater than 95% of the population. Other mutant genes persisted but at lower abundance, including hfq, consistent with its demonstrated frequency-dependent fitness under glucose limitation. Other persistent, newly identified low-frequency mutations were in the aceF, galF, ribD and asm genes, in noncoding regulatory regions, three large indels and a tandem duplication; these were less affected by fluctuations involving more dominant mutations indicating separate evolutionary paths. Our results indicate a dynamic subpopulation structure with a minimum of 42 detectable mutations maintained over 60 days. We also conclude that the massive population-level mutation supply in combination with clonal interference leads to the soft sweeps observed, but not to the exclusion of an occasional hard sweep. PMID:25589261

  10. Genetic and epigenetic contributions to the cortical phenotype in mammals☆

    PubMed Central

    Larsen, DeLaine D.; Krubitzer, Leah

    2008-01-01

    One aspect of cortical organization, cortical field size, is variable both within and across species. The observed variability arises from a variety of sources, including genes intrinsic to the neocortex and a number of extrinsic and epigenetic factors. Genes intrinsic to the cortex are directly involved in the development and specification of cortical fields and are regulated from both signaling centers located outside of the neocortex, which secrete diffusible molecules, and the expression of transcription factors within the neocortex. In addition, extrinsic factors such as the type, location and density of sensory receptor arrays and how these receptor arrays are utilized, are also strongly related to cortical field size. Epigenetic factors including the relative activity patterns generated by the different types of physical stimuli in a given environment also contribute to differences in cortical organization, including cortical field size. Since both genetic and epigenetic factors contribute to cortical organization, some aspects of the cortical phenotype evolve, while other aspects of the cortical phenotype persist only if the environment in which an individual develops is relatively stable. PMID:18331904

  11. From genetic variability to phenotypic expression of blood group systems.

    PubMed

    Raud, L; Férec, C; Fichou, Y

    2017-06-29

    More than 300 red blood cell (RBC) antigens belonging to 36 blood group systems have been officially reported in humans by the International Society of Blood Transfusion (ISBT). Phenotypic variability is directly linked to the expression of the 41 blood group genes. The Rh blood group system, which is composed of 54 antigens, is the most complex and polymorphic system. Many rare genetic variants within the RH (RHD and RHCE) genes, involving various mutational mechanisms (single-nucleotide substitutions, short insertions/deletions, rearrangements, large deletions), have been reported in the literature and reference databases. Expression of the variants induces variable clinical outcomes depending on their nature and impact on antigen structure. Their respective molecular and cellular effects remain however poorly studied. Biological resources to conduct this research are also barely available. We have paid a specific attention to three different classes of single-nucleotide substitutions: 1/ splice site variants in the Rh, Kell, Kidd, Junior and Langereis systems by the minigene splicing assay developed locally; 2/ missense variants in the RhD protein and their effect on intermolecular interaction with its protein partner RhAG, intracellular trafficking and plasma membrane integration; and 3/ synonymous variants in the RHD gene. Overall not only this project has fundamental objectives by analyzing the functional effect of variants in order to make genotype-phenotype correlation, but the aim is also to develop/engineer molecular tools and cell models to carry out those studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Genetic Determinism vs. Phenotypic Plasticity in Protist Morphology.

    PubMed

    Mulot, Matthieu; Marcisz, Katarzyna; Grandgirard, Lara; Lara, Enrique; Kosakyan, Anush; Robroek, Bjorn J M; Lamentowicz, Mariusz; Payne, Richard J; Mitchell, Edward A D

    2017-02-23

    Untangling the relationships between morphology and phylogeny is key to building a reliable taxonomy, but is especially challenging for protists, where the existence of cryptic or pseudocryptic species makes finding relevant discriminant traits difficult. Here we use Hyalosphenia papilio (a testate amoeba) as a model species to investigate the contribution of phylogeny and phenotypic plasticity in its morphology. We study the response of H. papilio morphology (shape and pores number) to environmental variables in (i) a manipulative experiment with controlled conditions (water level), (ii) an observational study of a within-site natural ecological gradient (water level), and (iii) an observational study across 37 European peatlands (climate). We showed that H. papilio morphology is correlated to environmental conditions (climate and water depth) as well as geography, while no relationship between morphology and phylogeny was brought to light. The relative contribution of genetic inheritance and phenotypic plasticity in shaping morphology varies depending on the taxonomic group and the trait under consideration. Thus, our data call for a reassessment of taxonomy based on morphology alone. This clearly calls for a substantial increase in taxonomic research on these globally still under-studied organisms leading to a reassessment of estimates of global microbial eukaryotic diversity.

  13. Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

    PubMed Central

    Lahm, Harald; Schön, Patric; Doppler, Stefanie; Dreßen, Martina; Cleuziou, Julie; Deutsch, Marcus-André; Ewert, Peter; Lange, Rüdiger; Krane, Markus

    2015-01-01

    In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS. PMID:26069455

  14. Using Genetic Networks and Homology to Understand the Evolution of Phenotypic Traits

    PubMed Central

    McCune, Amy R; Schimenti, John C

    2012-01-01

    Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, “biological homology” emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as “the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features.” Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its “essential identity” (a Character Identity Network or “ChIN”) must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits. PMID:22942677

  15. Mouse model phenotypes provide information about human drug targets

    PubMed Central

    Hoehndorf, Robert; Hiebert, Tanya; Hardy, Nigel W.; Schofield, Paul N.; Gkoutos, Georgios V.; Dumontier, Michel

    2014-01-01

    Motivation: Methods for computational drug target identification use information from diverse information sources to predict or prioritize drug targets for known drugs. One set of resources that has been relatively neglected for drug repurposing is animal model phenotype. Results: We investigate the use of mouse model phenotypes for drug target identification. To achieve this goal, we first integrate mouse model phenotypes and drug effects, and then systematically compare the phenotypic similarity between mouse models and drug effect profiles. We find a high similarity between phenotypes resulting from loss-of-function mutations and drug effects resulting from the inhibition of a protein through a drug action, and demonstrate how this approach can be used to suggest candidate drug targets. Availability and implementation: Analysis code and supplementary data files are available on the project Web site at https://drugeffects.googlecode.com. Contact: leechuck@leechuck.de or roh25@aber.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:24158600

  16. Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

    PubMed Central

    Goddard, M. E.; Kemper, K. E.; MacLeod, I. M.; Chamberlain, A. J.; Hayes, B. J.

    2016-01-01

    Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement. PMID:27440663

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

    PubMed Central

    2012-01-01

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

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

    PubMed

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

    2012-02-20

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

  19. The genetics of phenotypic plasticity. X. Variation versus uncertainty

    PubMed Central

    Scheiner, Samuel M; Holt, Robert D

    2012-01-01

    Despite the apparent advantages of adaptive plasticity, it is not common. We examined the effects of variation and uncertainty on selection for plasticity using an individual-based computer simulation model. In the model, the environment consisted of a linear gradient of 50 demes with dispersal occurring either before or after selection. Individuals consisted of multiple loci whose phenotypic expression either are affected (plastic) or are not affected (nonplastic) by the environment. Typically, evolution occurred first as genetic differentiation, which was then replaced by the evolution of adaptive plasticity, opposite to the evolutionary trend that is often assumed. Increasing dispersal rates selected for plasticity, if selection occurred before dispersal. If selection occurred after dispersal, the highest plasticity was at intermediate dispersal rates. Temporal variation in the environment occurring after development, but before selection, favored the evolution of plasticity. With dispersal before selection, such temporal variation resulted in hyperplasticity, with a reaction norm much steeper than the optimum. This effect was enhanced with negative temporal autocorrelation and can be interpreted as representing a form of bet hedging. As the number of nonplastic loci increased, plasticity was disfavored due to an increase in the uncertainty of the genomic environment. This effect was reversed with temporal variation. Thus, variation and uncertainty affect whether or not plasticity is favored with different sources of variation—arising from the amount and timing of dispersal, from temporal variation, and even from the genetic architecture underlying the phenotype—having contrasting, interacting, and at times unexpected effects. PMID:22837824

  20. Detecting Major Genetic Loci Controlling Phenotypic Variability in Experimental Crosses

    PubMed Central

    Rönnegård, Lars; Valdar, William

    2011-01-01

    Traditional methods for detecting genes that affect complex diseases in humans or animal models, milk production in livestock, or other traits of interest, have asked whether variation in genotype produces a change in that trait’s average value. But focusing on differences in the mean ignores differences in variability about that mean. The robustness, or uniformity, of an individual’s character is not only of great practical importance in medical genetics and food production but is also of scientific and evolutionary interest (e.g., blood pressure in animal models of heart disease, litter size in pigs, flowering time in plants). We describe a method for detecting major genes controlling the phenotypic variance, referring to these as vQTL. Our method uses a double generalized linear model with linear predictors based on probabilities of line origin. We evaluate our method on simulated F2 and collaborative cross data, and on a real F2 intercross, demonstrating its accuracy and robustness to the presence of ordinary mean-controlling QTL. We also illustrate the connection between vQTL and QTL involved in epistasis, explaining how these concepts overlap. Our method can be applied to a wide range of commonly used experimental crosses and may be extended to genetic association more generally. PMID:21467569

  1. Genetic and phenotypic consequences of introgression between humans and Neanderthals.

    PubMed

    Wills, Christopher

    2011-01-01

    Strong evidence for introgression of Neanderthal genes into parts of the modern human gene pool has recently emerged. The evidence indicates that some populations of modern humans have received infusions of genes from two different groups of Neanderthals. One of these Neanderthal groups lived in the Middle East and Central Europe and the other group (the Denisovans) is known to have lived in Central Asia and was probably more widespread. This review examines two questions. First, how were these introgressions detected and what does the genetic evidence tell us about their nature and extent? We will see that an unknown but possibly large fraction of the entire Neanderthal gene complement may have survived in modern humans. Even though each modern European and Asian carries only a few percent of genes that can be traced back to Neanderthals, different individuals carry different subgroups of these introgressed genes. Second, what is the likelihood that this Neanderthal genetic legacy has had phenotypic effects on modern humans? We examine evidence for and against the possibility that some of the surviving fragments of Neanderthal genomes have been preserved by natural selection, and we explore the ways in which more evidence bearing on this question will become available in the future.

  2. [Genetic information and future medicine].

    PubMed

    Sakurai, Akihiro

    2012-11-01

    Rapid technological advances in genetic analysis have revealed the genetic background of various diseases. Elucidation of the genes responsible for a disease enables better clinical management of the disease and helps to develop targeted drugs. Also, early diagnosis and management of at-risk family members can be made by identification of a genetic disease in the proband. On the other hand, genetic issues often cause psychological distress to the family. To perform genetic testing appropriately and to protect patients and family members from any harm, guidelines for genetic testing were released from the alliance of Japanese genetics-related academic societies in 2003. As genetic testing is becoming incorporated into clinical practice more broadly, the guideline was revised and released by the Japanese Society of Medical Sciences in 2011. All medical professionals in Japan are expected to follow this guideline.

  3. The Phenotypic and Genetic Underpinnings of Flower Size in Polemoniaceae.

    PubMed

    Landis, Jacob B; O'Toole, Rebecca D; Ventura, Kayla L; Gitzendanner, Matthew A; Oppenheimer, David G; Soltis, Douglas E; Soltis, Pamela S

    2015-01-01

    Corolla length is a labile flower feature and has strong implications for pollinator success. However, the phenotypic and genetic bases of corolla elongation are not well known, largely due to a lack of good candidate genes for potential genetic exploration and functional work. We investigate both the cellular phenotypic differences in corolla length, as well as the genetic control of this trait, in Saltugilia (Polemoniaceae). Taxa in this clade exhibit a large range of flower sizes and differ dramatically in pollinator guilds. Flowers of each species were collected from multiple individuals during four stages of flower development to ascertain if cell number or cell size is more important in determining flower size. In Saltugilia, increased flower size during development appears to be driven more by cell size than cell number. Differences in flower size between species are governed by both cell size and cell number, with the large-flowered S. splendens subsp. grantii having nearly twice as many cells as the small-flowered species. Fully mature flowers of all taxa contain jigsaw cells similar to cells seen in sepals and leaves; however, these cells are not typically found in the developing flowers of most species. The proportion of this cell type in mature flowers appears to have substantial implications, comprising 17-68% of the overall flower size. To identify candidate genes responsible for differences in cell area and cell type, transcriptomes were generated for two individuals of the species with the smallest (S. australis) and largest (S. splendens subsp. grantii) flowers across the same four developmental stages visualized with confocal microscopy. Analyses identified genes associated with cell wall formation that are up-regulated in the mature flower stage compared to mid-stage flowers (75% of mature size). This developmental change is associated with the origin of jigsaw cells in the corolla tube of mature flowers. Further comparisons between mature

  4. The Phenotypic and Genetic Underpinnings of Flower Size in Polemoniaceae

    PubMed Central

    Landis, Jacob B.; O'Toole, Rebecca D.; Ventura, Kayla L.; Gitzendanner, Matthew A.; Oppenheimer, David G.; Soltis, Douglas E.; Soltis, Pamela S.

    2016-01-01

    Corolla length is a labile flower feature and has strong implications for pollinator success. However, the phenotypic and genetic bases of corolla elongation are not well known, largely due to a lack of good candidate genes for potential genetic exploration and functional work. We investigate both the cellular phenotypic differences in corolla length, as well as the genetic control of this trait, in Saltugilia (Polemoniaceae). Taxa in this clade exhibit a large range of flower sizes and differ dramatically in pollinator guilds. Flowers of each species were collected from multiple individuals during four stages of flower development to ascertain if cell number or cell size is more important in determining flower size. In Saltugilia, increased flower size during development appears to be driven more by cell size than cell number. Differences in flower size between species are governed by both cell size and cell number, with the large-flowered S. splendens subsp. grantii having nearly twice as many cells as the small-flowered species. Fully mature flowers of all taxa contain jigsaw cells similar to cells seen in sepals and leaves; however, these cells are not typically found in the developing flowers of most species. The proportion of this cell type in mature flowers appears to have substantial implications, comprising 17–68% of the overall flower size. To identify candidate genes responsible for differences in cell area and cell type, transcriptomes were generated for two individuals of the species with the smallest (S. australis) and largest (S. splendens subsp. grantii) flowers across the same four developmental stages visualized with confocal microscopy. Analyses identified genes associated with cell wall formation that are up-regulated in the mature flower stage compared to mid-stage flowers (75% of mature size). This developmental change is associated with the origin of jigsaw cells in the corolla tube of mature flowers. Further comparisons between mature

  5. Sequential phenotypic constraints on social information use in wild baboons

    PubMed Central

    Carter, Alecia J; Torrents Ticó, Miquel; Cowlishaw, Guy

    2016-01-01

    Social information allows the rapid dissemination of novel information among individuals. However, an individual’s ability to use information is likely to be dependent on phenotypic constraints operating at three successive steps: acquisition, application, and exploitation. We tested this novel framework by quantifying the sequential process of social information use with experimental food patches in wild baboons (Papio ursinus). We identified phenotypic constraints at each step of the information use sequence: peripheral individuals in the proximity network were less likely to acquire and apply social information, while subordinate females were less likely to exploit it successfully. Social bonds and personality also played a limiting role along the sequence. As a result of these constraints, the average individual only acquired and exploited social information on <25% and <5% of occasions. Our study highlights the sequential nature of information use and the fundamental importance of phenotypic constraints on this sequence. DOI: http://dx.doi.org/10.7554/eLife.13125.001 PMID:27067236

  6. The phenotypic difference discards sib-pair QTL linkage information

    SciTech Connect

    Wright, F.A. |

    1997-03-01

    Kruglyak and Lander provide an important synthesis of methods for (IBD) sib-pair linkage mapping, with an emphasis on the use of complete multipoint inheritance information for each sib pair. These procedures are implemented in the computer program MAPMAKER/SIBS, which performs interval mapping for dichotomous and quantitative traits. The authors present three methods for mapping quantitative trait loci (QTLs): a variant of the commonly used Haseman-Elston regression approach, a maximum-likelihood procedure involving variance components, and a rank-based nonparametric procedure. These approaches and related work use the magnitude of the difference in the sibling phenotype values for each sib pair as the observation for analysis. Linkage is detected if siblings sharing more alleles IBD have similar phenotypes (i.e., a small difference in the phenotype values), while siblings sharing fewer alleles IBD have less similar phenotypes. Such techniques have been used to detect linkage for a number of quantitative traits. However, the exclusive reliance on the phenotypic differences may be due in large part to historical inertia. A likelihood argument is presented here to show that, under certain classical assumptions, the phenotypic differences do not contain the full likelihood information for QTL mapping. Furthermore, considerable gains in power to detect linkage can be achieved with an expanded likelihood model. The development here is related to previous work, which incorporates the full set of phenotypic data using likelihood and robust quasi-likelihood methods. The purpose of this letter is not to endorse a particular approach but to spur research in alternative and perhaps more powerful linkage tests. 17 refs.

  7. eCOMPAGT – efficient Combination and Management of Phenotypes and Genotypes for Genetic Epidemiology

    PubMed Central

    Schönherr, Sebastian; Weißensteiner, Hansi; Coassin, Stefan; Specht, Günther; Kronenberg, Florian; Brandstätter, Anita

    2009-01-01

    Background High-throughput genotyping and phenotyping projects of large epidemiological study populations require sophisticated laboratory information management systems. Most epidemiological studies include subject-related personal information, which needs to be handled with care by following data privacy protection guidelines. In addition, genotyping core facilities handling cooperative projects require a straightforward solution to monitor the status and financial resources of the different projects. Description We developed a database system for an efficient combination and management of phenotypes and genotypes (eCOMPAGT) deriving from genetic epidemiological studies. eCOMPAGT securely stores and manages genotype and phenotype data and enables different user modes with different rights. Special attention was drawn on the import of data deriving from TaqMan and SNPlex genotyping assays. However, the database solution is adjustable to other genotyping systems by programming additional interfaces. Further important features are the scalability of the database and an export interface to statistical software. Conclusion eCOMPAGT can store, administer and connect phenotype data with all kinds of genotype data and is available as a downloadable version at . PMID:19432954

  8. Variation in clinical phenotype of human infection among genetic groups of Blastomyces dermatitidis

    USGS Publications Warehouse

    Meece, Jennifer K.; Anderson, Jennifer L.; Gruszka, Sarah; Sloss, Brian L.; Sullivan, Bradley; Reed, Kurt D.

    2013-01-01

    Background. Blastomyces dermatitidis, the etiologic agent of blastomycosis, has 2 genetic groups and shows varied clinical presentation, ranging from silent infections to fulminant respiratory disease and dissemination. The objective of this study was to determine whether clinical phenotype and outcomes vary based on the infecting organism's genetic group.Methods. We used microsatellites to genotype 227 clinical isolates of B. dermatitidis from Wisconsin patients. For each isolate, corresponding clinical disease characteristics and patient demographic information were abstracted from electronic health records and Wisconsin Division of Health reportable disease forms and questionnaires.Results. In univariate analysis, group 1 isolates were more likely to be associated with pulmonary-only infections (P < .0001) and constitutional symptoms such as fever (P < .0001). In contrast, group 2 isolates were more likely to be associated with disseminated disease (P < .0001), older patient age (P < .0001), and comorbidities (P = .0019). In multivariate analysis, disease onset to diagnosis of >1 month (P < .0001), older age at diagnosis (P < .0001), and current smoking status (P = .0001) remained predictors for group 2 infections.Conclusions. This study identified previously unknown associations between clinical phenotype of human infection and genetic groups of B. dermatitidis and provides a framework for further investigations of the genetic basis for virulence in B. dermatitidis.

  9. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis

    SciTech Connect

    Palmer, S.E. |; Dale, D.C.

    1996-12-30

    Cyclic hematopoiesis (CH, or cyclic neutropenia) is a rare disease manifested by transient severe neutropenia that recurs approximately every 21 days. The hematologic profile of families with the autosomal dominant form (ADCH) has not been well characterized, and it is unknown if the phenotype is distinct from the more common sporadic congenital or acquired forms of CH. We studied nine ADCH families whose children displayed typical CH blood patterns. Pedigrees confirmed dominant inheritance without evidence of heterogeneity or decreased penetrance; three pedigrees suggested new mutations. Families were Caucasian with exception of one with a Cherokee Native American founder. A wide spectrum of symptom severity, ranging from asymptomatic to life-threatening illness, was observed within families. The phenotype changed with age. Children displayed typical neutrophil cycles with symptoms of mucosal ulceration, lymphadenopathy, and infections. Adults often had fewer and milder symptoms, sometimes accompanied by mild chronic neutropenia without distinct cycles. While CH is commonly described as {open_quotes}benign{close_quotes}, four children in three of the nine families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases. Genetic counseling requires specific histories and complete blood counts in relatives at risk to assess status regardless of symptoms, especially to determine individuals with new mutations. We propose diagnostic criteria for ADCH in affected children and adults. Recombinant human granulocyte colony-stimulating factor treatment resulted in dramatic improvement of neutropenia and morbidity. The differential diagnosis from other forms of familial neutropenia is reviewed. 45 refs., 4 figs., 1 tab.

  10. The 1001 Arabidopsis DNA Methylomes: An Important Resource for Studying Natural Genetic, Epigenetic, and Phenotypic Variation.

    PubMed

    Lang, Zhaobo; Xie, Shaojun; Zhu, Jian-Kang

    2016-11-01

    Intraspecific phenotypic diversity is controlled by natural genetic and epigenetic variation. Kawakatsu et al. recently sequenced the DNA methylomes of a global collection of over 1000 Arabidopsis accessions, and have thereby provided a comprehensive resource for studying natural genetic and epigenetic variation as well as the association of such variation with phenotypic diversity.

  11. Predicting Phenotypes from Genetic Crosses: A Mathematical Concept to Help Struggling Biology Students

    ERIC Educational Resources Information Center

    Baurhoo, Neerusha; Darwish, Shireef

    2012-01-01

    Predicting phenotypic outcomes from genetic crosses is often very difficult for biology students, especially those with learning disabilities. With our mathematical concept, struggling students in inclusive biology classrooms are now better equipped to solve genetic problems and predict phenotypes, because of improved understanding of dominance…

  12. Predicting Phenotypes from Genetic Crosses: A Mathematical Concept to Help Struggling Biology Students

    ERIC Educational Resources Information Center

    Baurhoo, Neerusha; Darwish, Shireef

    2012-01-01

    Predicting phenotypic outcomes from genetic crosses is often very difficult for biology students, especially those with learning disabilities. With our mathematical concept, struggling students in inclusive biology classrooms are now better equipped to solve genetic problems and predict phenotypes, because of improved understanding of dominance…

  13. Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

    PubMed Central

    Blanco-Gómez, Adrián; Castillo-Lluva, Sonia; del Mar Sáez-Freire, María; Hontecillas-Prieto, Lourdes; Mao, Jian Hua; Castellanos-Martín, Andrés; Pérez-Losada, Jesus

    2016-01-01

    Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability”. Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. PMID:27241833

  14. Signal function drives phenotypic and genetic diversity: the effects of signalling individual identity, quality or behavioural strategy.

    PubMed

    Tibbetts, Elizabeth A; Mullen, Sean P; Dale, James

    2017-07-05

    Animal coloration is influenced by selection pressures associated with communication. During communication, signallers display traits that inform receivers and modify receiver behaviour in ways that benefit signallers. Here, we discuss how selection on signallers to convey different kinds of information influences animal phenotypes and genotypes. Specifically, we address the phenotypic and genetic consequences of communicating three different kinds of information: individual identity, behavioural strategy and quality. Previous work has shown signals that convey different kinds of information differ in terms of the (i) type of selection acting on signallers (e.g. directional, stabilizing, or negative frequency dependent), and (ii) developmental basis of signals (i.e. heritability, genetic architecture). These differences result in signals that convey different information having consistently different phenotypic properties, including the amount, modality and continuity of intraspecific variation. Understanding how communication influences animal phenotypes may allow researchers to quickly identify putative functions of colour variation prior to experimentation. Signals that convey different information will also have divergent evolutionary consequences. For example, signalling individual identity can increase genetic diversity, signalling quality may decrease diversity, and signalling strategy can constrain adaptation and contribute to speciation. Considering recent advances in genomic resources, our framework highlights new opportunities to resolve the evolutionary consequences of selection on communication across diverse taxa and signal types.This article is part of the themed issue 'Animal coloration: production, perception, function and application'. © 2017 The Author(s).

  15. Genetic polymorphisms underlying the skeletal Class III phenotype.

    PubMed

    Cruz, Christiane Vasconcellos; Mattos, Claudia Trindade; Maia, José Calasans; Granjeiro, José Mauro; Reis, Maria Fernanda; Mucha, José Nelson; Vilella, Beatriz; Ruellas, Antonio Carlos; Luiz, Ronir Raggio; Costa, Marcelo Castro; Vieira, Alexandre Rezende

    2017-04-01

    Our goal was to verify the association between candidate polymorphisms and skeletal Class III malocclusion in a well-characterized homogeneous sample set. Thirty-five single-nucleotide polymorphisms were studied from 10 candidate loci in 54 Class III subjects and 120 controls. Skeletal Class III characteristics included ANB angle less than 0°, SNB angle greater than 83° (mandibular prognathism), SNA angle less than 79° (maxillary deficiency), Class III molar relationship, and negative overjet. Inclusion criteria for the controls were ANB angle between 0° and 4°, Class I molar relationship, and normal overjet. Chi-square and Fisher exact tests and principal component (PC) analysis were used to determine overrepresentation of marker alleles with alpha of 0.05. Odds ratios and 95% confidence intervals were calculated. MYO1H (rs10850110 Aphenotype. These results were confirmed by PC analysis, which showed 4 PCs representing the sample variations (PC1, 37.24%; PC2, 20.02%; PC3, 12.18%; and PC4, 11.40%), and PC1 was associated with MYO1H (P <0.001). We also found by PC analysis associations between MYO1H (P <0.001) and GHR (rs2973015 A>G) (P = 0.001) with PC2 and between FGF10 (rs593307 Agenetic susceptibility to Class III malocclusion with mandibular prognathism, and polymorphisms in GHR and FGF were associated with maxillomandibular discrepancies. This study may contribute to improved diagnosis and further research assessing possible differences in treatment responses based on genetic polymorphisms. Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  16. Phenotyping of genetically engineered mice: humane, ethical, environmental, and husbandry issues.

    PubMed

    Brown, Marilyn J; Murray, Kathleen A

    2006-01-01

    The growing use of genetically engineered (GE) mice in scientific research has raised many concerns about the animal welfare of such mice. The types of welfare concerns may differ within the three stages that comprise the establishment of GE animal models: development, production, and research use. The role and impact of the members of the research team on these concerns may also vary with each stage. To make both scientific and animal welfare decisions at each stage, it is necessary to have a thorough knowledge of the animal model-in this case, the phenotypic expression of the GE animal. Phenotype screening is the analysis of visible or measurable characteristics of an animal that result from the genotype and its interaction with the environment. Phenotypes expressed that are relevant to the research program are usually carefully investigated; however, those that may have an impact on the animal's welfare but have little or no impact on the disease process under study are often less carefully studied. Thorough analysis and documentation of the animal welfare aspects of phenotype provide the research team with the information they need to control the environment to minimize negative animal welfare effects. Such information is also essential to allow members of the institutional animal care and use committee to perform necessary cost:benefit ethical review of proposed GE animal studies. Investigators who submit information about models for publication should document all aspects of a phenotype, including the area of scientific interest as well as those areas that affect animal welfare, for clarity and for subsequent research with the respective models.

  17. Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice

    PubMed Central

    Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

    2014-01-01

    Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits. PMID:25295980

  18. Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice.

    PubMed

    Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

    2014-10-08

    Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits.

  19. Genetic code ambiguity: an unexpected source of proteome innovation and phenotypic diversity.

    PubMed

    Moura, Gabriela R; Carreto, Laura C; Santos, Manuel A S

    2009-12-01

    Translation of the genome into the proteome is a highly accurate biological process. However, the molecular mechanisms involved in protein synthesis are not error free and downstream protein quality control systems are needed to counteract the negative effects of translational errors (mistranslation) on proteome and cell homeostasis. This plus human and mice diseases caused by translational error generalized the idea that codon ambiguity is detrimental to life. Here we depart from this classical view of deleterious translational error and highlight how codon ambiguity can play important roles in the evolution of novel proteins. We also explain how tRNA mischarging can be relevant for the synthesis of functional proteomes, how codon ambiguity generates phenotypic and genetic diversity and how advantageous phenotypes can be selected, fixed, and inherited. A brief introduction to the molecular nature of translational error is provided; however, detailed information on the mechanistic aspects of mistranslation or comprehensive literature reviews of this topic should be obtained elsewhere.

  20. Genetic and phenotypic influences on copulatory plug survival in mice

    PubMed Central

    Mangels, R; Young, B; Keeble, S; Ardekani, R; Meslin, C; Ferreira, Z; Clark, N L; Good, J M; Dean, M D

    2015-01-01

    Across a diversity of animals, male seminal fluid coagulates upon ejaculation to form a hardened structure known as a copulatory plug. Previous studies suggest that copulatory plugs evolved as a mechanism for males to impede remating by females, but detailed investigations into the time course over which plugs survive in the female's reproductive tract are lacking. Here, we cross males from eight inbred strains to females from two inbred strains of house mice (Mus musculus domesticus). Plug survival was significantly affected by male genotype. Against intuition, plug survival time was negatively correlated with plug size: long-lasting plugs were small and relatively more susceptible to proteolysis. Plug size was associated with divergence in major protein composition of seminal vesicle fluid, suggesting that changes in gene expression may play an important role in plug dynamics. In contrast, we found no correlation to genetic variation in the protein-coding regions of five genes thought to be important in copulatory plug formation (Tgm4, Svs1, Svs2, Svs4 and Svs5). Our study demonstrates a complex relationship between copulatory plug characteristics and survival. We discuss several models to explain unexpected variation in plug phenotypes. PMID:26103947

  1. Absolute pitch exhibits phenotypic and genetic overlap with synesthesia.

    PubMed

    Gregersen, Peter K; Kowalsky, Elena; Lee, Annette; Baron-Cohen, Simon; Fisher, Simon E; Asher, Julian E; Ballard, David; Freudenberg, Jan; Li, Wentian

    2013-05-15

    Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.

  2. Absolute pitch exhibits phenotypic and genetic overlap with synesthesia

    PubMed Central

    Gregersen, Peter K.; Kowalsky, Elena; Lee, Annette; Baron-Cohen, Simon; Fisher, Simon E.; Asher, Julian E.; Ballard, David; Freudenberg, Jan; Li, Wentian

    2013-01-01

    Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region. PMID:23406871

  3. Role of phenotypic and genetic testing in managing clopidogrel therapy.

    PubMed

    Chan, Noel C; Eikelboom, John W; Ginsberg, Jeffrey S; Lauw, Mandy N; Vanassche, Thomas; Weitz, Jeffrey I; Hirsh, Jack

    2014-07-31

    The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor.

  4. X-linked dystonia parkinsonism: clinical phenotype, genetics and therapeutics.

    PubMed

    Rosales, Raymond L

    2010-10-01

    The clinical phenotype of X-Linked Dystonia Parkinsonism (XDP) is typically one that involves a Filipino adult male whose ancestry is mostly traced in the Philippine island of Panay. Dystonia usually starts focally in the lower limbs or oromandibular regions, then spreads to become generalized eventually. Parkinsonism sets in later into the disease and usually in combination with dystonia. /DYT3/ and /TAF1/ are the two genes associated with XDP. An SVA retrotransposon insertion in an intron of /TAF1/ may reduce neuron-specific expression of the /TAF1/ isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes. Polypharmacy with oral benzodiazepines, anticholinergic agents and muscle relaxants leaves much to be desired in terms of efficacy. The medications to date that may appear beneficial, especially in disabling dystonias, are zolpidem, muscle afferent block with lidocaine-ethanol and botulinum toxin type A. Despite the few cases undergoing deep brain stimulation, this functional surgery has shown the greatest promise in XDP. An illustrative case of XDP in a family depicts the variable course of illness, including a bout of "status dystonicus," challenges in therapy, reckoning with the social impact of the disease, and eventual patient demise. Indeed, there remains some gaps in understanding some phenomenological, genetic and treatment aspects of XDP, the areas upon which future research directions may be worthwhile.

  5. Expanding the Genetic and Phenotypic Spectrum of Popliteal Pterygium Disorders

    PubMed Central

    Leslie, Elizabeth J.; O'Sullivan, James; Cunningham, Michael L.; Singh, Ankur; Goudy, Steven L.; Ababneh, Faroug; Alsubaie, Lamia; Ch'ng, Gaik-Siew; van der Laar, Ingrid M.B.H.; Hoogeboom, A. Jeannette M.; Dunnwald, Martine; Kapoor, Seema; Jiramongkolchai, Pawina; Standley, Jennifer; Manak, J. Robert; Murray, Jeffrey C.; Dixon, Michael J.

    2015-01-01

    The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development. PMID:25691407

  6. Engineering microbial phenotypes through rewiring of genetic networks.

    PubMed

    Windram, Oliver P F; Rodrigues, Rui T L; Lee, Sangjin; Haines, Matthew; Bayer, Travis S

    2017-03-21

    The ability to program cellular behaviour is a major goal of synthetic biology, with applications in health, agriculture and chemicals production. Despite efforts to build 'orthogonal' systems, interactions between engineered genetic circuits and the endogenous regulatory network of a host cell can have a significant impact on desired functionality. We have developed a strategy to rewire the endogenous cellular regulatory network of yeast to enhance compatibility with synthetic protein and metabolite production. We found that introducing novel connections in the cellular regulatory network enabled us to increase the production of heterologous proteins and metabolites. This strategy is demonstrated in yeast strains that show significantly enhanced heterologous protein expression and higher titers of terpenoid production. Specifically, we found that the addition of transcriptional regulation between free radical induced signalling and nitrogen regulation provided robust improvement of protein production. Assessment of rewired networks revealed the importance of key topological features such as high betweenness centrality. The generation of rewired transcriptional networks, selection for specific phenotypes, and analysis of resulting library members is a powerful tool for engineering cellular behavior and may enable improved integration of heterologous protein and metabolite pathways.

  7. The relationship between parental genetic or phenotypic divergence and progeny variation in the maize nested association mapping population.

    PubMed

    Hung, H-Y; Browne, C; Guill, K; Coles, N; Eller, M; Garcia, A; Lepak, N; Melia-Hancock, S; Oropeza-Rosas, M; Salvo, S; Upadyayula, N; Buckler, E S; Flint-Garcia, S; McMullen, M D; Rocheford, T R; Holland, J B

    2012-05-01

    Appropriate selection of parents for the development of mapping populations is pivotal to maximizing the power of quantitative trait loci detection. Trait genotypic variation within a family is indicative of the family's informativeness for genetic studies. Accurate prediction of the most useful parental combinations within a species would help guide quantitative genetics studies. We tested the reliability of genotypic and phenotypic distance estimators between pairs of maize inbred lines to predict genotypic variation for quantitative traits within families derived from biparental crosses. We developed 25 families composed of ~200 random recombinant inbred lines each from crosses between a common reference parent inbred, B73, and 25 diverse maize inbreds. Parents and families were evaluated for 19 quantitative traits across up to 11 environments. Genetic distances (GDs) among parents were estimated with 44 simple sequence repeat and 2303 single-nucleotide polymorphism markers. GDs among parents had no predictive value for progeny variation, which is most likely due to the choice of neutral markers. In contrast, we observed for about half of the traits measured a positive correlation between phenotypic parental distances and within-family genetic variance estimates. Consequently, the choice of promising segregating populations can be based on selecting phenotypically diverse parents. These results are congruent with models of genetic architecture that posit numerous genes affecting quantitative traits, each segregating for allelic series, with dispersal of allelic effects across diverse genetic material. This architecture, common to many quantitative traits in maize, limits the predictive value of parental genotypic or phenotypic values on progeny variance.

  8. Phenotypic and genetic parameter estimates for reproductive traits in Zandi sheep.

    PubMed

    Mohammadi, Kourosh; Beigi Nassiri, Mohammad Taghi; Rahmatnejad, Enayat; Sheikh, Masoud; Fayazi, Jamal; Karimi Manesh, Amin

    2013-02-01

    This study reports on the phenotypic and genetic (co)variance components for reproductive traits in Zandi sheep, using between 1,859 and 2,588 records obtained from 577 ewes. The data were collected from the Khojir Breeding Station of Zandi sheep in Tehran, Iran from 1994 to 2008. The basic traits were litter size at birth (LSB), litter size at weaning (LSW), litter mean weight per lamb born (LMWLB), and litter mean weight per lamb weaned (LMWLW), and the composite traits were total litter weight at birth (TLWB) and total litter weight at weaning (TLWW). Genetic analyses were carried out using the restricted maximum likelihood method that was explored by fitting the additive direct genetic effects and permanent environmental effects of the ewes as random effects and the ewe age at lambing and lambing year as fixed effects for all of the investigated traits. Akaike's information criterion was used to choose the most appropriate model. LSB, LSW, LMWLB, LMWLW, TLWB, and TLWW direct heritability estimates were 0.07, 0.05, 0.12, 0.10, 0.08, and 0.14, respectively. The estimated fractions of variance due to the permanent environmental effects of the ewe ranged from 0.03 for LMWLB to 0.08 for LMWLW and TLWW. Corresponding repeatability estimates ranged from 0.10 for LSW to 0.22 for TLWW. Direct genetic correlations varied from -0.61 for LSB-LMWLB to 0.88 for LSB-LSW and LSB-TLWB. Results indicate that genetic change depends not only on the heritability of traits, but also on the observed phenotypic variation; therefore, improvement of non-genetic factors should be included in the breeding programs.

  9. Towards an informative mutant phenotype for every bacterial gene

    DOE PAGES

    Deutschbauer, Adam; Price, Morgan N.; Wetmore, Kelly M.; ...

    2014-08-11

    Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, inmore » Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.« less

  10. Towards an informative mutant phenotype for every bacterial gene

    SciTech Connect

    Deutschbauer, Adam; Price, Morgan N.; Wetmore, Kelly M.; Tarjan, Daniel R.; Xu, Zhuchen; Shao, Wenjen; Leon, Dacia; Arkin, Adam P.; Skerker, Jeffrey M.

    2014-08-11

    Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, in Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.

  11. TOMATOMA Update: Phenotypic and Metabolite Information in the Micro-Tom Mutant Resource.

    PubMed

    Shikata, Masahito; Hoshikawa, Ken; Ariizumi, Tohru; Fukuda, Naoya; Yamazaki, Yukiko; Ezura, Hiroshi

    2016-01-01

    TOMATOMA (http://tomatoma.nbrp.jp/) is a tomato mutant database providing visible phenotypic data of tomato mutant lines generated by ethylmethane sulfonate (EMS) treatment or γ-ray irradiation in the genetic background of Micro-Tom, a small and rapidly growing variety. To increase mutation efficiency further, mutagenized M3 seeds were subjected to a second round of EMS treatment; M3M1 populations were generated. These plants were self-pollinated, and 4,952 lines of M3M2 mutagenized seeds were generated. We checked for visible phenotypes in the M3M2 plants, and 618 mutant lines with 1,194 phenotypic categories were identified. In addition to the phenotypic information, we investigated Brix values and carotenoid contents in the fruits of individual mutants. Of 466 samples from 171 mutant lines, Brix values and carotenoid contents were between 3.2% and 11.6% and 6.9 and 37.3 µg g(-1) FW, respectively. This metabolite information concerning the mutant fruits would be useful in breeding programs as well as for the elucidation of metabolic regulation. Researchers are able to browse and search this phenotypic and metabolite information and order seeds of individual mutants via TOMATOMA. Our new Micro-Tom double-mutagenized populations and the metabolic information could provide a valuable genetic toolkit to accelerate tomato research and potential breeding programs. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Use of genetic data to infer population-specific ecological and phenotypic traits from mixed aggregations

    USGS Publications Warehouse

    Moran, Paul; Bromaghin, Jeffrey F.; Masuda, Michele

    2014-01-01

    Many applications in ecological genetics involve sampling individuals from a mixture of multiple biological populations and subsequently associating those individuals with the populations from which they arose. Analytical methods that assign individuals to their putative population of origin have utility in both basic and applied research, providing information about population-specific life history and habitat use, ecotoxins, pathogen and parasite loads, and many other non-genetic ecological, or phenotypic traits. Although the question is initially directed at the origin of individuals, in most cases the ultimate desire is to investigate the distribution of some trait among populations. Current practice is to assign individuals to a population of origin and study properties of the trait among individuals within population strata as if they constituted independent samples. It seemed that approach might bias population-specific trait inference. In this study we made trait inferences directly through modeling, bypassing individual assignment. We extended a Bayesian model for population mixture analysis to incorporate parameters for the phenotypic trait and compared its performance to that of individual assignment with a minimum probability threshold for assignment. The Bayesian mixture model outperformed individual assignment under some trait inference conditions. However, by discarding individuals whose origins are most uncertain, the individual assignment method provided a less complex analytical technique whose performance may be adequate for some common trait inference problems. Our results provide specific guidance for method selection under various genetic relationships among populations with different trait distributions.

  13. Demographic, genetic and phenotypic characteristics of centenarians in Italy: Focus on gender differences.

    PubMed

    Montesanto, Alberto; De Rango, Francesco; Pirazzini, Chiara; Guidarelli, Giulia; Domma, Filippo; Franceschi, Claudio; Passarino, Giuseppe

    2017-07-01

    An impressive and coherent series of epidemiological data from different populations (New England Americans, Mormons, Ashkenazi Jewish, Icelandic, Okinawan Japanese, Italians) suggests that long-lived subjects able to reach the extreme limits of human life, such as centenarians and supercentenarians, represent an extraordinary and informative model to identify the mechanisms responsible for healthy aging and human longevity. In most studies, genetic, demographic and phenotypic characteristics of longevity are discussed separately. However, longevity is a very complex trait due to the complicated interactions of numerous genetic and environmental factors. It is therefore necessary to analyse centenarians with a multidimensional approach, trying to consider different aspects simultaneously. In this review we will focus on Italian centenarians, who have been extensively studied for many years with different approaches, in order to show their peculiarities and the emerging data from the studies carried out on this exceptional population. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. [Phenotype-based genetic association studies (PGAS): a new approach to understanding the genotype contribution to schizophrenic phenotypes].

    PubMed

    Ehrenreich, H

    2013-05-01

    Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome...". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available.

  15. Genetic Association Studies: An Information Content Perspective

    PubMed Central

    Wu, Cen; Li, Shaoyu; Cui, Yuehua

    2012-01-01

    The availability of high-density single nucleotide polymorphisms (SNPs) data has made the human genetic association studies possible to identify common and rare variants underlying complex diseases in a genome-wide scale. A handful of novel genetic variants have been identified, which gives much hope and prospects for the future of genetic association studies. In this process, statistical and computational methods play key roles, among which information-based association tests have gained large popularity. This paper is intended to give a comprehensive review of the current literature in genetic association analysis casted in the framework of information theory. We focus our review on the following topics: (1) information theoretic approaches in genetic linkage and association studies; (2) entropy-based strategies for optimal SNP subset selection; and (3) the usage of theoretic information criteria in gene clustering and gene regulatory network construction. PMID:23633916

  16. Phenotypic and genetic analysis of biofilm formation by Staphylococcus epidermidis.

    PubMed

    Līduma, Iveta; Tračevska, Tatjana; Bērs, Uģis; Žileviča, Aija

    2012-01-01

    The most important virulence factor of Staphylococcus epidermidis is their capability to form a biofilm on the surfaces of implanted medical devices. The accumulative phase of biofilm formation is linked to the production of intercellular adhesin encoded by the icaADBC operon and accumulation-associated protein by the aap gene. The aim of the study was to investigate biofilm formation phenotypically and genetically in clinical strains of S. epidermidis in comparison with commensal strains. The study was carried out in 4 hospitals in Riga, Latvia. In total, 105 clinical strains of Staphylococcus epidermidis isolated from patients' blood (n=67) and intravenous catheters (n=38) in a case of laboratory-confirmed bacteremia were studied. Moreover, 60 Staphylococcus epidermidis commensal strains isolated from nose epithelium of healthy people were included as a control group. Appearance of the icaA and aap genes was tested by polymerase chain reaction. The microtiter plate method was used. Biofilm formation was detected in 50 (47%) of Staphylococcus epidermidis isolates in the clinical group and 15 (25%) of isolates in the control group (P=0.0049). Among 50 biofilm-forming clinical isolates, 46 (92%) were positive for the icaA and/or aap genes. The icaA and aap genes were not found only in 4 strains. The clinical isolates of Staphylococcus epidermidis were more likely to form biofilms than the commensal strains. The carriage of the icaA or aap gene alone, or their absence, is not applicable as a molecular marker for the discrimination invasive Staphylococcus epidermidis strains from contaminants.

  17. The genetics of maternal care: direct and indirect genetic effects on phenotype in the dung beetle Onthophagus taurus.

    PubMed

    Hunt, John; Simmons, Leigh W

    2002-05-14

    While theoretical models of the evolution of parental care are based on the assumption of underlying genetic variance, surprisingly few quantitative genetic studies of this life-history trait exist. Estimation of the degree of genetic variance in parental care is important because it can be a significant source of maternal effects, which, if genetically based, represent indirect genetic effects. A major prediction of indirect genetic effect theory is that traits without heritable variation can evolve because of the heritable environmental variation that indirect genetic effects provide. In the dung beetle, Onthophagus taurus, females provide care to offspring by provisioning a brood mass. The size of the brood mass has pronounced effects on offspring phenotype. Using a half-sib breeding design we show that the weight of the brood mass females produce exhibits significant levels of additive genetic variance due to sires. However, variance caused by dams is considerably larger, demonstrating that maternal effects are also important. Body size exhibited low additive genetic variance. However, body size exerts a strong maternal influence on the weight of brood masses produced, accounting for 22% of the nongenetic variance in offspring body size. Maternal body size also influenced the number of offspring produced but there was no genetic variance for this trait. Offspring body size and brood mass weight exhibited positive genetic and phenotypic correlations. We conclude that both indirect genetic effects, via maternal care, and nongenetic maternal effects, via female size, play important roles in the evolution of phenotype in this species.

  18. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus

    PubMed Central

    Sanchez, Elena; Nadig, Ajay; Richardson, Bruce C; Freedman, Barry I; Kaufman, Kenneth M; Kelly, Jennifer A; Niewold, Timothy B; Kamen, Diane L; Gilkeson, Gary S; Ziegler, Julie T; Langefeld, Carl D; Alarcón, Graciela S; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Brown, Elizabeth E; Kimberly, Robert P; Reveille, John D; Vilá, Luis M; Merrill, Joan T; Anaya, Juan-Manuel; James, Judith A; Pons-Estel, Bernardo A; Martin, Javier; Park, So-Yeon; Bang, So-Young; Bae, Sang-Cheol; Moser, Kathy L; Vyse, Timothy J; Criswell, Lindsey A; Gaffney, Patrick M; Tsao, Betty P; Jacob, Chaim O; Harley, John B; Alarcón-Riquelme, Marta E; Sawalha, Amr H

    2011-01-01

    Objective Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods 4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future. PMID:21719445

  19. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus.

    PubMed

    Sanchez, Elena; Nadig, Ajay; Richardson, Bruce C; Freedman, Barry I; Kaufman, Kenneth M; Kelly, Jennifer A; Niewold, Timothy B; Kamen, Diane L; Gilkeson, Gary S; Ziegler, Julie T; Langefeld, Carl D; Alarcón, Graciela S; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Brown, Elizabeth E; Kimberly, Robert P; Reveille, John D; Vilá, Luis M; Merrill, Joan T; Anaya, Juan-Manuel; James, Judith A; Pons-Estel, Bernardo A; Martin, Javier; Park, So-Yeon; Bang, So-Young; Bae, Sang-Cheol; Moser, Kathy L; Vyse, Timothy J; Criswell, Lindsey A; Gaffney, Patrick M; Tsao, Betty P; Jacob, Chaim O; Harley, John B; Alarcón-Riquelme, Marta E; Sawalha, Amr H

    2011-10-01

    Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. 4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10(-6), OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Signifi cant associations were found between clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

  20. Alpha-locus hexosaminidase genetic compound with juvenile gangliosidosis phenotype: clinical, genetic, and biochemical studies.

    PubMed Central

    Johnson, W G; Cohen, C S; Miranda, A F; Waran, S P; Chutorian, A M

    1980-01-01

    A 3-year-old boy developed progressive neurological deterioration in his third year, characterized by dementia, ataxia, myoclonic jerks, and bilateral macular cherry-red spots. Hexosaminidase A (HEX A) was partially decreased in the patient's serum, leukocytes, and cultured skin fibroblasts. Hexosaminidase was studied in serum and leukocytes from family members. Four members of the paternal branch appeared to be carriers of classical infantile Tay-Sachs allele, HEX alpha 2, probably receiving the gene from one great-grandparent of Ashkenazi origin. In the maternal branch, no one was a carrier of classical infantile Tay-Sachs disease, but five individuals were carriers of a milder alpha-locus defect. The patient, therefore, was a genetic compound of two different alpha-locus hexosaminidase mutations. At least 21 families with late-infantile or juvenile GM2 gangliosidosis have been reported, 18 of them with alpha-locus mutations, and three with beta-locus mutations. Genetic compounds of hexosaminidase have been reported in at least seven families, five with alpha-locus mutations and two with beta-locus mutations. The compound had the phenotype of infantile Tay-Sachs disease in one family, infantile Sandhoff disease in another, and the normal phenotype in the rest. PMID:6772023

  1. Cooperation between phenotypic plasticity and genetic mutations can account for the cumulative selection in evolution

    PubMed Central

    Nishikawa, Ken; Kinjo, Akira R.

    2014-01-01

    We propose the cooperative model of phenotype-driven evolution, in which natural selection operates on a phenotype caused by both genetic and epigenetic factors. The conventional theory of evolutionary synthesis assumes that a phenotypic value (P) is the sum of genotypic value (G) and environmental deviation (E), P=G+E, where E is the fluctuations of the phenotype among individuals in the absence of environmental changes. In contrast, the cooperative model assumes that an evolution is triggered by an environmental change and individuals respond to the change by phenotypic plasticity (epigenetic changes). The phenotypic plasticity, while essentially qualitative, is denoted by a quantitative value F which is modeled as a normal random variable like E, but with a much larger variance. Thus, the fundamental equation of the cooperative model is given as P=G+F where F includes the effect of E. Computer simulations using a genetic algorithm demonstrated that the cooperative model realized much faster evolution than the evolutionary synthesis. This accelerated evolution was found to be due to the cumulative evolution made possible by a ratchet mechanism due to the epigenetic contribution to the phenotypic value. The cooperative model can well account for the phenomenon of genetic assimilation, which, in turn, suggests the mechanism of cumulative selection. The cooperative model may also serve as a theoretical basis to understand various ideas and phenomena of the phenotype-driven evolution such as genetic assimilation, the theory of facilitated phenotypic variation, and epigenetic inheritance over generations. PMID:27493504

  2. Phenotypic and evolutionary consequences of social behaviours: interactions among individuals affect direct genetic effects.

    PubMed

    Trubenová, Barbora; Hager, Reinmar

    2012-01-01

    Traditional quantitative genetics assumes that an individual's phenotype is determined by both genetic and environmental factors. For many animals, part of the environment is social and provided by parents and other interacting partners. When expression of genes in social partners affects trait expression in a focal individual, indirect genetic effects occur. In this study, we explore the effects of indirect genetic effects on the magnitude and range of phenotypic values in a focal individual in a multi-member model analyzing three possible classes of interactions between individuals. We show that social interactions may not only cause indirect genetic effects but can also modify direct genetic effects. Furthermore, we demonstrate that both direct and indirect genetic effects substantially alter the range of phenotypic values, particularly when a focal trait can influence its own expression via interactions with traits in other individuals. We derive a function predicting the relative importance of direct versus indirect genetic effects. Our model reveals that both direct and indirect genetic effects can depend to a large extent on both group size and interaction strength, altering group mean phenotype and variance. This may lead to scenarios where between group variation is much higher than within group variation despite similar underlying genetic properties, potentially affecting the level of selection. Our analysis highlights key properties of indirect genetic effects with important consequences for trait evolution, the level of selection and potentially speciation.

  3. Genotypic and phenotypic characterization of genetic differentiation and diversity in the USDA rice mini-core collection.

    PubMed

    Li, Xiaobai; Yan, Wengui; Agrama, Hesham; Hu, Biaolin; Jia, Limeng; Jia, Melissa; Jackson, Aaron; Moldenhauer, Karen; McClung, Anna; Wu, Dianxing

    2010-12-01

    A rice mini-core collection consisting of 217 accessions has been developed to represent the USDA core and whole collections that include 1,794 and 18,709 accessions, respectively. To improve the efficiency of mining valuable genes and broadening the genetic diversity in breeding, genetic structure and diversity were analyzed using both genotypic (128 molecular markers) and phenotypic (14 numerical traits) data. This mini-core had 13.5 alleles per locus, which is the most among the reported germplasm collections of rice. Similarly, polymorphic information content (PIC) value was 0.71 in the mini-core which is the highest with one exception. The high genetic diversity in the mini-core suggests there is a good possibility of mining genes of interest and selecting parents which will improve food production and quality. A model-based clustering analysis resulted in lowland rice including three groups, aus (39 accessions), indica (71) and their admixtures (5), upland rice including temperate japonica (32), tropical japonica (40), aromatic (6) and their admixtures (12) and wild rice (12) including glaberrima and four other species of Oryza. Group differentiation was analyzed using both genotypic distance Fst from 128 molecular markers and phenotypic (Mahalanobis) distance D(2) from 14 traits. Both dendrograms built by Fst and D(2) reached similar-differentiative relationship among these genetic groups, and the correlation coefficient showed high value 0.85 between Fst matrix and D(2) matrix. The information of genetic and phenotypic differentiation could be helpful for the association mapping of genes of interest. Analysis of genotypic and phenotypic diversity based on genetic structure would facilitate parent selection for broadening genetic base of modern rice cultivars via breeding effort.

  4. Phenotypic characterization and genetic diversity of Flavobacterium columnare isolated from red tilapia, Oreochromis sp. in Thailand

    USDA-ARS?s Scientific Manuscript database

    Flavobacterium columnare is the etiologic agent of columnaris disease and severely affects various freshwater aquaculture fish species worldwide. The objectives of this study were to determine the phenotypic characteristics and genetic variability among F. columnare isolates isolated from red tilapi...

  5. Neurocognitive Phenotypes and Genetic Dissection of Disorders of Brain and Behavior

    PubMed Central

    Congdon, Eliza; Poldrack, Russell A.; Freimer, Nelson B.

    2014-01-01

    Summary Elucidating the molecular mechanisms underlying quantitative neurocognitive phenotypes will further our understanding of the brain’s structural and functional architecture and advance the diagnosis and treatment of the psychiatric disorders that these traits underlie. Although many neurocognitive traits are highly heritable, little progress has been made in identifying genetic variants unequivocally associated with these phenotypes. A major obstacle to such progress is the difficulty in identifying heritable neurocognitive measures which are precisely defined, systematically assessed and represent unambiguous mental constructs, yet are amenable to the high-throughput phenotyping necessary to obtain adequate power for genetic association studies. In this perspective we compare the current status of genetic investigations of neurocognitive phenotypes to that of other categories of biomedically relevant traits and suggest strategies for genetically dissecting traits that may underlie disorders of brain and behavior. PMID:20955930

  6. Environmental stress, inbreeding, and the nature of phenotypic and genetic variance in Drosophila melanogaster.

    PubMed Central

    Fowler, Kevin; Whitlock, Michael C

    2002-01-01

    Fifty-two lines of Drosophila melanogaster founded by single-pair population bottlenecks were used to study the effects of inbreeding and environmental stress on phenotypic variance, genetic variance and survivorship. Cold temperature and high density cause reduced survivorship, but these stresses do not cause repeatable changes in the phenotypic variance of most wing morphological traits. Wing area, however, does show increased phenotypic variance under both types of environmental stress. This increase is no greater in inbred than in outbred lines, showing that inbreeding does not increase the developmental effects of stress. Conversely, environmental stress does not increase the extent of inbreeding depression. Genetic variance is not correlated with environmental stress, although the amount of genetic variation varies significantly among environments and lines vary significantly in their response to environmental change. Drastic changes in the environment can cause changes in phenotypic and genetic variance, but not in a way reliably predicted by the notion of 'stress'. PMID:11934358

  7. In-depth metabolic phenotyping of genetically engineered mouse models in obesity and diabetes.

    PubMed

    Lee, Hui-Young; Jeong, Kyeong-Hoon; Choi, Cheol Soo

    2014-10-01

    The world-wide prevalence of obesity and diabetes has increased sharply during the last two decades. Accordingly, the metabolic phenotyping of genetically engineered mouse models is critical for evaluating the functional roles of target genes in obesity and diabetes, and for developing new therapeutic targets. In this review, we discuss the practical meaning of metabolic phenotyping, the strategy of choosing appropriate tests, and considerations when designing and performing metabolic phenotyping in mice.

  8. Development of resources and tools for mapping genetic sources of phenotypic variation

    USDA-ARS?s Scientific Manuscript database

    Commercial and experimental genetic resources were established and investigated for a range of reproductive and disease susceptibility phenotypes. The phenotyping efforts were accompanied with RNA and whole genome sequencing and novel assemblies of the swine genome. The efforts were complemented wit...

  9. Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility

    USDA-ARS?s Scientific Manuscript database

    Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of cholesterol deficiency (CD) and 17 other recessive haplotypes in Ayrshire (AY; n=1), Brown Swiss (BS; n = 5), Holstein (HO; n = 10), and Jersey (JE; n = 2) cattle on milk, fat, and protein yield...

  10. Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder.

    PubMed

    Labbe, Aurélie; Bureau, Alexandre; Moreau, Isabel; Roy, Marc-André; Chagnon, Yvon; Maziade, Michel; Merette, Chantal

    2012-11-01

    This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP.

  11. Religious aspects of human genetic information.

    PubMed

    Kimura, R

    1990-01-01

    To obtain human genetic information with the intention of treating and curing severe genetic disease would be considered to be a positive personal decision of a moral agent in various religious contexts. According to some religious teachings human suffering should not be regarded merely as a negative element of life; however, the scientific achievement of obtaining genetic information should surely increase the possibility of hope for the eventual cure of genetically determined diseases. The elimination of human suffering and tragedy in severe genetically determined illness, on the criterion of the benefit of the patient, is permitted by various contemporary religious teachings, according to an analysis of publications by the World Council of Churches and the Vatican and sources from Jewish, Islamic and Buddhist teachings.

  12. The role of genetic information in personalized medicine.

    PubMed

    Gamma, Alex

    2013-01-01

    Personalized medicine is the latest promise of a gene-centered biomedicine to provide treatments custom-tailored to the specific needs of patients. Although surrounded by much hype, personalized medicine at present lacks the empirical and theoretical foundations necessary to render it a realistic long-term perspective. In particular, the role of genetic data and the relationship between causal understanding, prediction, prevention, and treatment of a disease need clarifying. This article critically examines the concept of information in genetics and its relation to modern-day genetic determinism, using pharmacogenetics, personalized medicine's core discipline, as a test case. The article concludes that: (1) genetic knowledge does not constitute a privileged basis for personalized medicine because there is an a priori complete causal parity of genetic and nongenetic resources of development; and (2) prediction, prevention, and treatment all depend on a causal-mechanistic understanding that will follow only from integrating data across the whole gamut of developmental factors-genetic and non-genetic. In a future successful personalized medicine, genes will have no special status, either as determinants of phenotype, markers of disease or as targets of treatment.

  13. Bayesian estimation of genetic parameters for multivariate threshold and continuous phenotypes and molecular genetic data in simulated horse populations using Gibbs sampling

    PubMed Central

    Stock, Kathrin F; Distl, Ottmar; Hoeschele, Ina

    2007-01-01

    Background Requirements for successful implementation of multivariate animal threshold models including phenotypic and genotypic information are not known yet. Here simulated horse data were used to investigate the properties of multivariate estimators of genetic parameters for categorical, continuous and molecular genetic data in the context of important radiological health traits using mixed linear-threshold animal models via Gibbs sampling. The simulated pedigree comprised 7 generations and 40000 animals per generation. Additive genetic values, residuals and fixed effects for one continuous trait and liabilities of four binary traits were simulated, resembling situations encountered in the Warmblood horse. Quantitative trait locus (QTL) effects and genetic marker information were simulated for one of the liabilities. Different scenarios with respect to recombination rate between genetic markers and QTL and polymorphism information content of genetic markers were studied. For each scenario ten replicates were sampled from the simulated population, and within each replicate six different datasets differing in number and distribution of animals with trait records and availability of genetic marker information were generated. (Co)Variance components were estimated using a Bayesian mixed linear-threshold animal model via Gibbs sampling. Residual variances were fixed to zero and a proper prior was used for the genetic covariance matrix. Results Effective sample sizes (ESS) and biases of genetic parameters differed significantly between datasets. Bias of heritability estimates was -6% to +6% for the continuous trait, -6% to +10% for the binary traits of moderate heritability, and -21% to +25% for the binary traits of low heritability. Additive genetic correlations were mostly underestimated between the continuous trait and binary traits of low heritability, under- or overestimated between the continuous trait and binary traits of moderate heritability, and

  14. What information do cancer genetic counselees prioritize?

    PubMed

    Hayat Roshanai, Afsaneh; Lampic, Claudia; Ingvoldstad, Charlotta; Askmalm, Marie Stenmark; Bjorvatn, Chathrine; Rosenquist, Richard; Nordin, Karin

    2012-08-01

    This study explored the informational needs of individuals attending genetic counseling for hereditary cancer, using a free-choice and a forced choice method. Prior to the consultation the informational needs of 334 counselees from Sweden and Norway were assessed by the QUOTE-gene (ca) questionnaire and by a study specific forced choice method, using Q-methodology. Questionnaire responses indicated that counselees' major concerns pertained to the need to be taken seriously, to be provided with sufficient risk estimation and medical/genetic information and to be involved in the decision making process. Furthermore, prior to counseling, counselees noted that the counselors' consideration and skillfulness were also extremely important. Analysis of the Q-sorting results revealed that counselees' needs could be assigned to one of five groups: the "need for facts; caring communication and medical information; information and support in communicating the genetic information to others; practical care and practical/medical information". Particularly noteworthy, counselees with varying backgrounds characteristics prioritized different needs. Cancer genetic counselees probably have different needs due to their medical and demographic background when attending genetic counseling. Addressing counselees' specific concerns more sufficiently and thereby increasing the overall effectiveness of the counseling session requires increased insight into individual needs, by for instance, utilizing screening methods such as QUOTE-gene (ca) prior to the counseling session.

  15. 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

  16. Familial Transmission of Derived Phenotypes for Molecular Genetic Studies of Substance Use Disorders

    PubMed Central

    Faraone, Stephen V.; Adamson, Joel J.; Wilens, Timothy E.; Monuteaux, Michael C.; Biederman, Joseph

    2008-01-01

    Although family, twin, and adoption studies indicate that genes play a significant etiologic role in the development of substance use disorders (SUDs), detecting specific genes has been difficult due to uncertainties about how to define SUDs, genetic heterogeneity and variable phenotypic expression of SUD genotypes. We used data from families recruited into six contemporaneous studies of children and adults to derive candidate SUD phenotypes using principle factors factor analysis with varimax rotation. We previously found evidence of two SUD phenotypes in offspring: a psychopathology dimension and a cognitive impairment dimension. We found evidence for one SUD-related phenotype in adults that we term Psychopathology and Cognitive Impairment. Parental factor scores significantly predicted both offspring phenotypes, as well as parental SUD (OR=1.41,p<0.001) and offspring SUD (mother’s phenotype: OR=1.34,p=0.04; father’s phenotype: OR=1.33,p=0.01). Offspring phenotype predicted offspring SUD (psychopathology phenotype: OR=2.96,p<0.001; cognitive impairment: OR=1.33,p=0.04); in offspring, baseline psychopathology predicted SUD at follow-up assessments (OR=1.55,p=0.01). Results suggest that these candidate SUD phenotypes may be useful for genetic studies of SUD. PMID:17766060

  17. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

    PubMed

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-09

    Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with

  18. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    PubMed Central

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

  19. The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood.

    PubMed

    Waszczuk, Monika A; Zavos, Helena M S; Gregory, Alice M; Eley, Thalia C

    2014-08-01

    internalizing factor influencing depression and all anxiety subscales emerged, alongside a small significant genetic fear factor. These results provide preliminary evidence for different phenotypic and genetic structures of internalizing disorder symptoms in childhood, adolescence, and young adulthood, with depression and anxiety becoming more associated from adolescence. The results inform molecular genetics research and transdiagnostic treatment approaches. The findings affirm the need to continue examining the classification of mood and anxiety disorders in diagnostic systems.

  20. Environmental factors associated with genetic and phenotypic divergence among sympatric populations of Arctic charr (Salvelinus alpinus).

    PubMed

    Corrigan, L J; Lucas, M C; Winfield, I J; Hoelzel, A R

    2011-09-01

    The mechanisms by which phenotypic and genetic divergence may occur among sympatric, conspecific populations have been widely discussed but are still not well understood. Possible mechanisms include assortative mating based on morphology or variation in the reproductive behaviour of phenotypes, and both have been suggested to be relevant to the differentiation of salmonid populations in post-glacial lakes. Here, we studied Arctic charr (Salvelinus alpinus) in Windermere, where putative populations are defined by spatial and temporal variation in spawning. Genetic differentiation was assessed based on nine microsatellite loci, and phenotypic variation was assessed from morphometric characters. We test hypotheses about the relative role of morphology, spawning season and spawning habitat in the evolution of genetic divergence among these populations. Distinct from other lake systems, we find that both morphological and genetic differentiation are restricted primarily to one of two interconnecting basins, that genetic and morphological differentiation are decoupled in this lake and that both phenotype and environment have changed over the last 20 years. The implication is that breeding habitat plays a primary role in isolating populations that differentiate by drift and that phenotypically plastic changes, potentially related to foraging specializations, have either become secondarily decoupled from the genetically defined populations or were never fundamental in driving the evolution of genetic diversity in the Windermere system.

  1. Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes.

    PubMed

    Mosley, Jonathan D; Shoemaker, M Benjamin; Wells, Quinn S; Darbar, Dawood; Shaffer, Christian M; Edwards, Todd L; Bastarache, Lisa; McCarty, Catherine A; Thompson, Will; Chute, Christopher G; Jarvik, Gail P; Crosslin, David R; Larson, Eric B; Kullo, Iftikhar J; Pacheco, Jennifer A; Peissig, Peggy L; Brilliant, Murray H; Linneman, James G; Witte, John S; Denny, Josh C; Roden, Dan M

    2017-04-01

    One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]). The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity. © 2017 American Heart Association, Inc.

  2. Genetic Counselling: Information Given, Recall and Satisfaction.

    ERIC Educational Resources Information Center

    Michie, Susan; McDonald, Valerie; Marteau, Theresa M.

    1997-01-01

    A questionnaire was sent to counselors (N=32) to categorize the key points given in genetic counseling; to assess the amount and type of information recalled; and to examine the relationships between counselees' knowledge, satisfaction with information received, the meeting of expectations, concern, and anxiety. Results emphasize the importance of…

  3. Genetic Counselling: Information Given, Recall and Satisfaction.

    ERIC Educational Resources Information Center

    Michie, Susan; McDonald, Valerie; Marteau, Theresa M.

    1997-01-01

    A questionnaire was sent to counselors (N=32) to categorize the key points given in genetic counseling; to assess the amount and type of information recalled; and to examine the relationships between counselees' knowledge, satisfaction with information received, the meeting of expectations, concern, and anxiety. Results emphasize the importance of…

  4. Genetic Homozygosity and Phenotypic Variability in Craniosynostotic Rabbits.

    PubMed

    Gilbert, James R; Cray, James J; Kreithen, Amy; Marazita, Mary L; Cooper, Gregory M; Losee, Joseph E; Siegel, Michael I; Mooney, Mark P

    2017-01-01

      Craniosynostosis ranges in severity from single suture involvement with prenatal onset to multiple suture involvement with postnatal onset. The present study was designed to test the hypothesis that increasing homozygosity may be responsible for more severe phenotypic expression by examining the relationship between inbreeding and phenotypic expression in synostotic rabbits.   Data were obtained from 173 litters and 209 rabbits with familial craniosynostosis. Five distinct phenotypes were identified (normal n = 62; unicoronal delayed onset synostosis (DOS) n = 47; bicoronal DOS n = 21; unicoronal early onset synostosis (EOS) n = 26, and bicoronal EOS n= 53). Wright's coefficients of inbreeding (CI) were calculated using CompuPed software. Radiographs were taken at 10, 25, 42, 84, and 126 days of age to assess coronal suture, craniofacial, and skeletal growth. The relationship between CI and growth data was assessed using correlation coefficients.   Mean CIs ranged from 15.68 (±2.22) in normal rabbits to 25.89 (±5.03) in bicoronal DOS, to 36.29 (±2.10) in unicoronal EOS to 42.85 (±2.10) in bicoronal EOS rabbits. Significant differences were noted among groups (F = 11.48; P < .001). Significant negative correlations were noted between CI and sutural and craniofacial growth at 25 (r = -.45, P < .001; and r = -.66, P < .001) through 126 (r = -.40, P < .001 and r = -.46, P < .001) days of age.   While the synostotic phenotype is inherited in an autosomal dominant fashion in these rabbits, increasing homozygosity is associated with more severely affected phenotypes. These findings suggest that an accumulation of additional, modifier genes may determine the severity of the synostotic phenotype in rabbits.

  5. Toward Diagnostic and Phenotype Markers for Genetically Transmitted Speech Delay

    ERIC Educational Resources Information Center

    Shriberg, Lawrence D.; Lewis, Barbara A.; Tomblin, J. Bruce; McSweeny, Jane L.; Karlsson, Heather B.; Scheer, Alison R.

    2005-01-01

    Converging evidence supports the hypothesis that the most common subtype of childhood speech sound disorder (SSD) of currently unknown origin is genetically transmitted. We report the first findings toward a set of diagnostic markers to differentiate this proposed etiological subtype (provisionally termed "speech delay-genetic") from other…

  6. A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

    PubMed Central

    Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

    2011-01-01

    SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

  7. Autism Spectrum and Obsessive–Compulsive Disorders: OC Behaviors, Phenotypes and Genetics

    PubMed Central

    Jacob, Suma; Landeros-Weisenberger, Angeli; Leckman, James F.

    2014-01-01

    Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive–compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive–compulsive disorder (OCD). The OCB seen in ASD vary depending on the individual’s mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family-genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions. PMID:20029829

  8. GPA-MDS: A Visualization Approach to Investigate Genetic Architecture among Phenotypes Using GWAS Results.

    PubMed

    Wei, Wei; Ramos, Paula S; Hunt, Kelly J; Wolf, Bethany J; Hardiman, Gary; Chung, Dongjun

    2016-01-01

    Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. Recently, there has been accumulating evidence suggesting that different complex traits share a common risk basis, namely, pleiotropy. Previously, a statistical method, namely, GPA (Genetic analysis incorporating Pleiotropy and Annotation), was developed to improve identification of risk variants and to investigate pleiotropic structure through a joint analysis of multiple GWAS datasets. While GPA provides a statistically rigorous framework to evaluate pleiotropy between phenotypes, it is still not trivial to investigate genetic relationships among a large number of phenotypes using the GPA framework. In order to address this challenge, in this paper, we propose a novel approach, GPA-MDS, to visualize genetic relationships among phenotypes using the GPA algorithm and multidimensional scaling (MDS). This tool will help researchers to investigate common etiology among diseases, which can potentially lead to development of common treatments across diseases. We evaluate the proposed GPA-MDS framework using a simulation study and apply it to jointly analyze GWAS datasets examining 18 unique phenotypes, which helps reveal the shared genetic architecture of these phenotypes.

  9. GPA-MDS: A Visualization Approach to Investigate Genetic Architecture among Phenotypes Using GWAS Results

    PubMed Central

    Wei, Wei; Hunt, Kelly J.; Wolf, Bethany J.; Hardiman, Gary

    2016-01-01

    Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. Recently, there has been accumulating evidence suggesting that different complex traits share a common risk basis, namely, pleiotropy. Previously, a statistical method, namely, GPA (Genetic analysis incorporating Pleiotropy and Annotation), was developed to improve identification of risk variants and to investigate pleiotropic structure through a joint analysis of multiple GWAS datasets. While GPA provides a statistically rigorous framework to evaluate pleiotropy between phenotypes, it is still not trivial to investigate genetic relationships among a large number of phenotypes using the GPA framework. In order to address this challenge, in this paper, we propose a novel approach, GPA-MDS, to visualize genetic relationships among phenotypes using the GPA algorithm and multidimensional scaling (MDS). This tool will help researchers to investigate common etiology among diseases, which can potentially lead to development of common treatments across diseases. We evaluate the proposed GPA-MDS framework using a simulation study and apply it to jointly analyze GWAS datasets examining 18 unique phenotypes, which helps reveal the shared genetic architecture of these phenotypes. PMID:27868058

  10. Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation

    PubMed Central

    Busemeyer, Lucas; Ruckelshausen, Arno; Möller, Kim; Melchinger, Albrecht E.; Alheit, Katharina V.; Maurer, Hans Peter; Hahn, Volker; Weissmann, Elmar A.; Reif, Jochen C.; Würschum, Tobias

    2013-01-01

    To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high-dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping. PMID:23942574

  11. Toward a population genetic framework of developmental evolution: the costs, limits, and consequences of phenotypic plasticity

    PubMed Central

    Snell-Rood, Emilie C.; Van Dyken, James David; Cruickshank, Tami; Wade, Michael J.; Moczek, Armin P.

    2011-01-01

    Adaptive phenotypic plasticity allows organisms to cope with environmental variability, and yet, despite its adaptive significance, phenotypic plasticity is neither ubiquitous nor infinite. In this review, we merge developmental and population genetic perspectives to explore costs and limits on the evolution of plasticity. Specifically, we focus on the role of modularity in developmental genetic networks as a mechanism underlying phenotypic plasticity, and apply to it lessons learned from population genetic theory on the interplay between relaxed selection and mutation accumulation. We argue that the environmental specificity of gene expression and the associated reduction in pleiotropic constraints drive a fundamental tradeoff between the range of plasticity that can be accommodated and mutation accumulation in alternative developmental networks. This tradeoff has broad implications for understanding the origin and maintenance of plasticity and may contribute to a better understanding of the role of plasticity in the origin, diversification, and loss of phenotypic diversity. PMID:20020499

  12. Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation

    NASA Astrophysics Data System (ADS)

    Busemeyer, Lucas; Ruckelshausen, Arno; Möller, Kim; Melchinger, Albrecht E.; Alheit, Katharina V.; Maurer, Hans Peter; Hahn, Volker; Weissmann, Elmar A.; Reif, Jochen C.; Würschum, Tobias

    2013-08-01

    To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high-dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping.

  13. Searching the Mouse Genome Informatics (MGI) Resources for Information on Mouse Biology from Genotype to Phenotype.

    PubMed

    Shaw, David R

    2016-12-08

    The Mouse Genome Informatics (MGI) resource provides the research community with access to information on the genetics, genomics, and biology of the laboratory mouse. Core data in MGI include gene characterization and function, phenotype and disease model descriptions, DNA and protein sequence data, gene expression data, vertebrate homologies, SNPs, mapping data, and links to other bioinformatics databases. Semantic integration is supported through the use of standardized nomenclature, and through the use of controlled vocabularies such as the mouse Anatomical Dictionary, the Mammalian Phenotype Ontology, and the Gene Ontologies. MGI extracts and organizes data from primary literature. MGI data are shared with and widely displayed from other bioinformatics resources. The database is updated weekly with curated annotations, and regularly adds new datasets and features. This unit provides a guide to using the MGI bioinformatics resource. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

  14. Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population

    PubMed Central

    Arenas, I. A.; Tremblay, J.; Deslauriers, B.; Sandoval, J.; Šeda, O.; Gaudet, D.; Merlo, E.; Kotchen, T.; Cowley, A. W.

    2013-01-01

    Blood pressure (BP) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions. Standing upright is a recent evolutionary trait, and genetic factors that influence postural adaptations may contribute to BP variability. We studied the effect of posture on the genetics of BP and intermediate BP phenotypes. We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia. Blood pressure, three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright. The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees. Linkage was conducted on 196 candidate genes by sib-pair analyses, and empirical estimates of significance were obtained. A permutation algorithm was implemented to study the postural effect on linkage. ADRA1A, APO, CAST, CORIN, CRHR1, EDNRB, FGF2, GC, GJA1, KCNB2, MMP3, NPY, NR3C2, PLN, TGFBR2, TNFRSF6, and TRHR showed evidence of linkage with any phenotype in the supine position and not upon standing, whereas AKR1B1, CD36, EDNRA, F5, MMP9, PKD2, PON1, PPARG, PPARGC1A, PRKCA, and RET were specifically linked to standing phenotypes. Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture. When investigators perform genetic studies exclusively on a single posture, important genetic components of BP are missed. Supine and standing BPs have distinct genetic signatures. Standardized maneuvers influence the results of genetic investigations into BP, thus reflecting its dynamic regulation. PMID:23269701

  15. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins

    PubMed Central

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang; Zhang, Dongfeng; Duan, Haiping; Tan, Qihua; Hjelmborg, Jacob; Kruse, Torben; Dalgård, Christine

    2016-01-01

    Objective The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments. Materials and Methods The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18–65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23–64). The classical twin models were fitted to the longitudinal change in each phenotypephenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype. Results Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. Conclusion Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples. PMID:26862898

  16. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins.

    PubMed

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang; Zhang, Dongfeng; Duan, Haiping; Tan, Qihua; Hjelmborg, Jacob; Kruse, Torben; Dalgård, Christine

    2016-01-01

    The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments. The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18-65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23-64). The classical twin models were fitted to the longitudinal change in each phenotypephenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype. Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples.

  17. Genetic architecture underlying morning and evening circadian phenotypes in fruit flies Drosophila melanogaster

    PubMed Central

    Vaze, K M; Nikhil, K L; Sharma, V K

    2013-01-01

    Circadian rhythms are perhaps among the genetically best characterized behaviours. Several mutations with drastic effects on circadian processes have been identified and models developed to explain how clock genes and their products generate self-sustained oscillations. Although natural variations in circadian phenotypes have been studied extensively, the genetic basis of such adaptive variations remains largely unknown. Here we report the results of a preliminary genetic analysis of adaptive divergence of circadian phenotypes in populations of fruit flies Drosophila melanogaster. Two sets of populations, ‘early' and ‘late', were created in a long-term laboratory selection for morning and evening emergence, with four independent replicates each. Over the course of ∼55 generations, the early flies evolved increased morning emergence and a shorter circadian period, whereas late flies evolved increased evening emergence and longer period. To examine the genetic basis of circadian phenotypes, we set up crosses between early and late flies, and monitored emergence and activity/rest rhythms in the F1, backcrossed and F2 progeny. Our analysis suggests that the genetic basis of divergent circadian phenotypes in early and late stocks is primarily autosomal. Line-cross analysis revealed that additive and non-additive genetic effects contribute to the divergence of circadian phenotypes in early and late flies. PMID:23612693

  18. Genetic architecture underlying morning and evening circadian phenotypes in fruit flies Drosophila melanogaster.

    PubMed

    Vaze, K M; Nikhil, K L; Sharma, V K

    2013-10-01

    Circadian rhythms are perhaps among the genetically best characterized behaviours. Several mutations with drastic effects on circadian processes have been identified and models developed to explain how clock genes and their products generate self-sustained oscillations. Although natural variations in circadian phenotypes have been studied extensively, the genetic basis of such adaptive variations remains largely unknown. Here we report the results of a preliminary genetic analysis of adaptive divergence of circadian phenotypes in populations of fruit flies Drosophila melanogaster. Two sets of populations, 'early' and 'late', were created in a long-term laboratory selection for morning and evening emergence, with four independent replicates each. Over the course of ∼55 generations, the early flies evolved increased morning emergence and a shorter circadian period, whereas late flies evolved increased evening emergence and longer period. To examine the genetic basis of circadian phenotypes, we set up crosses between early and late flies, and monitored emergence and activity/rest rhythms in the F1, backcrossed and F2 progeny. Our analysis suggests that the genetic basis of divergent circadian phenotypes in early and late stocks is primarily autosomal. Line-cross analysis revealed that additive and non-additive genetic effects contribute to the divergence of circadian phenotypes in early and late flies.

  19. Exploring the genetics of nestling personality traits in a wild passerine bird: testing the phenotypic gambit.

    PubMed

    Brommer, Jon E; Kluen, Edward

    2012-12-01

    When several personality traits covary, they form a behavioral syndrome. Understanding the evolutionary dynamics of a behavioral syndrome requires knowledge of its genetic underpinning. At present, our understanding of the genetic basis of behavioral syndromes is largely restricted to domestic and laboratory animals. Wild behavioral syndromes are mostly inferred on the basis of phenotypic correlations, and thus make the "phenotypic gambit" of assuming that these phenotypic correlations capture the underlying genetic correlations. On the basis of 3 years of reciprocal cross-fostering of 2896 nestlings of 271 families within a pedigreed population, we show that the nestling personality traits handling aggression, breathing rate, and docility are heritable (h(2) = 16-29%), and often have a pronounced "nest-of-rearing" variance component (10-15%), but a relatively small "nest-of-origin" variance component (0-7%). The three nestling personality traits form a behavioral syndrome on the phenotypic and genetic level. Overall, the phenotypic correlations provide a satisfactory description of the genetic ones, but significantly underestimate the magnitude of one of the pairwise genetic correlations, which mirrors the conclusion based on domestic and laboratory studies.

  20. PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases.

    PubMed

    Buske, Orion J; Girdea, Marta; Dumitriu, Sergiu; Gallinger, Bailey; Hartley, Taila; Trang, Heather; Misyura, Andriy; Friedman, Tal; Beaulieu, Chandree; Bone, William P; Links, Amanda E; Washington, Nicole L; Haendel, Melissa A; Robinson, Peter N; Boerkoel, Cornelius F; Adams, David; Gahl, William A; Boycott, Kym M; Brudno, Michael

    2015-10-01

    The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered.

  1. The relationship between parental genetic or phenotypic divergence and progeny variation in the maize nested association mapping population

    PubMed Central

    Hung, H-Y; Browne, C; Guill, K; Coles, N; Eller, M; Garcia, A; Lepak, N; Melia-Hancock, S; Oropeza-Rosas, M; Salvo, S; Upadyayula, N; Buckler, E S; Flint-Garcia, S; McMullen, M D; Rocheford, T R; Holland, J B

    2012-01-01

    Appropriate selection of parents for the development of mapping populations is pivotal to maximizing the power of quantitative trait loci detection. Trait genotypic variation within a family is indicative of the family's informativeness for genetic studies. Accurate prediction of the most useful parental combinations within a species would help guide quantitative genetics studies. We tested the reliability of genotypic and phenotypic distance estimators between pairs of maize inbred lines to predict genotypic variation for quantitative traits within families derived from biparental crosses. We developed 25 families composed of ∼200 random recombinant inbred lines each from crosses between a common reference parent inbred, B73, and 25 diverse maize inbreds. Parents and families were evaluated for 19 quantitative traits across up to 11 environments. Genetic distances (GDs) among parents were estimated with 44 simple sequence repeat and 2303 single-nucleotide polymorphism markers. GDs among parents had no predictive value for progeny variation, which is most likely due to the choice of neutral markers. In contrast, we observed for about half of the traits measured a positive correlation between phenotypic parental distances and within-family genetic variance estimates. Consequently, the choice of promising segregating populations can be based on selecting phenotypically diverse parents. These results are congruent with models of genetic architecture that posit numerous genes affecting quantitative traits, each segregating for allelic series, with dispersal of allelic effects across diverse genetic material. This architecture, common to many quantitative traits in maize, limits the predictive value of parental genotypic or phenotypic values on progeny variance. PMID:22027895

  2. Human genetic information: the legal implications.

    PubMed

    Brahams, D

    1990-01-01

    This paper provides a brief summary of some of the key legal issues raised by human genetic information and research as viewed from a British common law standpoint. The law is basically reactive rather than prospective and problems posed by futuristic medico-scientific discoveries are likely to be dealt with by reference to established legal principles and analogies made with decided cases. The acquisition and research into human genetic information in the form of DNA profiling may have wide-ranging legal implications. Human genetic information may provide an evidential tool in the legal process when the identity of a specific individual or his family connections and relationships are called into question. It may also pose problems of confidentiality which could conflict with a duty of disclosure. In the future it may be possible to identify a propensity to develop a disease which may be seriously disabling or terminal long before any symptoms are detectable. This sensitive information could be of considerable interest to any prospective employer, insurer, marriage partner or family member and is of serious concern to the individual himself. How far should or could such information lawfully be made available and to whom? Legal debates are also likely to focus on ownership of human genetic information, the patenting of techniques to unravel it, and therapies and medicines developed therefrom. The law will be invoked to safeguard any intellectual property which may exist and to patent any inventive steps in the field.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Range-wide phenotypic and genetic differentiation in wild sunflower.

    PubMed

    McAssey, Edward V; Corbi, Jonathan; Burke, John M

    2016-11-10

    Divergent phenotypes and genotypes are key signals for identifying the targets of natural selection in locally adapted populations. Here, we used a combination of common garden phenotyping for a variety of growth, plant architecture, and seed traits, along with single-nucleotide polymorphism (SNP) genotyping to characterize range-wide patterns of diversity in 15 populations of wild sunflower (Helianthus annuus L.) sampled along a latitudinal gradient in central North America. We analyzed geographic patterns of phenotypic diversity, quantified levels of within-population SNP diversity, and also determined the extent of population structure across the range of this species. We then used these data to identify significantly over-differentiated loci as indicators of genomic regions that likely contribute to local adaptation. Traits including flowering time, plant height, and seed oil composition (i.e., percentage of saturated fatty acids) were significantly correlated with latitude, and thus differentiated northern vs. southern populations. Average pairwise FST was found to be 0.21, and a STRUCTURE analysis identified two significant clusters that largely separated northern and southern individuals. The significant FST outliers included a SNP in HaFT2, a flowering time gene that has been previously shown to co-localize with flowering time QTL, and which exhibits a known cline in gene expression. Latitudinal differentiation in both phenotypic traits and SNP allele frequencies is observed across wild sunflower populations in central North America. Such differentiation may play an important adaptive role across the range of this species, and could facilitate adaptation to a changing climate.

  4. Genetic and phenotypic population divergence on a microgeographic scale in brown trout.

    PubMed

    Stelkens, Rike B; Jaffuel, Geoffrey; Escher, Matthias; Wedekind, Claus

    2012-06-01

    Salmonid populations of many rivers are rapidly declining. One possible explanation is that habitat fragmentation increases genetic drift and reduces the populations' potential to adapt to changing environmental conditions. We measured the genetic and eco-morphological diversity of brown trout (Salmo trutta) in a Swiss stream system, using multivariate statistics and Bayesian clustering. We found large genetic and phenotypic variation within only 40 km of stream length. Eighty-eight percent of all pairwise F(ST) comparisons and 50% of the population comparisons in body shape were significant. High success rates of population assignment tests confirmed the distinctiveness of populations in both genotype and phenotype. Spatial analysis revealed that divergence increased with waterway distance, the number of weirs, and stretches of poor habitat between sampling locations, but effects of isolation-by-distance and habitat fragmentation could not be fully disentangled. Stocking intensity varied between streams but did not appear to erode genetic diversity within populations. A lack of association between phenotypic and genetic divergence points to a role of local adaptation or phenotypically plastic responses to habitat heterogeneity. Indeed, body shape could be largely explained by topographic stream slope, and variation in overall phenotype matched the flow regimes of the respective habitats. © 2012 Blackwell Publishing Ltd.

  5. The Influence of Genetics on Cystic Fibrosis Phenotypes

    PubMed Central

    Knowles, Michael R.; Drumm, Mitchell

    2012-01-01

    Technological advances in genetics have made feasible and affordable large studies to identify genetic variants that cause or modify a trait. Genetic studies have been carried out to assess variants in candidate genes, as well as polymorphisms throughout the genome, for their associations with heritable clinical outcomes of cystic fibrosis (CF), such as lung disease, meconium ileus, and CF-related diabetes. The candidate gene approach has identified some predicted relationships, while genome-wide surveys have identified several genes that would not have been obvious disease-modifying candidates, such as a methionine sulfoxide transferase gene that influences intestinal obstruction, or a region on chromosome 11 proximate to genes encoding a transcription factor and an apoptosis controller that associates with lung function. These unforeseen associations thus provide novel insight into disease pathophysiology, as well as suggesting new therapeutic strategies for CF. PMID:23209180

  6. Genetic and Phenotypic Characterization of a Salmonella enterica serovar Enteritidis Emerging Strain with Superior Intra-macrophage Replication Phenotype

    PubMed Central

    Shomer, Inna; Avisar, Alon; Desai, Prerak; Azriel, Shalhevet; Smollan, Gill; Belausov, Natasha; Keller, Nathan; Glikman, Daniel; Maor, Yasmin; Peretz, Avi; McClelland, Michael; Rahav, Galia; Gal-Mor, Ohad

    2016-01-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is one of the ubiquitous Salmonella serovars worldwide and a major cause of food-born outbreaks, which are often associated with poultry and poultry derivatives. Here we report a nation-wide S. Enteritidis clonal outbreak that occurred in Israel during the last third of 2015. Pulsed field gel electrophoresis and whole genome sequencing identified genetically related strains that were circulating in Israel as early as 2008. Global comparison linked this outbreak strain to several clinical and marine environmental isolates that were previously isolated in California and Canada, indicating that similar strains are prevalent outside of Israel. Phenotypic comparison between the 2015 outbreak strain and other clinical and reference S. Enteritidis strains showed only limited intra-serovar phenotypic variation in growth in rich medium, invasion into Caco-2 cells, uptake by J774.1A macrophages, and host cell cytotoxicity. In contrast, significant phenotypic variation was shown among different S. Enteritidis isolates when biofilm-formation, motility, invasion into HeLa cells and uptake by THP-1 human macrophages were studied. Interestingly, the 2015 outbreak clone was found to possess superior intra-macrophage replication ability within both murine and human macrophages in comparison to the other S. Enteritidis strains studied. This phenotype is likely to play a role in the virulence and host-pathogen interactions of this emerging clone. PMID:27695450

  7. Israeli nurses and genetic information disclosure.

    PubMed

    Barnoy, Sivia; Tabak, Nili

    2007-05-01

    The debate continues about whether people have a duty to pass on the positive results of their genetic tests to relatives who are at risk from the same disease, and, should they refuse, whether physicians and genetic counselors then have the duty to do so. To date, the role and views of nurses in this debate have not been investigated. In our study, a sample of Israeli nurses, untrained in genetics, were asked for their theoretical opinions and what practical steps they would take in the case of patients' refusal to disclose. The nurses were very sure that patients should inform their families but were equally sure that nurses must respect their decision to disclose or not. Few said they would take practical steps to disclose information if the patient objected. The authors believe that the most useful and appropriate role for nurses in this field is in working to bring about co-operation between patients and family members.

  8. Developmental cognitive genetics: how psychology can inform genetics and vice versa.

    PubMed

    Bishop, Dorothy V M

    2006-07-01

    Developmental neuropsychology is concerned with uncovering the underlying basis of developmental disorders such as specific language impairment (SLI), developmental dyslexia, and autistic disorder. Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for the underlying cause of developmental disorders may be misguided, because they are complex and heterogeneous and are associated with multiple risk factors that only cause serious disability when they occur in combination.

  9. Developmental cognitive genetics: How psychology can inform genetics and vice versa

    PubMed Central

    Bishop, Dorothy V. M.

    2006-01-01

    Developmental neuropsychology is concerned with uncovering the underlying basis of developmental disorders such as specific language impairment (SLI), developmental dyslexia, and autistic disorder. Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for the underlying cause of developmental disorders may be misguided, because they are complex and heterogeneous and are associated with multiple risk factors that only cause serious disability when they occur in combination. PMID:16769616

  10. Brugada Syndrome and Early Repolarisation: Distinct Clinical Entities or Different Phenotypes of the Same Genetic Disease?

    PubMed Central

    Caputo, Maria Luce; Regoli, François; Moccetti, Tiziano; Brugada, Pedro; Auricchio, Angelo

    2016-01-01

    Brugada and early repolarisation (ER) syndromes are currently considered two distinct inherited electrical disorders with overlapping clinical and electrocardiographic features. A considerable number of patients diagnosed with ER syndrome have a genetic mutation related to Brugada syndrome (BrS). Due to the high variable phenotypic manifestation, patients with BrS may present with inferolateral repolarisation abnormalities only, resembling the ER pattern. Moreover, the complex genotype–phenotype interaction in BrS can lead to the occurrence of mixed phenotypes with ER syndrome. The first part of this review focuses on specific clinical and electrocardiographic features of BrS and ER syndrome, highlighting the similarity shared by the two primary electrical disorders. The genetic background, with emphasis on the complexity of genotype–phenotype interaction, is explored in the second part of this review. PMID:27617086

  11. Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment

    PubMed Central

    Globa, Evgenia; Zelinska, Nataliya; Mackay, Deborah J.G.; Temple, Karen I.; Houghton, Jayne A.L.; Hattersley, Andrew T.; Flanagan, Sarah E.; Ellard, Sian

    2016-01-01

    Background Neonatal diabetes has not been previously studied in Ukraine. We investigated the genetic etiology in patients with onset of diabetes during the first 9 months of life. Methods We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 42 patients with permanent or transient diabetes diagnosed within the first 6 months of life (n=22) or permanent diabetes diagnosed between 6 and 9 months (n=20). Results We determined the genetic etiology in 23 of 42 (55%) patients; 86% of the patients diagnosed before 6 months and 20% diagnosed between 6 and 9 months. The incidence of neonatal diabetes in Ukraine was calculated to be 1 in 126,397 live births. Conclusions Genetic testing for patients identified through the Ukrainian Pediatric Diabetes Register identified KCNJ11 and ABCC8 mutations as the most common cause (52%) of neonatal diabetes. Transfer to sulfonylureas improved glycemic control in all 11 patients. PMID:26208381

  12. Toward diagnostic and phenotype markers for genetically transmitted speech delay.

    PubMed

    Shriberg, Lawrence D; Lewis, Barbara A; Tomblin, J Bruce; McSweeny, Jane L; Karlsson, Heather B; Scheer, Alison R

    2005-08-01

    Converging evidence supports the hypothesis that the most common subtype of childhood speech sound disorder (SSD) of currently unknown origin is genetically transmitted. We report the first findings toward a set of diagnostic markers to differentiate this proposed etiological subtype (provisionally termed speech delay-genetic) from other proposed subtypes of SSD of unknown origin. Conversational speech samples from 72 preschool children with speech delay of unknown origin from 3 research centers were selected from an audio archive. Participants differed on the number of biological, nuclear family members (0 or 2+) classified as positive for current and/or prior speech-language disorder. Although participants in the 2 groups were found to have similar speech competence, as indexed by their Percentage of Consonants Correct scores, their speech error patterns differed significantly in 3 ways. Compared with children who may have reduced genetic load for speech delay (no affected nuclear family members), children with possibly higher genetic load (2+ affected members) had (a) a significantly higher proportion of relative omission errors on the Late-8 consonants; (b) a significantly lower proportion of relative distortion errors on these consonants, particularly on the sibilant fricatives /s/, /z/, and //; and (c) a significantly lower proportion of backed /s/ distortions, as assessed by both perceptual and acoustic methods. Machine learning routines identified a 3-part classification rule that included differential weightings of these variables. The classification rule had diagnostic accuracy value of 0.83 (95% confidence limits = 0.74-0.92), with positive and negative likelihood ratios of 9.6 (95% confidence limits = 3.1-29.9) and 0.40 (95% confidence limits = 0.24-0.68), respectively. The diagnostic accuracy findings are viewed as promising. The error pattern for this proposed subtype of SSD is viewed as consistent with the cognitive-linguistic processing deficits

  13. Genetically and Phenotypically Distinct Pseudomonas aeruginosa Cystic Fibrosis Isolates Share a Core Proteomic Signature

    PubMed Central

    Penesyan, Anahit; Kumar, Sheemal S.; Kamath, Karthik; Shathili, Abdulrahman M.; Venkatakrishnan, Vignesh; Krisp, Christoph; Packer, Nicolle H.; Molloy, Mark P.; Paulsen, Ian T.

    2015-01-01

    The opportunistic pathogen Pseudomonas aeruginosa is among the main colonizers of the lungs of cystic fibrosis (CF) patients. We have isolated and sequenced several P. aeruginosa isolates from the sputum of CF patients and compared them with each other and with the model strain PAO1. Phenotypic analysis of CF isolates showed significant variability in colonization and virulence-related traits suggesting different strategies for adaptation to the CF lung. Genomic analysis indicated these strains shared a large set of core genes with the standard laboratory strain PAO1, and identified the genetic basis for some of the observed phenotypic differences. Proteomics revealed that in a conventional laboratory medium PAO1 expressed 827 proteins that were absent in the CF isolates while the CF isolates shared a distinctive signature set of 703 proteins not detected in PAO1. PAO1 expressed many transporters for the uptake of organic nutrients and relatively few biosynthetic pathways. Conversely, the CF isolates expressed a narrower range of transporters and a broader set of metabolic pathways for the biosynthesis of amino acids, carbohydrates, nucleotides and polyamines. The proteomic data suggests that in a common laboratory medium PAO1 may transport a diverse set of “ready-made” nutrients from the rich medium, whereas the CF isolates may only utilize a limited number of nutrients from the medium relying mainly on their own metabolism for synthesis of essential nutrients. These variations indicate significant differences between the metabolism and physiology of P. aeruginosa CF isolates and PAO1 that cannot be detected at the genome level alone. The widening gap between the increasing genomic data and the lack of phenotypic data means that researchers are increasingly reliant on extrapolating from genomic comparisons using experimentally characterized model organisms such as PAO1. While comparative genomics can provide valuable information, our data suggests that such

  14. Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation.

    PubMed

    Gresele, Paolo; Bury, Loredana; Falcinelli, Emanuela

    2016-04-01

    Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  15. Genetic and Molecular Characterization of Drosophia Brakeless: A Novel Modifier of Merlin Phenotypes

    DTIC Science & Technology

    2005-07-01

    transcription. From genetic epistasis , we know that Merlin functions upstream of scribbler and Cyclin E. We are currently in the process of determining...modifier of sbb gain-of-function and CycE Merlin acts as a dominant modifier of sbb gain-of-function phenotypes. Heterozygosity for a recessive null...hypomorphic allele of Cyclin E that expresses a small eye and small wing phenotype (Secombe et al., 1998; Fig. 2C, D). Heterozygosity for recessive mutant

  16. Phenotypic, genetic, and environmental relationships between self-reported talents and measured intelligence.

    PubMed

    Schermer, Julie Aitken; Johnson, Andrew M; Jang, Kerry L; Vernon, Philip A

    2015-02-01

    The relationship between self-report abilities and measured intelligence was examined at both the phenotypic (zero-order) level as well as at the genetic and environmental levels. Twins and siblings (N = 516) completed a timed intelligence test and a self-report ability questionnaire, which has previously been found to produce 10 factors, including: politics, interpersonal relationships, practical tasks, intellectual pursuits, academic skills, entrepreneur/business, domestic skills, vocal abilities, and creativity. At the phenotypic level, the correlations between the ability factor scores and intelligence ranged from 0.01 to 0.42 (between self-report academic abilities and verbal intelligence). Further analyses found that some of the phenotypic relationships between self-report ability scores and measured intelligence also had significant correlations at the genetic and environmental levels, suggesting that some of the observed relationships may be due to common genetic and/or environmental factors.

  17. Bi- and multivariate analyses of diallel crosses: a tool for the genetic dissection of neurobehavioral phenotypes.

    PubMed

    Crusio, W E

    1993-01-01

    The genetic-correlational approach provides a very powerful tool for the analysis of causal relationships between phenotypes. It appears to be particularly appropriate for investigating the functional organization of behavior and/or causal relationships between brain and behavior. A method for the bivariate analysis of diallel crosses that permits the estimation of correlations due to environmental effects, additive-genetic effects, and/or dominance deviations is described, together with a worked-out example stemming from a five times replicated 4 x 4 diallel cross between inbred mouse strains. The phenotypes chosen to illustrate the analysis were locomotor activity and rearing frequency in an open field. Large, positive additive-genetic and dominance correlations between these two phenotypes were obtained. This finding was replicated in another, independently executed, diallel cross.

  18. Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles.

    PubMed

    Brown, E A; Gay, L; Vasudev, R; Tregenza, T; Eady, P E; Hosken, D J

    2009-10-01

    Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity.

  19. Effect of genetic background on the dystrophic phenotype in mdx mice

    PubMed Central

    Coley, William D.; Bogdanik, Laurent; Vila, Maria Candida; Yu, Qing; Van Der Meulen, Jack H.; Rayavarapu, Sree; Novak, James S.; Nearing, Marie; Quinn, James L.; Saunders, Allison; Dolan, Connor; Andrews, Whitney; Lammert, Catherine; Austin, Andrew; Partridge, Terence A.; Cox, Gregory A.; Lutz, Cathleen; Nagaraju, Kanneboyina

    2016-01-01

    Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits. PMID:26566673

  20. Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

    PubMed

    Huang, Minjun; Graham, Britney E; Zhang, Ge; Harder, Reed; Kodaman, Nuri; Moore, Jason H; Muglia, Louis; Williams, Scott M

    2016-01-01

    Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with

  1. Phenotypic novelty in experimental hybrids is predicted by the genetic distance between species of cichlid fish

    PubMed Central

    2009-01-01

    Background Transgressive segregation describes the occurrence of novel phenotypes in hybrids with extreme trait values not observed in either parental species. A previously experimentally untested prediction is that the amount of transgression increases with the genetic distance between hybridizing species. This follows from QTL studies suggesting that transgression is most commonly due to complementary gene action or epistasis, which become more frequent at larger genetic distances. This is because the number of QTLs fixed for alleles with opposing signs in different species should increase with time since speciation provided that speciation is not driven by disruptive selection. We measured the amount of transgression occurring in hybrids of cichlid fish bred from species pairs with gradually increasing genetic distances and varying phenotypic similarity. Transgression in multi-trait shape phenotypes was quantified using landmark-based geometric morphometric methods. Results We found that genetic distance explained 52% and 78% of the variation in transgression frequency in F1 and F2 hybrids, respectively. Confirming theoretical predictions, transgression when measured in F2 hybrids, increased linearly with genetic distance between hybridizing species. Phenotypic similarity of species on the other hand was not related to the amount of transgression. Conclusion The commonness and ease with which novel phenotypes are produced in cichlid hybrids between unrelated species has important implications for the interaction of hybridization with adaptation and speciation. Hybridization may generate new genotypes with adaptive potential that did not reside as standing genetic variation in either parental population, potentially enhancing a population's responsiveness to selection. Our results make it conceivable that hybridization contributed to the rapid rates of phenotypic evolution in the large and rapid adaptive radiations of haplochromine cichlids. PMID:19961584

  2. Imaging Phenotypes of Major Depressive Disorder: Genetic Correlates

    PubMed Central

    Savitz, Jonathan B; Drevets, Wayne C

    2009-01-01

    Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT1A gene (HTR1A: –1019C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the serotonin transporter has been reported. Challenges facing the field include

  3. [Phenotypic and genetic features in neurofibromatosis type 1 in children].

    PubMed

    Duat Rodríguez, A; Martos Moreno, G Á; Martín Santo-Domingo, Y; Hernández Martín, A; Espejo-Saavedra Roca, J M; Ruiz-Falcó Rojas, M L; Argente, J

    2015-09-01

    Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease, nevertheless the number of publications providing clinical and genetic data from a significant number of children is limited. The available clinical, epidemiological, radiological and genetic data from 239 children with NF1, who attended at a specialist NF1 clinic between January 2011 and December 2013 were recorded. All the 239 patients had a clinical and/or genetic diagnosis of NF1. The mean age at diagnosis was 2.65±2.85 years. In our series 99.6% met the diagnostic criteria of café au lait spots, 93.7% those of axillary and inguinal freckling, 7.1% showed typical bone lesion, 38.1% neurofibromas, 23% plexiform neurofibromas, 31.4% optic pathway glioma, Lisch nodules were present in 43.1%, and 28% patients had a first degree relative affected with NF1. The NF1 genetic study was performed in 86 patients, and a description of the gene mutations found in 72 of them is presented. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed. The difficulty for clinical diagnosis of NF1 early ages is still evident. Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  4. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    NASA Astrophysics Data System (ADS)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  5. The Evolutionary Genetics of the Genes Underlying Phenotypic Associations for Loblolly Pine (Pinus taeda, Pinaceae)

    PubMed Central

    Eckert, Andrew J.; Wegrzyn, Jill L.; Liechty, John D.; Lee, Jennifer M.; Cumbie, W. Patrick; Davis, John M.; Goldfarb, Barry; Loopstra, Carol A.; Palle, Sreenath R.; Quesada, Tania; Langley, Charles H.; Neale, David B.

    2013-01-01

    A primary goal of evolutionary genetics is to discover and explain the genetic basis of fitness-related traits and how this genetic basis evolves within natural populations. Unprecedented technological advances have fueled the discovery of genetic variants associated with ecologically relevant phenotypes in many different life forms, as well as the ability to scan genomes for deviations from selectively neutral models of evolution. Theoretically, the degree of overlap between lists of genomic regions identified using each approach is related to the genetic architecture of fitness-related traits and the strength and type of natural selection molding variation at these traits within natural populations. Here we address for the first time in a plant the degree of overlap between these lists, using patterns of nucleotide diversity and divergence for >7000 unique amplicons described from the extensive expressed sequence tag libraries generated for loblolly pine (Pinus taeda L.) in combination with the >1000 published genetic associations. We show that loci associated with phenotypic traits are distinct with regard to neutral expectations. Phenotypes measured at the whole plant level (e.g., disease resistance) exhibit an approximately twofold increase in the proportion of adaptive nonsynonymous substitutions over the genome-wide average. As expected for polygenic traits, these signals were apparent only when loci were considered at the level of functional sets. The ramifications of this result are discussed in light of the continued efforts to dissect the genetic basis of quantitative traits. PMID:24121773

  6. The evolutionary genetics of the genes underlying phenotypic associations for loblolly pine (Pinus taeda, Pinaceae).

    PubMed

    Eckert, Andrew J; Wegrzyn, Jill L; Liechty, John D; Lee, Jennifer M; Cumbie, W Patrick; Davis, John M; Goldfarb, Barry; Loopstra, Carol A; Palle, Sreenath R; Quesada, Tania; Langley, Charles H; Neale, David B

    2013-12-01

    A primary goal of evolutionary genetics is to discover and explain the genetic basis of fitness-related traits and how this genetic basis evolves within natural populations. Unprecedented technological advances have fueled the discovery of genetic variants associated with ecologically relevant phenotypes in many different life forms, as well as the ability to scan genomes for deviations from selectively neutral models of evolution. Theoretically, the degree of overlap between lists of genomic regions identified using each approach is related to the genetic architecture of fitness-related traits and the strength and type of natural selection molding variation at these traits within natural populations. Here we address for the first time in a plant the degree of overlap between these lists, using patterns of nucleotide diversity and divergence for >7000 unique amplicons described from the extensive expressed sequence tag libraries generated for loblolly pine (Pinus taeda L.) in combination with the >1000 published genetic associations. We show that loci associated with phenotypic traits are distinct with regard to neutral expectations. Phenotypes measured at the whole plant level (e.g., disease resistance) exhibit an approximately twofold increase in the proportion of adaptive nonsynonymous substitutions over the genome-wide average. As expected for polygenic traits, these signals were apparent only when loci were considered at the level of functional sets. The ramifications of this result are discussed in light of the continued efforts to dissect the genetic basis of quantitative traits.

  7. The Baldwin effect and genetic assimilation: revisiting two mechanisms of evolutionary change mediated by phenotypic plasticity.

    PubMed

    Crispo, Erika

    2007-11-01

    Two different, but related, evolutionary theories pertaining to phenotypic plasticity were proposed by James Mark Baldwin and Conrad Hal Waddington. Unfortunately, these theories are often confused with one another. Baldwin's notion of organic selection posits that plasticity influences whether an individual will survive in a new environment, thus dictating the course of future evolution. Heritable variations can then be selected upon to direct phenotypic evolution (i.e., "orthoplasy"). The combination of these two processes (organic selection and orthoplasy) is now commonly referred to as the "Baldwin effect." Alternately, Waddington's genetic assimilation is a process whereby an environmentally induced phenotype, or "acquired character," becomes canalized through selection acting upon the developmental system. Genetic accommodation is a modern term used to describe the process of heritable changes that occur in response to a novel induction. Genetic accommodation is a key component of the Baldwin effect, and genetic assimilation is a type of genetic accommodation. I here define both the Baldwin effect and genetic assimilation in terms of genetic accommodation, describe cases in which either should occur in nature, and propose that each could play a role in evolutionary diversification.

  8. Genetic and phenotypic characterization of complex hereditary spastic paraplegia

    PubMed Central

    Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; Lynch, David S.; Elpidorou, Marilena; Bettencourt, Conceicao; Chelban, Viorica; Manole, Andreea; Hamed, Sherifa A.; Haridy, Nourelhoda A.; Federoff, Monica; Preza, Elisavet; Hughes, Deborah; Pittman, Alan; Jaunmuktane, Zane; Brandner, Sebastian; Xiromerisiou, Georgia; Wiethoff, Sarah; Schottlaender, Lucia; Proukakis, Christos; Morris, Huw; Warner, Tom; Bhatia, Kailash P.; Korlipara, L.V. Prasad; Singleton, Andrew B.; Hardy, John; Wood, Nicholas W.; Lewis, Patrick A.

    2016-01-01

    The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next

  9. Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

    PubMed Central

    Vockley, Jerry; Ensenauer, Regina

    2008-01-01

    Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years. PMID:16602101

  10. Limited genetic variability and phenotypic plasticity detected for cavitation resistance in a Mediterranean pine.

    PubMed

    Lamy, Jean-Baptiste; Delzon, Sylvain; Bouche, Pauline S; Alia, Ricardo; Vendramin, Giovanni Giuseppe; Cochard, Hervé; Plomion, Christophe

    2014-02-01

    Resistance to cavitation is a major determinant of plant survival under severe drought and can be used to quantify species adaptive potential. Interspecific variation in this key trait is well defined in woody species, but intraspecific variation (level and structure) resulting from standing genetic variation and phenotypic plasticity has never been determined. Combining for the first time in situ characterization of natural populations and two reciprocal common gardens in dry and wet sites, we estimated variance components (phenotypic, genetic, environmental, and genetic × environmental) of cavitation resistance based on 513 genotypes of a Mediterranean pine, Pinus pinaster. Despite the selected populations being climatically contrasted, phenotypic plasticity in resistance to cavitation remained low and was essentially attributed to family level. Between-population variation in cavitation resistance for both phenotypic and genetic variation was limited. These results strongly suggest that cavitation resistance is buffered against genetic and to a lesser extent environmental variation (canalization) in maritime pine. Consequently, in a drier world, the increasing drought tolerance of Pinus species might be severely constrained by the low level of cavitation resistance variation, resulting in a large-scale loss of productivity.

  11. Dissecting High-Dimensional Phenotypes with Bayesian Sparse Factor Analysis of Genetic Covariance Matrices

    PubMed Central

    Runcie, Daniel E.; Mukherjee, Sayan

    2013-01-01

    Quantitative genetic studies that model complex, multivariate phenotypes are important for both evolutionary prediction and artificial selection. For example, changes in gene expression can provide insight into developmental and physiological mechanisms that link genotype and phenotype. However, classical analytical techniques are poorly suited to quantitative genetic studies of gene expression where the number of traits assayed per individual can reach many thousand. Here, we derive a Bayesian genetic sparse factor model for estimating the genetic covariance matrix (G-matrix) of high-dimensional traits, such as gene expression, in a mixed-effects model. The key idea of our model is that we need consider only G-matrices that are biologically plausible. An organism’s entire phenotype is the result of processes that are modular and have limited complexity. This implies that the G-matrix will be highly structured. In particular, we assume that a limited number of intermediate traits (or factors, e.g., variations in development or physiology) control the variation in the high-dimensional phenotype, and that each of these intermediate traits is sparse – affecting only a few observed traits. The advantages of this approach are twofold. First, sparse factors are interpretable and provide biological insight into mechanisms underlying the genetic architecture. Second, enforcing sparsity helps prevent sampling errors from swamping out the true signal in high-dimensional data. We demonstrate the advantages of our model on simulated data and in an analysis of a published Drosophila melanogaster gene expression data set. PMID:23636737

  12. Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum

    PubMed Central

    Maria, Maleeha; Lamers, Ideke J. C.; Schmidts, Miriam; Ajmal, Muhammad; Jaffar, Sulman; Ullah, Ehsan; Mustafa, Bilal; Ahmad, Shakeel; Nazmutdinova, Katia; Hoskins, Bethan; van Wijk, Erwin; Koster-Kamphuis, Linda; Khan, Muhammad Imran; Beales, Phil L.; Cremers, Frans P. M.; Roepman, Ronald; Azam, Maleeha; Arts, Heleen H.; Qamar, Raheel

    2016-01-01

    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell’s signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician’s ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals. PMID:27708425

  13. Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum.

    PubMed

    Maria, Maleeha; Lamers, Ideke J C; Schmidts, Miriam; Ajmal, Muhammad; Jaffar, Sulman; Ullah, Ehsan; Mustafa, Bilal; Ahmad, Shakeel; Nazmutdinova, Katia; Hoskins, Bethan; van Wijk, Erwin; Koster-Kamphuis, Linda; Khan, Muhammad Imran; Beales, Phil L; Cremers, Frans P M; Roepman, Ronald; Azam, Maleeha; Arts, Heleen H; Qamar, Raheel

    2016-10-06

    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician's ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals.

  14. Searching Online Mendelian Inheritance in Man (OMIM) for information on genetic loci involved in human disease.

    PubMed

    Borate, Bhavesh; Baxevanis, Andreas D

    2009-09-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of information on human genes and genetic disorders, with a particular emphasis on the interplay between observed phenotypes and underlying genotypes. This unit focuses on the basic methodology for formulating OMIM searches and illustrates the types of information that can be retrieved from OMIM, including descriptions of clinical manifestations resulting from genetic abnormalities. This unit also provides information on additional relevant medical and molecular biology databases. A basic knowledge of OMIM should be part of the armamentarium of physicians and scientists with an interest in research on and clinical aspects of genetic disorders.

  15. Searching Online Mendelian Inheritance in Man (OMIM) for information on genetic loci involved in human disease.

    PubMed

    Baxevanis, Andreas D

    2012-04-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of information on human genes and genetic disorders, with a particular emphasis on the interplay between observed phenotypes and underlying genotypes. This unit focuses on the basic methodology for formulating OMIM searches and illustrates the types of information that can be retrieved from OMIM, including descriptions of clinical manifestations resulting from genetic abnormalities. This unit also provides information on additional relevant medical and molecular biology databases. A basic knowledge of OMIM should be part of the armamentarium of physicians and scientists with an interest in research on the clinical aspects of genetic disorders.

  16. A QTL model to map the common genetic basis for correlative phenotypic plasticity.

    PubMed

    Zhou, Tao; Lyu, Yafei; Xu, Fang; Bo, Wenhao; Zhai, Yi; Zhang, Jian; Pang, Xiaoming; Zheng, Bingsong; Wu, Rongling

    2015-01-01

    As an important mechanism for adaptation to heterogeneous environment, plastic responses of correlated traits to environmental alteration may also be genetically correlated, but less is known about the underlying genetic basis. We describe a statistical model for mapping specific quantitative trait loci (QTLs) that control the interrelationship of phenotypic plasticity between different traits. The model is constructed by a bivariate mixture setting, implemented with the EM algorithm to estimate the genetic effects of QTLs on correlative plastic response. We provide a series of procedure that test (1) how a QTL controls the phenotypic plasticity of a single trait; and (2) how the QTL determines the correlation of environment-induced changes of different traits. The model is readily extended to test how epistatic interactions among QTLs play a part in the correlations of different plastic traits. The model was validated through computer simulation and used to analyse multi-environment data of genetic mapping in winter wheat, showing its utilization in practice.

  17. Phenotypic and genetic associations between the big five and trait emotional intelligence.

    PubMed

    Vernon, Philip A; Villani, Vanessa C; Schermer, Julie Aitken; Petrides, K V

    2008-10-01

    This study reports the first behavioral genetic investigation of the extent to which genetic and/or environmental factors contribute to the relationship between the Big Five personality factors and trait emotional intelligence. 213 pairs of adult monozygotic twins and 103 pairs of same-sex dizygotic twins completed the NEO-PI-R and the Trait Emotional Intelligence Questionnaire (TEIQue). Replicating previous non-twin studies, many significant phenotypic correlations were found between the Big Five factors - especially Neuroticism, Extraversion, and Conscientiousness - and the facets, factors, and global scores derived from the TEIQue. Bivariate behavioral genetic model-fitting analyses revealed that these phenotypic correlations were primarily attributable to correlated genetic factors and secondarily to correlated non-shared environmental factors. The results support the feasibility of incorporating EI as a trait within existing personality taxonomies.

  18. Genetic Variation Controlling Wrinkled Seed Phenotypes in Pisum: How Lucky Was Mendel?

    PubMed

    Rayner, Tracey; Moreau, Carol; Ambrose, Mike; Isaac, Peter G; Ellis, Noel; Domoney, Claire

    2017-06-06

    One of the traits studied by Mendel in pea (Pisum sativum L.) was the wrinkled-seeded phenotype, and the molecular basis for a mutation underlying this phenotype was discovered in the 1990s. Although the starch-branching enzyme gene mutation identified at the genetic locus r is most likely to be that in seeds available to Mendel in the mid-1800s, it has remained an open question as to whether or not additional natural mutations in this gene exist within Pisum germplasm collections. Here, we explore this question and show that all but two wrinkled-seeded variants in one such collection correspond to either the mutant allele described previously for the r locus or a mutation at a second genetic locus, rb, affecting the gene encoding the large subunit of Adenosine diphosphoglucose (ADP-glucose) pyrophosphorylase; the molecular basis for the rb mutation is described here. The genetic basis for the phenotype of one (JI 2110) of the two lines which are neither r nor rb has been studied in crosses with a round-seeded variant (JI 281); for which extensive genetic marker data were expected. In marked contrast to the trait studied by Mendel and the rb phenotype; the data suggest that the wrinkled-seeded phenotype in JI 2110 is maternally determined, controlled by two genetic loci, and the extent to which it is manifested is very sensitive to the environment. Metabolite analysis of the cotyledons of JI 2110 revealed a profile for sucrose and sucrose-derived compounds that was more similar to that of wild-type round-seeded, than that of wrinkled-seeded r, pea lines. However, the metabolite profile of the seed coat (testa) of JI 2110 was distinct from that of other round-seeded genotypes tested which, together with analysis of recombinant inbred progeny lines, suggests an explanation for the seed phenotype.

  19. Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history

    SciTech Connect

    Palmer, S.E.; Stephens, K.; Dale, D.C.

    1994-09-01

    Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.

  20. Establishing Genetic Interactions by a Synthetic Dosage Lethality Phenotype

    PubMed Central

    Kroll, E. S.; Hyland, K. M.; Hieter, P.; Li, J. J.

    1996-01-01

    We have devised a genetic screen, termed synthetic dosage lethality, in which a cloned ``reference'' gene is inducibly overexpressed in a set of mutant strains carrying potential ``target'' mutations. To test the specificity of the method, two reference genes, CTF13, encoding a centromere binding protein, and ORC6, encoding a subunit of the origin of replication binding complex, were overexpressed in a large collection of mutants defective in either chromosome segregation or replication. CTF13 overexpression caused synthetic dosage lethality in combination with ctf14-42 (cbf2, ndc10), ctf17-61 (chl4), ctf19-58 and ctf19-26. ORC6 overexpression caused synthetic dosage lethality in combination with cdc2-1, cdc6-1, cdc14-1, cdc16-1 and cdc46-1. These relationships reflect specific interactions, as overexpression of CTF13 caused lethality in kinetochore mutants and overexpression of ORC6 caused lethality in replication mutants. In contrast, only one case of dosage suppression was observed. We suggest that synthetic dosage lethality identifies a broad spectrum of interacting mutations and is of general utility in detecting specific genetic interactions using a cloned wild-type gene as a starting point. Furthermore, synthetic dosage lethality is easily adapted to the study of cloned genes in other organisms. PMID:8722765

  1. Heritability and genetic and phenotypic correlations of apple (Malus x domestica) fruit volatiles in a genetically diverse breeding population.

    PubMed

    Rowan, Daryl D; Hunt, Martin B; Alspach, Peter A; Whitworth, Claire J; Oraguzie, Nnadozie C

    2009-09-09

    Flavor is an important quality trait of fruit and a target for improvement through plant breeding. Eighty-nine flavor volatiles from 240 apple (Malus domestica) genotypes from a highly diverse breeding population were measured by headspace gas chromatography-mass spectrometry (GC-MS) over 2 years. Heritabilities and phenotypic and genetic correlations were calculated for 23 flavor volatiles. Genetic correlations showed coinheritance of five groups of volatiles, ethyl esters, alcohols and alpha-farnesene, propyl and butyl esters, propanoate and 2-methylbutanoate esters, and acetate esters, consistent with our knowledge of volatile biosynthesis in apple. This work demonstrates a genetic structure underlying the highly variable volatile profiles observed for apple fruit and the potential of GC-MS volatile profiling for the genetic analysis of aroma volatiles in genetically diverse populations.

  2. Genetic service delivery: infrastructure, assessment and information.

    PubMed

    Kaye, C I

    2012-01-01

    Identification of genomic determinants of complex disorders such as cancer, diabetes and cardiovascular disease has prompted public health systems to focus on genetic service delivery for prevention of these disorders, adding to their previous efforts in birth defects prevention and newborn screening. This focus is consistent with previously identified obligations of the public health system as well as the core functions of public health identified by the Institute of Medicine. Models of service delivery include provision of services by the primary care provider in conjunction with subspecialists, provision of services through the medical home with co-management by genetics providers, provision of services in conjunction with disorder-specific treatment centers, and provision of services through a network of genetics clinics linked to medical homes. Whatever the model for provision of genetic services, tools to assist providers include facilities for outreach and telemedicine, information technology, just-in-time management plans, and emergency management tools. Assessment tools to determine which care is best are critical for quality improvement and development of best practices. Because the workforce of genetics providers is not keeping pace with the need for services, an understanding of the factors contributing to this lag is important, as is the development of an improved knowledge base in genomics for primary care providers. Copyright © 2012 S. Karger AG, Basel.

  3. Habitat Fragmentation Differentially Affects Genetic Variation, Phenotypic Plasticity and Survival in Populations of a Gypsum Endemic.

    PubMed

    Matesanz, Silvia; Rubio Teso, María Luisa; García-Fernández, Alfredo; Escudero, Adrián

    2017-01-01

    Habitat fragmentation, i.e., fragment size and isolation, can differentially alter patterns of neutral and quantitative genetic variation, fitness and phenotypic plasticity of plant populations, but their effects have rarely been tested simultaneously. We assessed the combined effects of size and connectivity on these aspects of genetic and phenotypic variation in populations of Centaurea hyssopifolia, a narrow endemic gypsophile that previously showed performance differences associated with fragmentation. We grew 111 maternal families sampled from 10 populations that differed in their fragment size and connectivity in a common garden, and characterized quantitative genetic variation, phenotypic plasticity to drought for key functional traits, and plant survival, as a measure of population fitness. We also assessed neutral genetic variation within and among populations using eight microsatellite markers. Although C. hyssopifolia is a narrow endemic gypsophile, we found substantial neutral genetic variation and quantitative variation for key functional traits. The partition of genetic variance indicated that a higher proportion of variation was found within populations, which is also consistent with low population differentiation in molecular markers, functional traits and their plasticity. This, combined with the generally small effect of habitat fragmentation suggests that gene flow among populations is not restricted, despite large differences in fragment size and isolation. Importantly, population's similarities in genetic variation and plasticity did not reflect the lower survival observed in isolated populations. Overall, our results indicate that, although the species consists of genetically variable populations able to express functional plasticity, such aspects of adaptive potential may not always reflect populations' survival. Given the differential effects of habitat connectivity on functional traits, genetic variation and fitness, our study highlights

  4. Habitat Fragmentation Differentially Affects Genetic Variation, Phenotypic Plasticity and Survival in Populations of a Gypsum Endemic

    PubMed Central

    Matesanz, Silvia; Rubio Teso, María Luisa; García-Fernández, Alfredo; Escudero, Adrián

    2017-01-01

    Habitat fragmentation, i.e., fragment size and isolation, can differentially alter patterns of neutral and quantitative genetic variation, fitness and phenotypic plasticity of plant populations, but their effects have rarely been tested simultaneously. We assessed the combined effects of size and connectivity on these aspects of genetic and phenotypic variation in populations of Centaurea hyssopifolia, a narrow endemic gypsophile that previously showed performance differences associated with fragmentation. We grew 111 maternal families sampled from 10 populations that differed in their fragment size and connectivity in a common garden, and characterized quantitative genetic variation, phenotypic plasticity to drought for key functional traits, and plant survival, as a measure of population fitness. We also assessed neutral genetic variation within and among populations using eight microsatellite markers. Although C. hyssopifolia is a narrow endemic gypsophile, we found substantial neutral genetic variation and quantitative variation for key functional traits. The partition of genetic variance indicated that a higher proportion of variation was found within populations, which is also consistent with low population differentiation in molecular markers, functional traits and their plasticity. This, combined with the generally small effect of habitat fragmentation suggests that gene flow among populations is not restricted, despite large differences in fragment size and isolation. Importantly, population’s similarities in genetic variation and plasticity did not reflect the lower survival observed in isolated populations. Overall, our results indicate that, although the species consists of genetically variable populations able to express functional plasticity, such aspects of adaptive potential may not always reflect populations’ survival. Given the differential effects of habitat connectivity on functional traits, genetic variation and fitness, our study

  5. Cortical Thickness or Grey Matter Volume? The Importance of Selecting the Phenotype for Imaging Genetics Studies

    PubMed Central

    Kochunov, Peter; Blangero, John; Almasy, Laura; Zilles, Karl; Fox, Peter T.; Duggirala, Ravindranath; Glahn, David C.

    2010-01-01

    Choosing the appropriate neuroimaging phenotype is critical to successfully identify genes that influence brain structure or function. While neuroimaging methods provide numerous potential phenotypes, their role for imaging genetics studies are unclear. Here we examine the relationship between brain volume, grey matter volume, cortical thickness and surface area, from a genetic standpoint. Four hundred and eighty-six individuals from randomly ascertained extended pedigrees with high-quality T1-weighted neuroanatomic MRI images participated in the study. Surface-based and voxel-based representations of brain structure were derived, using automated methods, and these measurements were analysed using a variance-components method to identify the heritability of these traits and their genetic correlations. All neuroanatomic traits were significantly influenced by genetic factors. Cortical thickness and surface area measurements were found to be genetically and phenotypically independent. While both thickness and area influenced volume measurements of cortical grey matter, volume was more closely related to surface area than cortical thickness. This trend was observed for both the volume-based and surface-based techniques. The results suggest that surface area and cortical thickness measurements should be considered separately and preferred over gray matter volumes for imaging genetic studies. PMID:20006715

  6. Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans.

    PubMed

    Saykin, Andrew J; Shen, Li; Yao, Xiaohui; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L; Ramanan, Vijay K; Foroud, Tatiana M; Faber, Kelley M; Sarwar, Nadeem; Munsie, Leanne M; Hu, Xiaolan; Soares, Holly D; Potkin, Steven G; Thompson, Paul M; Kauwe, John S K; Kaddurah-Daouk, Rima; Green, Robert C; Toga, Arthur W; Weiner, Michael W

    2015-07-01

    Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant

  7. Genetic Studies of Quantitative MCI and AD Phenotypes in ADNI: Progress, Opportunities, and Plans

    PubMed Central

    Saykin, Andrew J.; Shen, Li; Yao, Xiaohui; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Ramanan, Vijay K.; Foroud, Tatiana M.; Faber, Kelly M.; Sarwar, Nadeem; Munsie, Leanne M.; Hu, Xiaolan; Soares, Holly D.; Potkin, Steven G.; Thompson, Paul M.; Kauwe, John S.K.; Kaddurah-Daouk, Rima; Green, Robert C.; Toga, Arthur W.; Weiner, Michael W.

    2015-01-01

    INTRODUCTION Genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been crucial in advancing the understanding of AD pathophysiology. Here we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing (WES, WGS) data have been obtained and disseminated. RESULTS ADNI genetic data have been downloaded thousands of times and over 300 publications have resulted, including reports of large scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies employed ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first WES and WGS data sets and reports in healthy controls, MCI, and AD. DISCUSSION Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data, and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multi-omics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological

  8. Genetic and phenotypic characteristics of baker's yeast: relevance to baking.

    PubMed

    Randez-Gil, Francisca; Córcoles-Sáez, Isaac; Prieto, José A

    2013-01-01

    Yeasts rarely encounter ideal physiological conditions during their industrial life span; therefore, their ability to adapt to changing conditions determines their usefulness and applicability. This is especially true for baking strains of Saccharomyces cerevisiae. The success of this yeast in the ancient art of bread making is based on its capacity to rapidly transform carbohydrates into CO2 rather than its unusual resistance to environmental stresses. Moreover, baker's yeast must exhibit efficient respiratory metabolism during yeast manufacturing, which determines biomass yield. However, optimal growth conditions often have negative consequences in other commercially important aspects, such as fermentative power or stress tolerance. This article reviews the genetic and physiological characteristics of baking yeast strains, emphasizing the activation of regulatory mechanisms in response to carbon source and stress signaling and their importance in defining targets for strain selection and improvement.

  9. The evolution of phenotypic plasticity: genealogy of a debate in genetics.

    PubMed

    Nicoglou, Antonine

    2015-04-01

    The paper describes the context and the origin of a particular debate that concerns the evolution of phenotypic plasticity. In 1965, British biologist A. D. Bradshaw proposed a widely cited model intended to explain the evolution of norms of reaction, based on his studies of plant populations. Bradshaw's model went beyond the notion of the "adaptive norm of reaction" discussed before him by Dobzhansky and Schmalhausen by suggesting that "plasticity"--the ability of a phenotype to be modified by the environment--should be genetically determined. To prove Bradshaw's hypothesis, it became necessary for some authors to identify the pressures exerted by natural selection on phenotypic plasticity in particular traits, and thus to model its evolution. In this paper, I contrast two different views, based on quantitative genetic models, proposed in the mid-1980s: Russell Lande and Sara Via's conception of phenotypic plasticity, which assumes that the evolution of plasticity is linked to the evolution of the plastic trait itself, and Samuel Scheiner and Richard Lyman's view, which assumes that the evolution of plasticity is independent from the evolution of the trait. I show how the origin of this specific debate, and different assumptions about the evolution of phenotypic plasticity, depended on Bradshaw's definition of plasticity and the context of quantitative genetics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Phenotypic and genetic divergence within a single whitefish form – detecting the potential for future divergence

    PubMed Central

    Hirsch, Philipp Emanuel; Eckmann, Reiner; Oppelt, Claus; Behrmann-Godel, Jasminca

    2013-01-01

    Human-induced nutrient input can change the selection regime and lead to the loss of biodiversity. For example, eutrophication caused speciation reversal in polymorphic whitefish populations through a flattening of littoral–pelagic selection gradients. We investigated the current state of phenotypic and genetic diversity in whitefish (Coregonus macrophthalmus) in a newly restored lake whose nutrient load has returned to pre-eutrophication levels and found that whitefish spawning at different depths varied phenotypically and genetically: individuals spawning at shallower depth had fewer gill rakers, faster growth, and a morphology adapted to benthic feeding, and they showed higher degrees of diet specialization than deeper spawning individuals. Microsatellite analyses complemented the phenotype analyses by demonstrating reproductive isolation along different spawning depths. Our results indicate that whitefish still retain or currently regain phenotypic and genetic diversity, which was lost during eutrophication. Hence, the population documented here has a potential for future divergence because natural selection can target phenotypes specialized along re-established littoral–pelagic selection gradients. The biodiversity, however, will have better chances to return if managers acknowledge the evolutionary potential within the local whitefish and adapt fishing and stocking measures. PMID:24478795

  11. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    EPA Science Inventory

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to
    Cadmium-Induced Testicular Injury in Mice

    Jie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2
    and Curtis D. Klaassen1

    ABSTRACT

    Parenteral administrati...

  12. Association of genetic and phenotypic variability with geography and climate in three southern California oaks.

    PubMed

    Riordan, Erin C; Gugger, Paul F; Ortego, Joaquín; Smith, Carrie; Gaddis, Keith; Thompson, Pam; Sork, Victoria L

    2016-01-01

    Geography and climate shape the distribution of organisms, their genotypes, and their phenotypes. To understand historical and future evolutionary and ecological responses to climate, we compared the association of geography and climate of three oak species (Quercus engelmannii, Quercus berberidifolia, and Quercus cornelius-mulleri) in an environmentally heterogeneous region of southern California at three organizational levels: regional species distributions, genetic variation, and phenotypic variation. We identified climatic variables influencing regional distribution patterns using species distribution models (SDMs), and then tested whether those individual variables are important in shaping genetic (microsatellite) and phenotypic (leaf morphology) variation. We estimated the relative contributions of geography and climate using multivariate redundancy analyses (RDA) with variance partitioning. The modeled distribution of each species was influenced by climate differently. Our analysis of genetic variation using RDA identified small but significant associations between genetic variation with climate and geography in Q. engelmannii and Q. cornelius-mulleri, but not in Q. berberidifolia, and climate explained more of the variation. Our analysis of phenotypic variation in Q. engelmannii indicated that climate had more impact than geography, but not in Q. berberidifolia. Throughout our analyses, we did not find a consistent pattern in effects of individual climatic variables. Our comparative analysis illustrates that climate influences tree response at all organizational levels, but the important climate factors vary depending on the level and on the species. Because of these species-specific and level-specific responses, today's sympatric species are unlikely to have similar distributions in the future. © 2016 Botanical Society of America.

  13. The ecology and evolution of animal medication: genetically fixed response versus phenotypic plasticity.

    PubMed

    Choisy, Marc; de Roode, Jacobus C

    2014-08-01

    Animal medication against parasites can occur either as a genetically fixed (constitutive) or phenotypically plastic (induced) behavior. Taking the tritrophic interaction between the monarch butterfly Danaus plexippus, its protozoan parasite Ophryocystis elektroscirrha, and its food plant Asclepias spp. as a test case, we develop a game-theory model to identify the epidemiological (parasite prevalence and virulence) and environmental (plant toxicity and abundance) conditions that predict the evolution of genetically fixed versus phenotypically plastic forms of medication. Our model shows that the relative benefits (the antiparasitic properties of medicinal food) and costs (side effects of medicine, the costs of searching for medicine, and the costs of plasticity itself) crucially determine whether medication is genetically fixed or phenotypically plastic. Our model suggests that animals evolve phenotypic plasticity when parasite risk (a combination of virulence and prevalence and thus a measure of the strength of parasite-mediated selection) is relatively low to moderately high and genetically fixed medication when parasite risk becomes very high. The latter occurs because at high parasite risk, the costs of plasticity are outweighed by the benefits of medication. Our model provides a simple and general framework to study the conditions that drive the evolution of alternative forms of animal medication.

  14. Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed

    USDA-ARS?s Scientific Manuscript database

    The measure of flight speed for cattle has been shown to be a predictive indicator of temperament and has also been associated with feed efficiency phenotypes, thus, genetic markers associated with both traits may assist with the selection of animals with calmer disposition and economic value. Chrom...

  15. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    EPA Science Inventory

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to
    Cadmium-Induced Testicular Injury in Mice

    Jie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2
    and Curtis D. Klaassen1

    ABSTRACT

    Parenteral administrati...

  16. Identification of Genetic Loci Underlying the Phenotypic Constructs of Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Liu, Xiao-Qing; Georgiades, Stelios; Duku, Eric; Thompson, Ann; Devlin, Bernie; Cook, Edwin H.; Wijsman, Ellen M.; Paterson, Andrew D.; Szatmari, Peter

    2011-01-01

    Objective: To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors. Method: Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from…

  17. Parapatric genetic introgression and phenotypic assimilation: testing conditions for introgression between Hercules beetles (Dynastes, Dynastinae).

    PubMed

    Huang, Jen-Pan

    2016-11-01

    The prevalence and consequences of genetic introgression between species have been intensively debated. I used Hercules beetles as examples to test for conditions that may be associated with the occurrence of introgression. RADseq data were used to reconstruct the species tree and history of introgression between Hercules beetles. Image data from museum specimens were used to investigate the phenotypic similarity of two adaptive traits between species from two distinct climatic realms (Nearctic vs. Neotropical). Genetic introgression was identified between Hercules beetles living in geographic proximity (parapatric). Phylogenetic relatedness and phenotypic similarity did not predict nor preclude genetic introgression between species. Phenotypic assimilation in body coloration was evident between distantly related Hercules beetles codistributed in Central America, where directional introgression was also statistically supported from the putative donor to receiver lineages. The number of introgressed loci was significantly higher between species with than without phenotypic similarity. I discuss the implications of recent studies on adaptive genetic introgression by providing supporting evidence from the Hercules beetle system.

  18. Identification of Genetic Loci Underlying the Phenotypic Constructs of Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Liu, Xiao-Qing; Georgiades, Stelios; Duku, Eric; Thompson, Ann; Devlin, Bernie; Cook, Edwin H.; Wijsman, Ellen M.; Paterson, Andrew D.; Szatmari, Peter

    2011-01-01

    Objective: To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors. Method: Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from…

  19. Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype.

    PubMed

    Loland, Sigmund

    2015-09-01

    New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype.

  20. Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.

    PubMed

    Pontikos, Nikolas; Yu, Jing; Moghul, Ismail; Withington, Lucy; Blanco-Kelly, Fiona; Vulliamy, Tom; Wong, Tsz Lun Ernest; Murphy, Cian; Cipriani, Valentina; Fiorentino, Alessia; Arno, Gavin; Greene, Daniel; Jacobsen, Julius O B; Clark, Tristan; Gregory, David S; Nemeth, Andrea M; Halford, Stephanie; Inglehearn, Chris F; Downes, Susan; Black, Graeme C; Webster, Andrew R; Hardcastle, Alison J; Plagnol, Vincent

    2017-08-01

    Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases. A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts. n.pontikos@ucl.ac.uk. Supplementary data are available at Bioinformatics online.

  1. Identifying Multimodal Intermediate Phenotypes between Genetic Risk Factors and Disease Status in Alzheimer’s Disease

    PubMed Central

    Hao, Xiaoke; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L.; Saykin, Andrew J.; Zhang, Daoqiang; Shen, Li

    2016-01-01

    Neuroimaging genetics has attracted growing attention and interest, which is thought to be a powerful strategy to examine the influence of genetic variants (i.e., single nucleotide polymorphisms (SNPs)) on structures or functions of human brain. In recent studies, univariate or multivariate regression analysis methods are typically used to capture the effective associations between genetic variants and quantitative traits (QTs) such as brain imaging phenotypes. The identified imaging QTs, although associated with certain genetic markers, may not be all disease specific. A useful, but underexplored, scenario could be to discover only those QTs associated with both genetic markers and disease status for revealing the chain from genotype to phenotype to symptom. In addition, multimodal brain imaging phenotypes are extracted from different perspectives and imaging markers consistently showing up in multimodalities may provide more insights for mechanistic understanding of diseases (i.e., Alzheimer’s disease (AD)). In this work, we propose a general framework to exploit multi-modal brain imaging phenotypes as intermediate traits that bridge genetic risk factors and multi-class disease status. We applied our proposed method to explore the relation between the well-known AD risk SNP APOE rs429358 and three baseline brain imaging modalities (i.e., structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and F-18 florbetapir PET scans amyloid imaging (AV45)) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The empirical results demonstrate that our proposed method not only helps improve the performances of imaging genetic associations, but also discovers robust and consistent regions of interests (ROIs) across multi-modalities to guide the disease-induced interpretation. PMID:27277494

  2. Narcissism predicts impulsive buying: phenotypic and genetic evidence

    PubMed Central

    Cai, Huajian; Shi, Yuanyuan; Fang, Xiang; Luo, Yu L. L.

    2015-01-01

    Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship. PMID:26217251

  3. Genetic variation in aggregation behaviour and interacting phenotypes in Drosophila

    PubMed Central

    Philippe, Anne-Sophie; Jeanson, Raphael; Pasquaretta, Cristian; Rebaudo, Francois; Sueur, Cedric; Mery, Frederic

    2016-01-01

    Aggregation behaviour is the tendency for animals to group together, which may have important consequences on individual fitness. We used a combination of experimental and simulation approaches to study how genetic variation and social environment interact to influence aggregation dynamics in Drosophila. To do this, we used two different natural lines of Drosophila that arise from a polymorphism in the foraging gene (rovers and sitters). We placed groups of flies in a heated arena. Flies could freely move towards one of two small, cooler refuge areas. In groups of the same strain, sitters had a greater tendency to aggregate. The observed behavioural variation was based on only two parameters: the probability of entering a refuge and the likelihood of choosing a refuge based on the number of individuals present. We then directly addressed how different strains interact by mixing rovers and sitters within a group. Aggregation behaviour of each line was strongly affected by the presence of the other strain, without changing the decision rules used by each. Individuals obeying local rules shaped complex group dynamics via a constant feedback loop between the individual and the group. This study could help to identify the circumstances under which particular group compositions may improve individual fitness through underlying aggregation mechanisms under specific environmental conditions. PMID:27009219

  4. Narcissism predicts impulsive buying: phenotypic and genetic evidence.

    PubMed

    Cai, Huajian; Shi, Yuanyuan; Fang, Xiang; Luo, Yu L L

    2015-01-01

    Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship.

  5. Evolution of genetic redundancy: the relevance of complexity in genotype-phenotype mapping

    NASA Astrophysics Data System (ADS)

    Saito, Nen; Ishihara, Shuji; Kaneko, Kunihiko

    2014-06-01

    Despite its ubiquity among organisms, genetic redundancy is presumed to reduce total population fitness and is therefore unlikely to evolve. This study evaluates an evolutionary model with high-dimensional genotype-phenotype mapping (GPM) by applying a replica method to deal with quenched randomness. From the method, the dependence of fitness on genetic redundancy is analytically calculated. The results demonstrate that genetic redundancy can have higher population fitness under complex GPM, which tends to favor gene duplication in selection processes, further enhancing the potential for evolutionary innovations.

  6. Genetic parameters for both a liver damage phenotype caused by and antibody response to phenotype in dairy and beef cattle.

    PubMed

    Twomey, A J; Sayers, R G; Carroll, R I; Byrne, N; Brien, E O'; Doherty, M L; McClure, J C; Graham, D A; Berry, D P

    2016-10-01

    is a helminth parasite of economic importance to the global cattle industry, with documented high international herd prevalence. The objective of the present study was to generate the first published genetic parameter estimates for liver damage caused by as well as antibody response to in cattle. Abattoir data on the presence of live , or -damaged livers, were available between the years 2012 and 2015, inclusive. A second data set was available on cows from 68 selected dairy herds with a blood ELISA test for antibody response to in autumn 2015. Animals were identified as exposed by using herd mate phenotype, and only exposed animals were retained for analysis. The abattoir data set consisted of 20,481 dairy cows and 75,041 young dairy and beef animals, whereas the study herd data set consisted of 6,912 dairy cows. (Co)variance components for phenotypes in both data sets were estimated using animal linear mixed models. Fixed effects included in the model for both data sets were contemporary group, heterosis coefficient, recombination loss coefficient, parity, age relative to parity/age group, and stage of lactation. An additional fixed effect of abattoir by date of slaughter was included in the model for the analysis of the abattoir data. Direct additive genetic effects and a residual effect were included as random effects for all analyses. After data edits, the prevalence of liver damage caused by in cows and young cattle was 47% and 20%, respectively. The prevalence of a positive antibody response to in cows from the study herd data was 36% after data edits. The heritability of as a binary trait for dairy cows in abattoir data and study herd data was 0.03 ± 0.01 and 0.09 ± 0.02, respectively; heritability in young cattle was 0.01 ± 0.005. The additive genetic SD of as a binary trait was 0.069 and 0.050 for cows and young cattle from the abattoir data, respectively, and 0.112 from the study herd cows. The genetic correlation between liver damage caused by in

  7. Information theory and the ethylene genetic network

    PubMed Central

    González-García, José S

    2011-01-01

    The original aim of the Information Theory (IT) was to solve a purely technical problem: to increase the performance of communication systems, which are constantly affected by interferences that diminish the quality of the transmitted information. That is, the theory deals only with the problem of transmitting with the maximal precision the symbols constituting a message. In Shannon's theory messages are characterized only by their probabilities, regardless of their value or meaning. As for its present day status, it is generally acknowledged that Information Theory has solid mathematical foundations and has fruitful strong links with Physics in both theoretical and experimental areas. However, many applications of Information Theory to Biology are limited to using it as a technical tool to analyze biopolymers, such as DNA, RNA or protein sequences. The main point of discussion about the applicability of IT to explain the information flow in biological systems is that in a classic communication channel, the symbols that conform the coded message are transmitted one by one in an independent form through a noisy communication channel, and noise can alter each of the symbols, distorting the message; in contrast, in a genetic communication channel the coded messages are not transmitted in the form of symbols but signaling cascades transmit them. Consequently, the information flow from the emitter to the effector is due to a series of coupled physicochemical processes that must ensure the accurate transmission of the message. In this review we discussed a novel proposal to overcome this difficulty, which consists of the modeling of gene expression with a stochastic approach that allows Shannon entropy (H) to be directly used to measure the amount of uncertainty that the genetic machinery has in relation to the correct decoding of a message transmitted into the nucleus by a signaling pathway. From the value of H we can define a function I that measures the amount of

  8. Information theory and the ethylene genetic network.

    PubMed

    González-García, José S; Díaz, José

    2011-10-01

    The original aim of the Information Theory (IT) was to solve a purely technical problem: to increase the performance of communication systems, which are constantly affected by interferences that diminish the quality of the transmitted information. That is, the theory deals only with the problem of transmitting with the maximal precision the symbols constituting a message. In Shannon's theory messages are characterized only by their probabilities, regardless of their value or meaning. As for its present day status, it is generally acknowledged that Information Theory has solid mathematical foundations and has fruitful strong links with Physics in both theoretical and experimental areas. However, many applications of Information Theory to Biology are limited to using it as a technical tool to analyze biopolymers, such as DNA, RNA or protein sequences. The main point of discussion about the applicability of IT to explain the information flow in biological systems is that in a classic communication channel, the symbols that conform the coded message are transmitted one by one in an independent form through a noisy communication channel, and noise can alter each of the symbols, distorting the message; in contrast, in a genetic communication channel the coded messages are not transmitted in the form of symbols but signaling cascades transmit them. Consequently, the information flow from the emitter to the effector is due to a series of coupled physicochemical processes that must ensure the accurate transmission of the message. In this review we discussed a novel proposal to overcome this difficulty, which consists of the modeling of gene expression with a stochastic approach that allows Shannon entropy (H) to be directly used to measure the amount of uncertainty that the genetic machinery has in relation to the correct decoding of a message transmitted into the nucleus by a signaling pathway. From the value of H we can define a function I that measures the amount of

  9. Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

    PubMed Central

    Bruun, Camilla S; Jørgensen, Claus B; Bay, Lene; Cirera, Susanna; Jensen, Henrik E; Leifsson, Páll S; Nielsen, Jens; Christensen, Knud; Fredholm, Merete

    2008-01-01

    Background A pig phenotype characterized by juvenile hairlessness, thin skin and age dependent lung emphysema has been discovered in a Danish pig herd. The trait shows autosomal co-dominant inheritance with all three genotypes distinguishable. Since the phenotype shows resemblance to the integrin β6 -/- knockout phenotype seen in mice, the two genes encoding the two subunits of integrin αvβ6, i.e. ITGB6 and ITGAV, were considered candidate genes for this trait. Results The mutated pig phenotype is characterized by hairlessness until puberty, thin skin with few hair follicles and absence of musculi arrectores pili, and at puberty or later localized areas of emphysema are seen in the lungs. Comparative mapping predicted that the porcine ITGB6 andITGAV orthologs map to SSC15. In an experimental family (n = 113), showing segregation of the trait, the candidate region was confirmed by linkage analysis with four microsatellite markers. Mapping of the porcine ITGB6 and ITGAV in the IMpRH radiation hybrid panel confirmed the comparative mapping information. Sequencing of the ITGB6 and ITGAV coding sequences from affected and normal pigs revealed no evidence of a causative mutation, but alternative splicing of the ITGB6 pre-mRNA was detected. For both ITGB6 and ITGAV quantitative PCR revealed no significant difference in the expression levels in normal and affected animals. In a western blot, ITGB6 was detected in lung protein samples of all three genotypes. This result was supported by flow cytometric analyses which showed comparable reactions of kidney cells from affected and normal pigs with an integrin αvβ6 monoclonal antibody. Also, immunohistochemical staining of lung tissue with an integrin β6 antibody showed immunoreaction in both normal and affected pigs. Conclusion A phenotype resembling the integrin β6 -/- knockout phenotype seen in mice has been characterized in the pig. The candidate region on SSC15 has been confirmed by linkage analysis but molecular

  10. [Genetic components and the uncertainty of the phenotypic realization of the mass of newborns in domestic pigs Sus scrofa L].

    PubMed

    Nikitin, S V; Kniazev, S P; Ermolaev, V I

    2014-01-01

    In this article, we discuss the features of the genetic determination of a continuous quantitative trait, the mass of newborn offspring in populations of the domestic pig. We defined several components that determine the phenotypic trait, such as the maternal effect, complete dominance, interaction of the parental alleles in the genotype of the offspring, and the uncertainty of phenotypic realization of genotype. We found that a phenotypic trait of high genetic determinacy can also have a maximum range in phenotypic realization, in which case each genotype encountered in the population can realize within the entire range of possible phenotypes.

  11. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    ERIC Educational Resources Information Center

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  12. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    ERIC Educational Resources Information Center

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  13. Phenotypic and Genetic Variations in Obligate Parthenogenetic Populations of Eriosoma lanigerum Hausmann (Hemiptera: Aphididae).

    PubMed

    Ruiz-Montoya, L; Zúñiga, G; Cisneros, R; Salinas-Moreno, Y; Peña-Martínez, R; Machkour-M'Rabet, S

    2015-12-01

    The study of phenotypic and genetic variation of obligate parthenogenetic organisms contributes to an understanding of evolution in the absence of genetic variation produced by sexual reproduction. Eriosoma lanigerum Hausmann undergoes obligate parthenogenesis in Mexico City, Mexico, due to the unavailability of the host plants required for sexual reproduction. We analysed the phenotypic and genetic variation of E. lanigerum in relation to the dry and wet season and plant phenology. Aphids were collected on two occasions per season on a secondary host plant, Pyracantha koidzumii, at five different sites in the southern area of Mexico City, Mexico. Thirteen morphological characteristics were measured from 147 to 276 individuals per site and per season. A multivariate analysis of variance was performed to test the effect of the season, site and their interaction on morphological traits. Morphological variation was summarised using a principal component analysis. Genetic variation was described using six enzymatic loci, four of which were polymorphic. Our study showed that the site and season has a significant effect on morphological trait variation. The largest aphids were recorded during cold temperatures with low relative humidity and when the plant was at the end of the fruiting period. The mean genetic diversity was low (mean H e =  .161), and populations were genetically structured by season and site. Morphological and genetic variations appear to be associated with environmental factors that directly affect aphid development and/or indirectly by host plant phenology.

  14. Catch Me if You Can: Adaptation from Standing Genetic Variation to a Moving Phenotypic Optimum.

    PubMed

    Matuszewski, Sebastian; Hermisson, Joachim; Kopp, Michael

    2015-08-01

    Adaptation lies at the heart of Darwinian evolution. Accordingly, numerous studies have tried to provide a formal framework for the description of the adaptive process. Of these, two complementary modeling approaches have emerged: While so-called adaptive-walk models consider adaptation from the successive fixation of de novo mutations only, quantitative genetic models assume that adaptation proceeds exclusively from preexisting standing genetic variation. The latter approach, however, has focused on short-term evolution of population means and variances rather than on the statistical properties of adaptive substitutions. Our aim is to combine these two approaches by describing the ecological and genetic factors that determine the genetic basis of adaptation from standing genetic variation in terms of the effect-size distribution of individual alleles. Specifically, we consider the evolution of a quantitative trait to a gradually changing environment. By means of analytical approximations, we derive the distribution of adaptive substitutions from standing genetic variation, that is, the distribution of the phenotypic effects of those alleles from the standing variation that become fixed during adaptation. Our results are checked against individual-based simulations. We find that, compared to adaptation from de novo mutations, (i) adaptation from standing variation proceeds by the fixation of more alleles of small effect and (ii) populations that adapt from standing genetic variation can traverse larger distances in phenotype space and, thus, have a higher potential for adaptation if the rate of environmental change is fast rather than slow.

  15. Markers of Psychological Differences and Social and Health Inequalities: Possible Genetic and Phenotypic Overlaps.

    PubMed

    Mõttus, René; Marioni, Riccardo; Deary, Ian J

    2017-02-01

    Associations between markers of ostensible psychological characteristics and social and health inequalities are pervasive but difficult to explain. In some cases, there may be causal influence flowing from social and health inequalities to psychological differences, whereas sometimes it may be the other way around. Here, we focus on the possibility that some markers that we often consider as indexing different domains of individual differences may in fact reflect at least partially overlapping genetic and/or phenotypic bases. For example, individual differences in cognitive abilities and educational attainment appear to reflect largely overlapping genetic influences, whereas cognitive abilities and health literacy may be almost identical phenomena at the phenotypic, never mind genetic, level. We make the case for employing molecular genetic data and quantitative genetic techniques to better understand the associations of psychological individual differences with social and health inequalities. We illustrate these arguments by using published findings from the Lothian Birth Cohort and the Generation Scotland studies. We also present novel findings pertaining to longitudinal stability and change in older age personality traits and some correlates of the change, molecular genetic data-based heritability estimates of Neuroticism and Extraversion, and the genetic correlations of these personality traits with markers of social and health inequalities.

  16. Catch Me if You Can: Adaptation from Standing Genetic Variation to a Moving Phenotypic Optimum

    PubMed Central

    Matuszewski, Sebastian; Hermisson, Joachim; Kopp, Michael

    2015-01-01

    Adaptation lies at the heart of Darwinian evolution. Accordingly, numerous studies have tried to provide a formal framework for the description of the adaptive process. Of these, two complementary modeling approaches have emerged: While so-called adaptive-walk models consider adaptation from the successive fixation of de novo mutations only, quantitative genetic models assume that adaptation proceeds exclusively from preexisting standing genetic variation. The latter approach, however, has focused on short-term evolution of population means and variances rather than on the statistical properties of adaptive substitutions. Our aim is to combine these two approaches by describing the ecological and genetic factors that determine the genetic basis of adaptation from standing genetic variation in terms of the effect-size distribution of individual alleles. Specifically, we consider the evolution of a quantitative trait to a gradually changing environment. By means of analytical approximations, we derive the distribution of adaptive substitutions from standing genetic variation, that is, the distribution of the phenotypic effects of those alleles from the standing variation that become fixed during adaptation. Our results are checked against individual-based simulations. We find that, compared to adaptation from de novo mutations, (i) adaptation from standing variation proceeds by the fixation of more alleles of small effect and (ii) populations that adapt from standing genetic variation can traverse larger distances in phenotype space and, thus, have a higher potential for adaptation if the rate of environmental change is fast rather than slow. PMID:26038348

  17. Sources of Fungal Genetic Variation and Associating It with Phenotypic Diversity.

    PubMed

    Taylor, John W; Branco, Sara; Gao, Cheng; Hann-Soden, Chris; Montoya, Liliam; Sylvain, Iman; Gladieux, Pierre

    2017-09-01

    The first eukaryotic genome to be sequenced was fungal, and there continue to be more sequenced genomes in the kingdom Fungi than in any other eukaryotic kingdom. Comparison of these genomes reveals many sources of genetic variation, from single nucleotide polymorphisms to horizontal gene transfer and on to changes in the arrangement and number of chromosomes, not to mention endofungal bacteria and viruses. Population genomics shows that all sources generate variation all the time and implicate natural selection as the force maintaining genome stability. Variation in wild populations is a rich resource for associating genetic variation with phenotypic variation, whether through quantitative trait locus mapping, genome-wide association studies, or reverse ecology. Subjects of studies associating genetic and phenotypic variation include model fungi, e.g., Saccharomyces and Neurospora, but pioneering studies have also been made with fungi pathogenic to plants, e.g., Pyricularia (= Magnaporthe), Zymoseptoria, and Fusarium, and to humans, e.g., Coccidioides, Cryptococcus, and Candida.

  18. High-Throughput Phenotyping and QTL Mapping Reveals the Genetic Architecture of Maize Plant Growth.

    PubMed

    Zhang, Xuehai; Huang, Chenglong; Wu, Di; Qiao, Feng; Li, Wenqiang; Duan, Lingfeng; Wang, Ke; Xiao, Yingjie; Chen, Guoxing; Liu, Qian; Xiong, Lizhong; Yang, Wanneng; Yan, Jianbing

    2017-03-01

    With increasing demand for novel traits in crop breeding, the plant research community faces the challenge of quantitatively analyzing the structure and function of large numbers of plants. A clear goal of high-throughput phenotyping is to bridge the gap between genomics and phenomics. In this study, we quantified 106 traits from a maize (Zea mays) recombinant inbred line population (n = 167) across 16 developmental stages using the automatic phenotyping platform. Quantitative trait locus (QTL) mapping with a high-density genetic linkage map, including 2,496 recombinant bins, was used to uncover the genetic basis of these complex agronomic traits, and 988 QTLs have been identified for all investigated traits, including three QTL hotspots. Biomass accumulation and final yield were predicted using a combination of dissected traits in the early growth stage. These results reveal the dynamic genetic architecture of maize plant growth and enhance ideotype-based maize breeding and prediction.

  19. The effects of inbreeding, genetic dissimilarity and phenotype on male reproductive success in a dioecious plant.

    PubMed

    Austerlitz, Frédéric; Gleiser, Gabriela; Teixeira, Sara; Bernasconi, Giorgina

    2012-01-07

    Pollen fate can strongly affect the genetic structure of populations with restricted gene flow and significant inbreeding risk. We established an experimental population of inbred and outbred Silene latifolia plants to evaluate the effects of (i) inbreeding depression, (ii) phenotypic variation and (iii) relatedness between mates on male fitness under natural pollination. Paternity analysis revealed that outbred males sired significantly more offspring than inbred males. Independently of the effects of inbreeding, male fitness depended on several male traits, including a sexually dimorphic (flower number) and a gametophytic trait (in vitro pollen germination rate). In addition, full-sib matings were less frequent than randomly expected. Thus, inbreeding, phenotype and genetic dissimilarity simultaneously affect male fitness in this animal-pollinated plant. While inbreeding depression might threaten population persistence, the deficiency of effective matings between sibs and the higher fitness of outbred males will reduce its occurrence and counter genetic erosion.

  20. The effects of inbreeding, genetic dissimilarity and phenotype on male reproductive success in a dioecious plant

    PubMed Central

    Austerlitz, Frédéric; Gleiser, Gabriela; Teixeira, Sara; Bernasconi, Giorgina

    2012-01-01

    Pollen fate can strongly affect the genetic structure of populations with restricted gene flow and significant inbreeding risk. We established an experimental population of inbred and outbred Silene latifolia plants to evaluate the effects of (i) inbreeding depression, (ii) phenotypic variation and (iii) relatedness between mates on male fitness under natural pollination. Paternity analysis revealed that outbred males sired significantly more offspring than inbred males. Independently of the effects of inbreeding, male fitness depended on several male traits, including a sexually dimorphic (flower number) and a gametophytic trait (in vitro pollen germination rate). In addition, full-sib matings were less frequent than randomly expected. Thus, inbreeding, phenotype and genetic dissimilarity simultaneously affect male fitness in this animal-pollinated plant. While inbreeding depression might threaten population persistence, the deficiency of effective matings between sibs and the higher fitness of outbred males will reduce its occurrence and counter genetic erosion. PMID:21561968

  1. Exome sequence analysis suggests genetic burden contributes to phenotypic variability and complex neuropathy

    PubMed Central

    Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas O.; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. PMID:26257172

  2. Canine Behavioral Genetics: Pointing Out the Phenotypes and Herding up the Genes

    PubMed Central

    Spady, Tyrone C.; Ostrander, Elaine A.

    2008-01-01

    An astonishing amount of behavioral variation is captured within the more than 350 breeds of dog recognized worldwide. Inherent in observations of dog behavior is the notion that much of what is observed is breed specific and will persist, even in the absence of training or motivation. Thus, herding, pointing, tracking, hunting, and so forth are likely to be controlled, at least in part, at the genetic level. Recent studies in canine genetics suggest that small numbers of genes control major morphologic phenotypes. By extension, we hypothesize that at least some canine behaviors will also be controlled by small numbers of genes that can be readily mapped. In this review, we describe our current understanding of a representative subset of canine behaviors, as well as approaches for phenotyping, genome-wide scans, and data analysis. Finally, we discuss the applicability of studies of canine behavior to human genetics. PMID:18179880

  3. Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.

    PubMed

    O'Loughlin, Jennifer; Sylvestre, Marie-Pierre; Labbe, Aurélie; Low, Nancy C; Roy-Gagnon, Marie-Hélène; Dugas, Erika N; Karp, Igor; Engert, James C

    2014-01-01

    While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076. Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Dopaminergic pathways may be salient during early smoking and the development of ND.

  4. Phenotypic and genetic variation in longevity of Polish Landrace sows.

    PubMed

    Sobczyńska, M; Blicharski, T

    2015-08-01

    The influence of some production traits on the longevity of Polish Landrace sows was evaluated using survival analysis. Estimates of genetic parameters were obtained from the sire and animal components in linear and survival methodologies. Comparison between survival and linear models was based on heritabilities and ranking of estimated breeding values of sires. The same data set, 13,031 sows, was used for both methodologies, even in the presence of censored observations. The effects of herd*year and year*season of the first farrowing had the largest influence on the risk of culling of sows. Sows born in spring season (March-May) had a 24% (p < 0.001) lower hazard for removal than those born in winter (December-February). The age at first farrowing had a small but significant effect on culling: the hazard regression coefficient for this trait was 0.002 per day. Sows that had more piglets born alive and fewer stillborn in the first litter had a decreased risk of being culled. Within a contemporary group, slower growing gilts had decreased removal risk. The relative risk ratios show a marginal decreased rate of culling for sows with backfat thickness between 9.5 and 11 mm compared to the leaner sows. Loin depth had no effect on sow longevity. Heritability estimates ranged from 0.09 to 0.38 depending on the model and type of analysis. In survival analysis, all heritabilities for longevity were higher when analysed with sire models (0.21 and 0.38) compared to animal models (0.09 and 0.16). The use of animal or sire models in the linear analysis gave similar heritability estimates (0.12 and 0.10). Correlations between breeding values for sires were moderate and high, with absolute values from 0.51 to 0.99, depending on the model fitted and methodology. A stronger correlations within methodologies (0.83-0.99) than within models with different methodologies (0.51-0.63) were obtained.

  5. Experimental evolution of phenotypic plasticity: how predictive are cross-environment genetic correlations?

    PubMed

    Czesak, Mary Ellen; Fox, Charles W; Wolf, Jason B

    2006-09-01

    Genetic correlations are often predictive of correlated responses of one trait to selection on another trait. There are examples, however, in which genetic correlations are not predictive of correlated responses. We examine how well a cross-environment genetic correlation predicts correlated responses to selection and the evolution of phenotypic plasticity in the seed beetle Stator limbatus. This beetle exhibits adaptive plasticity in egg size by laying large eggs on a resistant host and small eggs on a high-quality host. From a half-sib analysis, the cross-environment genetic correlation estimate was large and positive (rA=0.99). However, an artificial-selection experiment on egg size found that the realized genetic correlations were positive but asymmetrical; that is, they depended on both the host on which selection was imposed and the direction of selection. The half-sib estimate poorly predicted the evolution of egg size plasticity; plasticity evolved when selection was imposed on one host but did not evolve when selection was imposed on the other host. We use a simple two-locus additive genetic model to explore the conditions that can generate the observed realized genetic correlation and the observed pattern of plasticity evolution. Our model and experimental results indicate that the ability of genetic correlations to predict correlated responses to selection depends on the underlying genetic architecture producing the genetic correlation.

  6. Accessing Genetic Information with Liquid Biopsies.

    PubMed

    Cai, Xuyu; Janku, Filip; Zhan, Qimin; Fan, Jian-Bing

    2015-10-01

    Recent scientific advances in understanding circulating tumor cells, cell-free DNA/RNA, and exosomes in blood have laid a solid foundation for the development of routine molecular 'liquid biopsies'. This approach provides non-invasive access to genetic information--somatic mutations, epigenetic changes, and differential expression--about the physiological conditions of our body and diseases. It opens a valuable avenue for future genetic studies and human disease diagnosis, including prenatal and neurodegenerative disease diagnosis, as well as for cancer screening and monitoring. With the rapid development of highly sensitive and accurate technologies such as next-generation sequencing, molecular 'liquid biopsies' will quickly become a central piece in the future of precision medicine.

  7. The birth of aposematism: High phenotypic divergence and low genetic diversity in a young clade of poison frogs.

    PubMed

    Tarvin, Rebecca D; Powell, Emily A; Santos, Juan C; Ron, Santiago R; Cannatella, David C

    2017-01-13

    Rapid radiation coupled with low genetic divergence often hinders species delimitation and phylogeny estimation even if putative species are phenotypically distinct. Some aposematic species, such as poison frogs (Dendrobatidae), have high levels of intraspecific color polymorphism, which can lead to overestimation of species when phenotypic divergence primarily guides species delimitation. We explored this possibility in the youngest origin of aposematism (3-7 MYA) in poison frogs, Epipedobates, by comparing genetic divergence with color and acoustic divergence. We found low genetic divergence (2.6% in the 16S gene) despite substantial differences in color and acoustic signals. While chemical defense is inferred to have evolved in the ancestor of Epipedobates, aposematic coloration evolved at least twice or was lost once in Epipedobates, suggesting that it is evolutionarily labile. We inferred at least one event of introgression between two cryptically colored species with adjacent ranges (E. boulengeri and E. machalilla). We also find evidence for peripheral isolation resulting in phenotypic divergence and potential speciation of the aposematic E. tricolor from the non-aposematic E. machalilla. However, we were unable to estimate a well-supported species tree or delimit species using multispecies coalescent models. We attribute this failure to factors associated with recent speciation including mitochondrial introgression, incomplete lineage sorting, and too few informative molecular characters. We suggest that species delimitation within young aposematic lineages such as Epipedobates will require genome-level molecular studies. We caution against relying solely on DNA barcoding for species delimitation or identification and highlight the value of phenotypic divergence and natural history in delimiting species.

  8. Mining Plant Genomic and Genetic Data Using the GnpIS Information System.

    PubMed

    Adam-Blondon, A-F; Alaux, M; Durand, S; Letellier, T; Merceron, G; Mohellibi, N; Pommier, C; Steinbach, D; Alfama, F; Amselem, J; Charruaud, D; Choisne, N; Flores, R; Guerche, C; Jamilloux, V; Kimmel, E; Lapalu, N; Loaec, M; Michotey, C; Quesneville, H

    2017-01-01

    GnpIS is an information system designed to help scientists working on plants and fungi to decipher the molecular and genetic architecture of trait variations by facilitating the navigation through genetic, genomic, and phenotypic information. The purpose of the present chapter is to illustrate how users can (1) explore datasets from phenotyping experiments in order to build new datasets for studying genotype × environment interactions in traits, (2) browse into the results of other genetic analysis data such as GWAS to generate or check working hypothesis about candidate genes or to identify important alleles and germplasms for breeding programs, and (3) explore the polymorphism in specific area of the genome using InterMine, JBrowse tools embedded in the GnpIS information system.

  9. Punctuated emergences of genetic and phenotypic innovations in eumetazoan, bilaterian, euteleostome, and hominidae ancestors.

    PubMed

    Wenger, Yvan; Galliot, Brigitte

    2013-01-01

    Phenotypic traits derive from the selective recruitment of genetic materials over macroevolutionary times, and protein-coding genes constitute an essential component of these materials. We took advantage of the recent production of genomic scale data from sponges and cnidarians, sister groups from eumetazoans and bilaterians, respectively, to date the emergence of human proteins and to infer the timing of acquisition of novel traits through metazoan evolution. Comparing the proteomes of 23 eukaryotes, we find that 33% human proteins have an ortholog in nonmetazoan species. This premetazoan proteome associates with 43% of all annotated human biological processes. Subsequently, four major waves of innovations can be inferred in the last common ancestors of eumetazoans, bilaterians, euteleostomi (bony vertebrates), and hominidae, largely specific to each epoch, whereas early branching deuterostome and chordate phyla show very few innovations. Interestingly, groups of proteins that act together in their modern human functions often originated concomitantly, although the corresponding human phenotypes frequently emerged later. For example, the three cnidarians Acropora, Nematostella, and Hydra express a highly similar protein inventory, and their protein innovations can be affiliated either to traits shared by all eumetazoans (gut differentiation, neurogenesis); or to bilaterian traits present in only some cnidarians (eyes, striated muscle); or to traits not identified yet in this phylum (mesodermal layer, endocrine glands). The variable correspondence between phenotypes predicted from protein enrichments and observed phenotypes suggests that a parallel mechanism repeatedly produce similar phenotypes, thanks to novel regulatory events that independently tie preexisting conserved genetic modules.

  10. Punctuated Emergences of Genetic and Phenotypic Innovations in Eumetazoan, Bilaterian, Euteleostome, and Hominidae Ancestors

    PubMed Central

    Wenger, Yvan; Galliot, Brigitte

    2013-01-01

    Phenotypic traits derive from the selective recruitment of genetic materials over macroevolutionary times, and protein-coding genes constitute an essential component of these materials. We took advantage of the recent production of genomic scale data from sponges and cnidarians, sister groups from eumetazoans and bilaterians, respectively, to date the emergence of human proteins and to infer the timing of acquisition of novel traits through metazoan evolution. Comparing the proteomes of 23 eukaryotes, we find that 33% human proteins have an ortholog in nonmetazoan species. This premetazoan proteome associates with 43% of all annotated human biological processes. Subsequently, four major waves of innovations can be inferred in the last common ancestors of eumetazoans, bilaterians, euteleostomi (bony vertebrates), and hominidae, largely specific to each epoch, whereas early branching deuterostome and chordate phyla show very few innovations. Interestingly, groups of proteins that act together in their modern human functions often originated concomitantly, although the corresponding human phenotypes frequently emerged later. For example, the three cnidarians Acropora, Nematostella, and Hydra express a highly similar protein inventory, and their protein innovations can be affiliated either to traits shared by all eumetazoans (gut differentiation, neurogenesis); or to bilaterian traits present in only some cnidarians (eyes, striated muscle); or to traits not identified yet in this phylum (mesodermal layer, endocrine glands). The variable correspondence between phenotypes predicted from protein enrichments and observed phenotypes suggests that a parallel mechanism repeatedly produce similar phenotypes, thanks to novel regulatory events that independently tie preexisting conserved genetic modules. PMID:24065732

  11. Genetic linkage analysis of longitudinal hypertension phenotypes using three summary measures

    PubMed Central

    Rao, Shaoqi; Li, Lin; Li, Xia; Moser, Kathy L; Guo, Zheng; Shen, Gongqing; Cannata, Ruth; Zirzow, Erich; Topol, Eric J; Wang, Qing

    2003-01-01

    Background Longitudinal data often have multiple (repeated) measures recorded along a time trajectory. For example, the two cohorts from the Framingham Heart Study (GAW13 Problem 1) contain 21 and 5 repeated measures for hypertension phenotypes as well as epidemiological risk factors, respectively. Direct modelling of a large number of serially and biologically correlated traits in the context of linkage analysis can be prohibitively complex. Alternatively, we may consider using univariate transformation for linkage analysis of longitudinal repeated measures. Results We evaluated the utility of three conventional summary measures (mean, slope, and principal components) for genetic linkage analysis of longitudinal phenotypes by analyzing the chromosome 10 data of the Framingham Heart Study. Except for the temporal slope, all of the summary methods and the multivariate analysis identified the previously reported region, marker GATA64A09, for systolic blood pressure or high blood pressure. Further analysis revealed that this region may harbor gene(s) affecting human blood pressure at multiple stages of life. Conclusion We conclude that mean and principal components are feasible alternatives for genetic linkage analysis of longitudinal phenotypes, but the slope might have a separate genetic basis from that of the original longitudinal phenotypes. PMID:14975092

  12. Evidence for multiple genetic forms with similar eyeless phenotypes in the blind cavefish, Astyanax mexicanus.

    PubMed

    Dowling, Thomas E; Martasian, David P; Jeffery, William R

    2002-04-01

    A diverse group of animals has adapted to caves and lost their eyes and pigmentation, but little is known about how these animals and their striking phenotypes have evolved. The teleost Astyanax mexicanus consists of an eyed epigean form (surface fish) and at least 29 different populations of eyeless hypogean forms (cavefish). Current alternative hypotheses suggest that adaptation to cave environments may have occurred either once or multiple times during the evolutionary history of this species. If the latter is true, the unique phenotypes of different cave-dwelling populations may result from convergence of form, and different genetic changes and developmental processes may have similar morphological consequences. Here we report an analysis of variation in the mitochondrial NADH dehydrogenase 2 (ND2) gene among different surface fish and cavefish populations. The results identify a minimum of two genetically distinctive cavefish lineages with similar eyeless phenotypes. The distinction between these divergent forms is supported by differences in the number of rib-bearing thoracic vertebrae in their axial skeletons. The geographic distribution of ND2 haplotypes is consistent with roles for multiple founder events and introgressive hybridization in the evolution of cave-related phenotypes. The existence of multiple genetic lineages makes A. mexicanus an excellent model to study convergence and the genes and developmental pathways involved in the evolution of the eye and pigment degeneration.

  13. Genetic diversity assessment of sesame core collection in China by phenotype and molecular markers and extraction of a mini-core collection.

    PubMed

    Zhang, Yanxin; Zhang, Xiurong; Che, Zhuo; Wang, Linhai; Wei, Wenliang; Li, Donghua

    2012-11-15

    Sesame (Sesamum indicum L.) is one of the four major oil crops in China. A sesame core collection (CC) was established in China in 2000, but no complete study on its genetic diversity has been carried out at either the phenotypic or molecular level. To provide technical guidance, a theoretical basis for further collection, effective protection, reasonable application, and a complete analysis of sesame genetic resources, a genetic diversity assessment of the sesame CC in China was conducted using phenotypic and molecular data and by extracting a sesame mini-core collection (MC). Results from a genetic diversity assessment of sesame CC in China were significantly inconsistent at the phenotypic and molecular levels. A Mantel test revealed the insignificant correlation between phenotype and molecular marker information (r = 0.0043, t = 0.1320, P = 0.5525). The Shannon-Weaver diversity index (I) and Nei genetic diversity index (h) were higher (I = 0.9537, h = 0.5490) when calculated using phenotypic data from the CC than when using molecular data (I = 0.3467, h = 0.2218). A mini-core collection (MC) containing 184 accessions was extracted based on both phenotypic and molecular data, with a low mean difference percentage (MD, 1.64%), low variance difference percentage (VD, 22.58%), large variable rate of coefficient of variance (VR, 114.86%), and large coincidence rate of range (CR, 95.76%). For molecular data, the diversity indices and the polymorphism information content (PIC) for the MC were significantly higher than for the CC. Compared to an alternative random sampling strategy, the advantages of capturing genetic diversity and validation by extracting a MC using an advanced maximization strategy were proven. This study provides a comprehensive characterization of the phenotypic and molecular genetic diversities of the sesame CC in China. A MC was extracted using both phenotypic and molecular data. Low MD% and VD%, and large VR% and CR% suggested that the MC

  14. Genetic diversity assessment of sesame core collection in China by phenotype and molecular markers and extraction of a mini-core collection

    PubMed Central

    2012-01-01

    Background Sesame (Sesamum indicum L.) is one of the four major oil crops in China. A sesame core collection (CC) was established in China in 2000, but no complete study on its genetic diversity has been carried out at either the phenotypic or molecular level. To provide technical guidance, a theoretical basis for further collection, effective protection, reasonable application, and a complete analysis of sesame genetic resources, a genetic diversity assessment of the sesame CC in China was conducted using phenotypic and molecular data and by extracting a sesame mini-core collection (MC). Results Results from a genetic diversity assessment of sesame CC in China were significantly inconsistent at the phenotypic and molecular levels. A Mantel test revealed the insignificant correlation between phenotype and molecular marker information (r = 0.0043, t = 0.1320, P = 0.5525). The Shannon-Weaver diversity index (I) and Nei genetic diversity index (h) were higher (I = 0.9537, h = 0.5490) when calculated using phenotypic data from the CC than when using molecular data (I = 0.3467, h = 0.2218). A mini-core collection (MC) containing 184 accessions was extracted based on both phenotypic and molecular data, with a low mean difference percentage (MD, 1.64%), low variance difference percentage (VD, 22.58%), large variable rate of coefficient of variance (VR, 114.86%), and large coincidence rate of range (CR, 95.76%). For molecular data, the diversity indices and the polymorphism information content (PIC) for the MC were significantly higher than for the CC. Compared to an alternative random sampling strategy, the advantages of capturing genetic diversity and validation by extracting a MC using an advanced maximization strategy were proven. Conclusions This study provides a comprehensive characterization of the phenotypic and molecular genetic diversities of the sesame CC in China. A MC was extracted using both phenotypic and molecular data. Low MD% and VD%, and large VR% and CR

  15. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms.

    PubMed

    Aggarwal, Annu; Schneider, Susanne A; Houlden, Henry; Silverdale, Monty; Paudel, Reema; Paisan-Ruiz, Coro; Desai, Shrinivas; Munshi, Mihir; Sanghvi, Darshana; Hardy, John; Bhatia, Kailash P; Bhatt, Mohit

    2010-07-30

    Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

  16. Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

    PubMed Central

    Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill; Cree, Bruce A. C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

    2016-01-01

    IMPORTANCE Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0–1.4] and 0 [−0.3 to 0.5], respectively; P = 1.8 × 10−27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset

  17. 29 CFR 1635.12 - Medical information that is not genetic information.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Medical information that is not genetic information. 1635... COMMISSION GENETIC INFORMATION NONDISCRIMINATION ACT OF 2008 § 1635.12 Medical information that is not genetic information. (a) Medical information about a manifested disease, disorder, or pathological...

  18. Genetic Variants Synthesize to Produce Paneth Cell Phenotypes that Define Subtypes of Crohn’s Disease

    PubMed Central

    VanDussen, Kelli L.; Liu, Ta-Chiang; Li, Dalin; Towfic, Fadi; Modiano, Nir; Winter, Rachel; Haritunians, Talin; Taylor, Kent D.; Dhall, Deepti; Targan, Stephan R.; Xavier, Ramnik J.; McGovern, Dermot P. B.; Stappenbeck, Thaddeus S.

    2014-01-01

    Background & Aims Genetic susceptibility loci for Crohn’s disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features. PMID:24076061

  19. Common Garden Experiment Reveals Genetic Control of Phenotypic Divergence between Swamp Sparrow Subspecies That Lack Divergence in Neutral Genotypes

    PubMed Central

    Ballentine, Barbara; Greenberg, Russell

    2010-01-01

    Background Adaptive divergence between populations in the face of strong selection on key traits can lead to morphological divergence between populations without concomitant divergence in neutral DNA. Thus, the practice of identifying genetically distinct populations based on divergence in neutral DNA may lead to a taxonomy that ignores evolutionarily important, rapidly evolving, locally-adapted populations. Providing evidence for a genetic basis of morphological divergence between rapidly evolving populations that lack divergence in selectively neutral DNA will not only inform conservation efforts but also provide insight into the mechanisms of the early processes of speciation. The coastal plain swamp sparrow, a recent colonist of tidal marsh habitat, differs from conspecific populations in a variety of phenotypic traits yet remains undifferentiated in neutral DNA. Methods and Principal Findings Here we use an experimental approach to demonstrate that phenotypic divergence between ecologically separated populations of swamp sparrows is the result of local adaptation despite the lack of divergence in neutral DNA. We find that morphological (bill size and plumage coloration) and life history (reproductive effort) differences observed between wild populations were maintained in laboratory raised individuals suggesting genetic divergence of fitness related traits. Conclusions and Significance Our results support the hypothesis that phenotypic divergence in swamps sparrows is the result of genetic differentiation, and demonstrate that adaptive traits have evolved more rapidly than neutral DNA in these ecologically divergent populations that may be in the early stages of speciation. Thus, identifying evolutionarily important populations based on divergence in selectively neutral DNA could miss an important level of biodiversity and mislead conservation efforts. PMID:20419104

  20. Genetic and phenotypic variation of the malaria vector Anopheles atroparvus in southern Europe

    PubMed Central

    2011-01-01

    Background There is a growing concern that global climate change will affect the potential for pathogen transmission by insect species that are vectors of human diseases. One of these species is the former European malaria vector, Anopheles atroparvus. Levels of population differentiation of An. atroparvus from southern Europe were characterized as a first attempt to elucidate patterns of population structure of this former malaria vector. Results are discussed in light of a hypothetical situation of re-establishment of malaria transmission. Methods Genetic and phenotypic variation was analysed in nine mosquito samples collected from five European countries, using eight microsatellite loci and geometric morphometrics on 21 wing landmarks. Results Levels of genetic diversity were comparable to those reported for tropical malaria vectors. Low levels of genetic (0.004 phenotypic differentiation were detected among An. atroparvus populations spanning over 3,000 km distance. Genetic differentiation (0.202 phenotype level. Conclusions Levels of population differentiation within An. atroparvus were low and not correlated with geographic distance or with putative physical barriers to gene flow (Alps and Pyrenées). While these results may suggest considerable levels of gene flow, other explanations such as the effect of historical population perturbations can also be hypothesized. PMID:21223582

  1. The alignment between phenotypic plasticity, the major axis of genetic variation and the response to selection

    PubMed Central

    Lind, Martin I.; Yarlett, Kylie; Reger, Julia; Carter, Mauricio J.; Beckerman, Andrew P.

    2015-01-01

    Phenotypic plasticity is the ability of a genotype to produce more than one phenotype in order to match the environment. Recent theory proposes that the major axis of genetic variation in a phenotypically plastic population can align with the direction of selection. Therefore, theory predicts that plasticity directly aids adaptation by increasing genetic variation in the direction favoured by selection and reflected in plasticity. We evaluated this theory in the freshwater crustacean Daphnia pulex, facing predation risk from two contrasting size-selective predators. We estimated plasticity in several life-history traits, the G matrix of these traits, the selection gradients on reproduction and survival, and the predicted responses to selection. Using these data, we tested whether the genetic lines of least resistance and the predicted response to selection aligned with plasticity. We found predator environment-specific G matrices, but shared genetic architecture across environments resulted in more constraint in the G matrix than in the plasticity of the traits, sometimes preventing alignment of the two. However, as the importance of survival selection increased, the difference between environments in their predicted response to selection increased and resulted in closer alignment between the plasticity and the predicted selection response. Therefore, plasticity may indeed aid adaptation to new environments. PMID:26423845

  2. The alignment between phenotypic plasticity, the major axis of genetic variation and the response to selection.

    PubMed

    Lind, Martin I; Yarlett, Kylie; Reger, Julia; Carter, Mauricio J; Beckerman, Andrew P

    2015-10-07

    Phenotypic plasticity is the ability of a genotype to produce more than one phenotype in order to match the environment. Recent theory proposes that the major axis of genetic variation in a phenotypically plastic population can align with the direction of selection. Therefore, theory predicts that plasticity directly aids adaptation by increasing genetic variation in the direction favoured by selection and reflected in plasticity. We evaluated this theory in the freshwater crustacean Daphnia pulex, facing predation risk from two contrasting size-selective predators. We estimated plasticity in several life-history traits, the G matrix of these traits, the selection gradients on reproduction and survival, and the predicted responses to selection. Using these data, we tested whether the genetic lines of least resistance and the predicted response to selection aligned with plasticity. We found predator environment-specific G matrices, but shared genetic architecture across environments resulted in more constraint in the G matrix than in the plasticity of the traits, sometimes preventing alignment of the two. However, as the importance of survival selection increased, the difference between environments in their predicted response to selection increased and resulted in closer alignment between the plasticity and the predicted selection response. Therefore, plasticity may indeed aid adaptation to new environments.

  3. Sponge and dough bread making: genetic and phenotypic relationships with wheat quality traits.

    PubMed

    Cavanagh, Colin R; Taylor, Julian; Larroque, Oscar; Coombes, Neil; Verbyla, Arunas P; Nath, Zena; Kutty, Ibrahim; Rampling, Lynette; Butow, Barbara; Ral, Jean-Philippe; Tomoskozi, Sandor; Balazs, Gabor; Békés, Ferenc; Mann, Gulay; Quail, Ken J; Southan, Michael; Morell, Matthew K; Newberry, Marcus

    2010-09-01

    The genetic and phenotypic relationships among wheat quality predictors and sponge and dough bread making were evaluated in a population derived from a cross between an Australian cultivar 'Chara' and a Canadian cultivar 'Glenlea'. The genetic correlation across sites for sponge and dough loaf volume was high; however, phenotypic correlations across sites for loaf volume were relatively low compared with rheological tests. The large difference between sites was most likely due to temperature differences during grain development reflected in a decrease in the percentage of unextractable polymeric protein and mixing time. Predictive tests (mixograph, extensograph, protein content and composition, micro-zeleny and flour viscosity) showed inconsistent and generally poor correlations with end-product performance (baking volume and slice area) at both sites, with no single parameter being effective as a predictor of end-product performance. The difference in the relationships between genetic and phenotypic correlations highlights the requirement to develop alternative methods of selection for breeders and bakers in order to maximise both genetic gain and predictive assessment of grain quality.

  4. Independent genetic control of maize (Zea mays L.) kernel weight determination and its phenotypic plasticity.

    PubMed

    Alvarez Prado, Santiago; Sadras, Víctor O; Borrás, Lucas

    2014-08-01

    Maize kernel weight (KW) is associated with the duration of the grain-filling period (GFD) and the rate of kernel biomass accumulation (KGR). It is also related to the dynamics of water and hence is physiologically linked to the maximum kernel water content (MWC), kernel desiccation rate (KDR), and moisture concentration at physiological maturity (MCPM). This work proposed that principles of phenotypic plasticity can help to consolidated the understanding of the environmental modulation and genetic control of these traits. For that purpose, a maize population of 245 recombinant inbred lines (RILs) was grown under different environmental conditions. Trait plasticity was calculated as the ratio of the variance of each RIL to the overall phenotypic variance of the population of RILs. This work found a hierarchy of plasticities: KDR ≈ GFD > MCPM > KGR > KW > MWC. There was no phenotypic and genetic correlation between traits per se and trait plasticities. MWC, the trait with the lowest plasticity, was the exception because common quantitative trait loci were found for the trait and its plasticity. Independent genetic control of a trait per se and genetic control of its plasticity is a condition for the independent evolution of traits and their plasticities. This allows breeders potentially to select for high or low plasticity in combination with high or low values of economically relevant traits.

  5. Feasibility of a bilateral 4000–6000 Hz notch as a phenotype for genetic association analysis

    PubMed Central

    Phillips, Susan L.; Richter, Scott J.; Teglas, Sandra L.; Bhatt, Ishan S.; Morehouse, Robin C.; Hauser, Elizabeth R.; Henrich, Vincent C.

    2016-01-01

    Objective Noise-induced hearing loss (NIHL) is a worldwide health problem and a growing concern among young people. Although some people appear to be more susceptible to NIHL, genetic association studies lack a specific phenotype. We tested the feasibility of a bilateral 4000–6000 Hz audiometric notch as a phenotype for identifying genetic contributions to hearing loss in young adults. Design A case-control-control study was conducted to examine selected SNPs in 52 genes previously associated with hearing loss and/or expressed in the cochlea. A notch was defined as a minimum of a 15-dB drop at 4000–6000 Hz from the previous best threshold with a 5-dB ‘recovery’ at 8000 Hz. Study sample Participants were 252 individuals of European descent taken from a population of 640 young adults who are students of classical music. Participants were grouped as No-notch (NN), Unilateral Notch (UN), or Bilateral Notch (BN). Results The strongest evidence of a genetic association with the 4000–6000 Hz notch was a nonsynonymous SNP variant in the ESRR? gene (rs61742642:C>T, P386S). Carriers of the minor allele accounted for 26% of all bilateral losses. Conclusion This study indicates that the 4000–6000 Hz bilateral notch is a feasible phenotype for identifying genetic susceptibility to hearing loss. PMID:25938503

  6. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.

    PubMed

    Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W; Shaw, Natalie D; Al-Tassan, Nada; Plummer, Lacey; Dwyer, Andrew A; Buck, Cassandra L; Choi, Jin-Ho; Seminara, Stephanie B; Quinton, Richard; Monies, Dorota; Meyer, Brian; Hall, Janet E; Pitteloud, Nelly; Crowley, William F

    2013-05-01

    The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Reproductive and nonreproductive phenotypes within each genetic group were measured. Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

  7. Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

    PubMed Central

    Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W.; Shaw, Natalie D.; Al-Tassan, Nada; Plummer, Lacey; Dwyer, Andrew A.; Buck, Cassandra L.; Choi, Jin-Ho; Seminara, Stephanie B.; Quinton, Richard; Monies, Dorota; Meyer, Brian; Hall, Janet E.; Pitteloud, Nelly

    2013-01-01

    Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening. PMID:23533228

  8. Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors.

    PubMed

    Peralta, Victor; Fañanás, Lourdes; Martín-Reyes, Migdyrai; Cuesta, Manuel J

    2017-09-14

    This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders. Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h(2)) was estimated by linear mixed models using family membership as a random effect, with h(2) indicating the portion of phenotypic variance accounted for by family membership. Familiality estimates highly varied for individual catatonia signs (h(2)=0.17-0.65), principal component analysis-derived factors (h(2)=0.29-0.49), number of catatonia signs present (h(2)=0.03-0.43) and severity of the catatonia syndrome (h(2)=0.25-0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h(2)=0.65), presence of ≥5 catatonia signs (h(2)=0.43), a classical catatonia factor (h(2)=0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h(2)=0.59) and the diagnostic construct of psychosis with prominent catatonia features (h(2)=0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h(2)=0.40-0.47). The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial-genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases

    PubMed Central

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-01-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  10. The information value of non-genetic inheritance in plants and animals.

    PubMed

    English, Sinead; Pen, Ido; Shea, Nicholas; Uller, Tobias

    2015-01-01

    Parents influence the development of their offspring in many ways beyond the transmission of DNA. This includes transfer of epigenetic states, nutrients, antibodies and hormones, and behavioural interactions after birth. While the evolutionary consequences of such non-genetic inheritance are increasingly well understood, less is known about how inheritance mechanisms evolve. Here, we present a simple but versatile model to explore the adaptive evolution of non-genetic inheritance. Our model is based on a switch mechanism that produces alternative phenotypes in response to different inputs, including genes and non-genetic factors transmitted from parents and the environment experienced during development. This framework shows how genetic and non-genetic inheritance mechanisms and environmental conditions can act as cues by carrying correlational information about future selective conditions. Differential use of these cues is manifested as different degrees of genetic, parental or environmental morph determination. We use this framework to evaluate the conditions favouring non-genetic inheritance, as opposed to genetic determination of phenotype or within-generation plasticity, by applying it to two putative examples of adaptive non-genetic inheritance: maternal effects on seed germination in plants and transgenerational phase shift in desert locusts. Our simulation models show how the adaptive value of non-genetic inheritance depends on its mechanism, the pace of environmental change, and life history characteristics.

  11. Genetic Information Nondiscrimination Act. Final rule.

    PubMed

    2016-05-17

    The Equal Employment Opportunity Commission (EEOC or Commission) is issuing a final rule to amend the regulations implementing Title II of the Genetic Information Nondiscrimination Act of 2008 as they relate to employer-sponsored wellness programs. This rule addresses the extent to which an employer may offer an inducement to an employee for the employee's spouse to provide information about the spouse's manifestation of disease or disorder as part of a health risk assessment (HRA) administered in connection with an employer-sponsored wellness program. Several technical changes to the existing regulations are included. Published elsewhere in this issue of the Federal Register, the EEOC also issued a final rule to amend the regulations and interpretive guidance implementing Title I of the Americans with Disabilities Act (ADA) that addresses the extent to which employers may use incentives to encourage employees to participate in wellness programs that ask them to respond to disability-related inquiries and/or undergo medical examinations.

  12. Genetic information and insurance: some ethical issues.

    PubMed Central

    O'Neill, O

    1997-01-01

    Life is risky, and insurance provides one of the best developed ways of controlling risks. By pooling, and so transferring risks, those who turn out to suffer antecedently uncertain harms can be assured in advance that they will be helped if those harms arise; they can then plan their lives and activities with confidence that they are less at the mercy of ill fortune. Both publicly organized and commercial insurance can organize the pooling of risk in ways that are beneficial for all concerned. They provide standard ways of securing fundamental ethical values such as solidarity and mutuality. Although policy holders do not know or contract with one another, each benefits from the contribution of others to a shared scheme for pooling and so controlling risk. Although there is a limit to the degree to which commercially-based insurance, where premiums depend on risk level, can go beyond mutuality towards solidarity, in practice it too often achieves a measure of solidarity by taking a broad brush approach to pooling risk. However, the ordinary practices of insurance, and in particular of commercial insurance, also raise ethical questions. These may be put in simple terms by contrasting the way in which an insurance market discriminates between different people, on the basis of characteristics that (supposedly) determine their risk level, and our frequent abhorrence of discrimination, in particular on the basis on religious, racial and gender characteristics. Are the discriminations on which insurance practice relies upon as standard acceptable or not? The increasing availability of genetic information, which testing (of individuals) and screening (of populations) may provide, could lend urgency to these questions. Genetic information may provide a way of obtaining more accurate assessment of individual risks to health and life. This information could be used to discriminate more finely between the risk levels of different individuals, and then to alter the

  13. Evidence of Phenotypic and Genetic Relationships between Sociality, Emotional Reactivity and Production Traits in Japanese Quail

    PubMed Central

    Recoquillay, Julien; Leterrier, Christine; Calandreau, Ludovic; Bertin, Aline; Pitel, Frédérique; Gourichon, David; Vignal, Alain; Beaumont, Catherine; Le Bihan-Duval, Elisabeth; Arnould, Cécile

    2013-01-01

    The social behavior of animals, which is partially controlled by genetics, is one of the factors involved in their adaptation to large breeding groups. To understand better the relationships between different social behaviors, fear behaviors and production traits, we analyzed the phenotypic and genetic correlations of these traits in Japanese quail by a second generation crossing of two lines divergently selected for their social reinstatement behavior. Analyses of results for 900 individuals showed that the phenotypic correlations between behavioral traits were low with the exception of significant correlations between sexual behavior and aggressive pecks both at phenotypic (0.51) and genetic (0.90) levels. Significant positive genetic correlations were observed between emotional reactivity toward a novel object and sexual (0.89) or aggressive (0.63) behaviors. The other genetic correlations were observed mainly between behavioral and production traits. Thus, the level of emotional reactivity, estimated by the duration of tonic immobility, was positively correlated with weight at 17 and 65 days of age (0.76 and 0.79, respectively) and with delayed egg laying onset (0.74). In contrast, a higher level of social reinstatement behavior was associated with an earlier egg laying onset (-0.71). In addition, a strong sexual motivation was correlated with an earlier laying onset (-0.68) and a higher number of eggs laid (0.82). A low level of emotional reactivity toward a novel object and also a higher aggressive behavior were genetically correlated with a higher number of eggs laid (0.61 and 0.58, respectively). These results bring new insights into the complex determinism of social and emotional reactivity behaviors in birds and their relationships with production traits. Furthermore, they highlight the need to combine animal welfare and production traits in selection programs by taking into account traits of sociability and emotional reactivity. PMID:24324761

  14. Evidence of phenotypic and genetic relationships between sociality, emotional reactivity and production traits in Japanese quail.

    PubMed

    Recoquillay, Julien; Leterrier, Christine; Calandreau, Ludovic; Bertin, Aline; Pitel, Frédérique; Gourichon, David; Vignal, Alain; Beaumont, Catherine; Le Bihan-Duval, Elisabeth; Arnould, Cécile

    2013-01-01

    The social behavior of animals, which is partially controlled by genetics, is one of the factors involved in their adaptation to large breeding groups. To understand better the relationships between different social behaviors, fear behaviors and production traits, we analyzed the phenotypic and genetic correlations of these traits in Japanese quail by a second generation crossing of two lines divergently selected for their social reinstatement behavior. Analyses of results for 900 individuals showed that the phenotypic correlations between behavioral traits were low with the exception of significant correlations between sexual behavior and aggressive pecks both at phenotypic (0.51) and genetic (0.90) levels. Significant positive genetic correlations were observed between emotional reactivity toward a novel object and sexual (0.89) or aggressive (0.63) behaviors. The other genetic correlations were observed mainly between behavioral and production traits. Thus, the level of emotional reactivity, estimated by the duration of tonic immobility, was positively correlated with weight at 17 and 65 days of age (0.76 and 0.79, respectively) and with delayed egg laying onset (0.74). In contrast, a higher level of social reinstatement behavior was associated with an earlier egg laying onset (-0.71). In addition, a strong sexual motivation was correlated with an earlier laying onset (-0.68) and a higher number of eggs laid (0.82). A low level of emotional reactivity toward a novel object and also a higher aggressive behavior were genetically correlated with a higher number of eggs laid (0.61 and 0.58, respectively). These results bring new insights into the complex determinism of social and emotional reactivity behaviors in birds and their relationships with production traits. Furthermore, they highlight the need to combine animal welfare and production traits in selection programs by taking into account traits of sociability and emotional reactivity.

  15. Genotype-environment interactions reveal causal pathways that mediate genetic effects on phenotype.

    PubMed

    Gagneur, Julien; Stegle, Oliver; Zhu, Chenchen; Jakob, Petra; Tekkedil, Manu M; Aiyar, Raeka S; Schuon, Ann-Kathrin; Pe'er, Dana; Steinmetz, Lars M

    2013-01-01

    Unraveling the molecular processes that lead from genotype to phenotype is crucial for the understanding and effective treatment of genetic diseases. Knowledge of the causative genetic defect most often does not enable treatment; therefore, causal intermediates between genotype and phenotype constitute valuable candidates for molecular intervention points that can be therapeutically targeted. Mapping genetic determinants of gene expression levels (also known as expression quantitative trait loci or eQTL studies) is frequently used for this purpose, yet distinguishing causation from correlation remains a significant challenge. Here, we address this challenge using extensive, multi-environment gene expression and fitness profiling of hundreds of genetically diverse yeast strains, in order to identify truly causal intermediate genes that condition fitness in a given environment. Using functional genomics assays, we show that the predictive power of eQTL studies for inferring causal intermediate genes is poor unless performed across multiple environments. Surprisingly, although the effects of genotype on fitness depended strongly on environment, causal intermediates could be most reliably predicted from genetic effects on expression present in all environments. Our results indicate a mechanism explaining this apparent paradox, whereby immediate molecular consequences of genetic variation are shared across environments, and environment-dependent phenotypic effects result from downstream integration of environmental signals. We developed a statistical model to predict causal intermediates that leverages this insight, yielding over 400 transcripts, for the majority of which we experimentally validated their role in conditioning fitness. Our findings have implications for the design and analysis of clinical omics studies aimed at discovering personalized targets for molecular intervention, suggesting that inferring causation in a single cellular context can benefit from

  16. Expected time for random genetic drift of a population between stable phenotypic states.

    PubMed Central

    Lande, R

    1985-01-01

    Natural selection and random genetic drift are modeled by using diffusion equations for the mean phenotype of a quantitative (polygenic) character in a finite population with two available adaptive zones or ecological niches. When there is appreciable selection, the population is likely to spend a very long time drifting around the peak in its original adaptive zone. With the mean phenotype initially anywhere near the local optimum, the expected time until a shift between phenotypic adaptive peaks increases approximately exponentially with the effective population size. In comparison, the expected duration of intermediate forms in the actual transition between adaptive peaks is extremely short, generally below the level of resolution in the fossil record, and increases approximately logarithmically with the effective population size. The evolutionary dynamics of this model conform to the pattern of current paleontological concepts of morphological "stasis" and "punctuated equilibria." PMID:3865184

  17. Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"?

    PubMed

    Carlier, Nina; Marshe, Victoria S; Cmorejova, Jana; Davis, Caroline; Müller, Daniel J

    2015-12-01

    There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder.

  18. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates.

    PubMed

    Storz, Jay F; Scott, Graham R; Cheviron, Zachary A

    2010-12-15

    High-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high- and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.

  19. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

    PubMed Central

    Storz, Jay F.; Scott, Graham R.; Cheviron, Zachary A.

    2010-01-01

    High-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high- and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change. PMID:21112992

  20. Pedimap: Software for the Visualization of Genetic and Phenotypic Data in Pedigrees

    PubMed Central

    2012-01-01

    Pedimap is a user-friendly software tool for visualizing phenotypic and genotypic data for related individuals linked in pedigrees. Genetic data can include marker scores, Identity-by-Descent probabilities, and marker linkage map positions, allowing the visualization of haplotypes through lineages. The pedigrees can accommodate all types of inheritance, including selfing, cloning, and repeated backcrossing, and all ploidy levels are supported. Visual association of the genetic data with phenotypic data simplifies the exploration of large data sets, thereby improving breeding decision making. Data are imported from text files; in addition data exchange with other software packages (FlexQTLTM and GenomeStudioTM) is possible. Instructions for use and an executable version compatible with the Windows platform are available for free from http://www.plantbreeding.wur.nl/UK/software_pedimap.html. PMID:23087384

  1. Phenotypic and genetic relations between the HEXACO dimensions and trait emotional intelligence.

    PubMed

    Veselka, Livia; Petrides, K V; Schermer, Julie Aitken; Cherkas, Lynn F; Spector, Tim D; Vernon, Philip A

    2010-02-01

    The present study investigated the location of trait emotional intelligence (trait EI or trait emotional self-efficacy) within the context of the HEXACO model - a more comprehensive personality framework than the conventional Big Five structure. A total of 666 MZ and 526 DZ adult twin pairs from the United Kingdom completed the short form of the Trait Emotional Intelligence Questionnaire (TEIQue-SF) and the short form of the HEXACO Personality Inventory (HEXACO-60). Many significant phenotypic correlations between the TEIQue-SF and the HEXACO-60 were obtained, which were strongest for HEXACO Extraversion, and weakest for HEXACO Honesty-Humility. As was expected, Emotionality was the only HEXACO dimension to correlate negatively with TEIQue-SF scores. Bivariate behavioral genetic analyses revealed that all phenotypic correlations were attributable to common genetic and common nonshared environmental factors. The study confirms the validity of trait EI as a constellation of emotional self-perceptions located at the lower levels of personality.

  2. Internet and print resources to facilitate pathology analysis when phenotyping genetically engineered rodents.

    PubMed

    Bolon, B; Couto, S; Fiette, L; Perle, K La

    2012-01-01

    Genetically engineered mice and rats are increasingly used as models for exploring disease progression and mechanisms. The full spectrum of anatomic, biochemical, and functional changes that develop in novel, genetically engineered mouse and rat lines must be cataloged before predictions regarding the significance of the mutation may be extrapolated to diseases in other vertebrate species, including humans. A growing list of reference materials, including books, journal articles, and websites, has been produced in the last 2 decades to assist researchers in phenotyping newly engineered rodent lines. This compilation provides an extensive register of materials related to the pathology component of rodent phenotypic analysis. In this article, the authors annotate the resources they use most often, to allow for quick determination of their relevance to research projects.

  3. Melanic through nature or nurture: genetic polymorphism and phenotypic plasticity in Harmonia axyridis.

    PubMed

    Michie, L J; Mallard, F; Majerus, M E N; Jiggins, F M

    2010-08-01

    Individuals can adapt to heterogeneity in their environment through either local adaptation or phenotypic plasticity. Colour forms of the ladybird Harmonia axyridis are a classic example of local adaptation, in which the frequency of melanic forms varies greatly between populations. In some populations, there are also large seasonal changes in allele frequency, with melanism being costly in summer and beneficial in winter. We report that the non-melanic morph of H. axyridis dramatically increases its degree of melanization at cold temperatures. Furthermore, there is genetic variation in reaction norms, with different families responding to temperature in different ways. Variation at different spatial and temporal scales appears to have selected for either genetic or phenotypically plastic adaptations, which may be important in thermoregulation. As melanism is known to have a large effect on fitness in H. axyridis, this plasticity of melanization may have hastened its spread as an invasive species.

  4. Pedimap: software for the visualization of genetic and phenotypic data in pedigrees.

    PubMed

    Voorrips, Roeland E; Bink, Marco C A M; van de Weg, W Eric

    2012-01-01

    Pedimap is a user-friendly software tool for visualizing phenotypic and genotypic data for related individuals linked in pedigrees. Genetic data can include marker scores, Identity-by-Descent probabilities, and marker linkage map positions, allowing the visualization of haplotypes through lineages. The pedigrees can accommodate all types of inheritance, including selfing, cloning, and repeated backcrossing, and all ploidy levels are supported. Visual association of the genetic data with phenotypic data simplifies the exploration of large data sets, thereby improving breeding decision making. Data are imported from text files; in addition data exchange with other software packages (FlexQTL(TM) and GenomeStudio(TM)) is possible. Instructions for use and an executable version compatible with the Windows platform are available for free from http://www.plantbreeding.wur.nl/UK/software_pedimap.html.

  5. Evolution of elaborate parental care: phenotypic and genetic correlations between parent and offspring traits

    PubMed Central

    Andrews, Clare P.; Kruuk, Loeske E. B.

    2017-01-01

    The evolution of elaborate forms of parental care is an important topic in behavioral ecology, yet the factors shaping the evolution of complex suites of parental and offspring traits are poorly understood. Here, we use a multivariate quantitative genetic approach to study phenotypic and genetic correlations between parental and offspring traits in the burying beetle Nicrophorus vespilloides. To this end, we recorded 2 prenatal traits (clutch size and egg size), 2 postnatal parental behaviors (direct care directed toward larvae and indirect care directed toward resource maintenance), 1 offspring behavior (begging), and 2 measures of breeding success (larval dispersal mass and number of dispersing larvae). Females breeding on larger carcasses provided less direct care but produced larger larvae than females breeding on smaller carcasses. Furthermore, there were positive phenotypic correlations between clutch size, direct, and indirect care. Both egg size and direct care were positively correlated with dispersal mass, whereas clutch size was negatively correlated with dispersal mass. Clutch size and number of dispersed larvae showed genetic variance both in terms of differences between populations of origin and significant heritabilities. However, we found no evidence of genetic variance underlying other parental or offspring traits. Our results suggest that correlations between suites of parental traits are driven by variation in individual quality rather than trade-offs, that some parental traits promote offspring growth while others increase the number of offspring produced, and that parental and offspring traits might respond slowly to selection due to low levels of additive genetic variance. PMID:28127224

  6. Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype.

    PubMed

    Chaston, John M; Dobson, Adam J; Newell, Peter D; Douglas, Angela E

    2015-11-13

    A wealth of studies has demonstrated that resident microorganisms (microbiota) influence the pattern of nutrient allocation to animal protein and energy stores, but it is unclear how the effects of the microbiota interact with other determinants of animal nutrition, including animal genetic factors and diet. Here, we demonstrate that members of the gut microbiota in Drosophila melanogaster mediate the effect of certain animal genetic determinants on an important nutritional trait, triglyceride (lipid) content. Parallel analysis of the taxonomic composition of the associated bacterial community and host nutritional indices (glucose, glycogen, triglyceride, and protein contents) in multiple Drosophila genotypes revealed significant associations between the abundance of certain microbial taxa, especially Acetobacteraceae and Xanthamonadaceae, and host nutritional phenotype. By a genome-wide association study of Drosophila lines colonized with a defined microbiota, multiple host genes were statistically associated with the abundance of one bacterium, Acetobacter tropicalis. Experiments using mutant Drosophila validated the genetic association evidence and reveal that host genetic control of microbiota abundance affects the nutritional status of the flies. These data indicate that the abundance of the resident microbiota is influenced by host genotype, with consequent effects on nutrient allocation patterns, demonstrating that host genetic control of the microbiome contributes to the genotype-phenotype relationship of the animal host.

  7. Genetic diversity in soybean genotypes using phenotypic characters and enzymatic markers.

    PubMed

    Zambiazzi, E V; Bruzi, A T; Sales, A P; Borges, I M M; Guilherme, S R; Zuffo, A M; Lima, J G; Ribeiro, F O; Mendes, A E S; Godinho, S H M; Carvalho, M L M

    2017-09-21

    The objective of this study was to evaluate the genetic diversity of soybean cultivars by adopting phenotypic traits and enzymatic markers, the relative contribution of agronomic traits to diversity, as well as diversity between the level of technology used in soybean cultivars and genetic breeding programs in which cultivars were inserted. The experiments were conducted on the field at the Center for Scientific and Technological Development in crop-livestock production and the Electrophoresis Laboratory of Lavras Federal University. The agronomic traits adopted were grain yield, plant height, first legume insertion, plant lodging, the mass of one thousand seeds, and days for complete maturation, in which the Euclidean distance, grouped by Tocher and UPGMA criteria, was obtained. After electrophorese gels for enzymatic systems, dehydrogenase alcohol, esterase, superoxide dismutase, and peroxidase were performed. The genetic similarity estimative was also obtained between genotypes by the Jaccard coefficient with subsequent grouping by the UPGMA method. The formation of two groups was shown using phenotypic characters in the genetic diversity study and individually discriminating the cultivar 97R73 RR. The character with the greatest contribution to the genetic divergence was grain yield with contribution higher than 90.0%. To obtain six different groups, individually discriminating the cultivars CG 8166 RR, FPS Jupiter RR, and BRS MG 780 RR, enzymatic markers were used. Cultivars carrying the RR technology presented more divergence than conventional cultivars and IPRO cultivars.

  8. Genetic and phenotypic stability of measures of neuroticism over 22 years.

    PubMed

    Wray, Naomi R; Birley, Andrew J; Sullivan, Patrick F; Visscher, Peter M; Martin, Nicholas G

    2007-10-01

    People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this dimension of personality can therefore give insights into the etiology of important psychiatric disorders. Neuroticism can be assessed easily via self-report questionnaires in large population samples. We have examined the genetic and phenotypic stability of neuroticism, measured up to 4 times over 22 years, on different scales, on a data set of 4,999 families with over 20,000 individuals completing at least 1 neuroticism questionnaire. The neuroticism scales used were the Eysenck Personality Questionnaire revised (EPQ-R), the EPQ-R shortened form, and the NEO 5 factor inventory personality questionnaire. The estimates of heritability of the individual measures ranged from .26 +/- .04 to .36 +/- .03. Genetic, environmental, and phenotypic correlations averaged .91, .42, and .57 respectively. Despite the range in heritabilities, a more parsimonious 'repeatability model' of equal additive genetic variances and genetic correlations of unity could not be rejected. Use of multiple measures increases the effective heritability from .33 for a single measure to .43 for mean score because of the reduction in the estimate of the environmental variance, and this will increase power in genetic linkage or association studies of neuroticism.

  9. Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype

    PubMed Central

    Chaston, John M.; Dobson, Adam J.; Newell, Peter D.

    2015-01-01

    A wealth of studies has demonstrated that resident microorganisms (microbiota) influence the pattern of nutrient allocation to animal protein and energy stores, but it is unclear how the effects of the microbiota interact with other determinants of animal nutrition, including animal genetic factors and diet. Here, we demonstrate that members of the gut microbiota in Drosophila melanogaster mediate the effect of certain animal genetic determinants on an important nutritional trait, triglyceride (lipid) content. Parallel analysis of the taxonomic composition of the associated bacterial community and host nutritional indices (glucose, glycogen, triglyceride, and protein contents) in multiple Drosophila genotypes revealed significant associations between the abundance of certain microbial taxa, especially Acetobacteraceae and Xanthamonadaceae, and host nutritional phenotype. By a genome-wide association study of Drosophila lines colonized with a defined microbiota, multiple host genes were statistically associated with the abundance of one bacterium, Acetobacter tropicalis. Experiments using mutant Drosophila validated the genetic association evidence and reveal that host genetic control of microbiota abundance affects the nutritional status of the flies. These data indicate that the abundance of the resident microbiota is influenced by host genotype, with consequent effects on nutrient allocation patterns, demonstrating that host genetic control of the microbiome contributes to the genotype-phenotype relationship of the animal host. PMID:26567306

  10. Phenotypic and genetic associations between reading and attention-deficit/hyperactivity disorder dimensions in adolescence.

    PubMed

    Plourde, Vickie; Boivin, Michel; Brendgen, Mara; Vitaro, Frank; Dionne, Ginette

    2017-10-01

    Multiple studies have shown that reading abilities and attention-deficit/hyperactivity disorder symptoms, mainly inattention symptoms, are phenotypically and genetically associated during childhood. However, few studies have looked at these associations during adolescence to investigate possible developmental changes. The aim of the study is to examine the genetic and environmental etiology of the associations between inattention and hyperactivity reported by parents, and reading accuracy, reading speed, and word reading in a population-based twin sample (Quebec Newborn Twin Study). Participants were between 14 and 15 years of age at the time of testing (N = 668-837). Phenotypic results showed that when nonverbal and verbal abilities were controlled, inattention, but not hyperactivity/impulsivity, was a modest and significant predictor of reading accuracy, reading speed, and word reading. The associations between inattention and all reading abilities were partly explained by genetic and unique environmental factors. However, the genetic correlations were no longer significant after controlling for verbal abilities. In midadolescence, inattention is the attention-deficit/hyperactivity disorder dimension associated with reading abilities, but they could also share genetic factors with general verbal skills.

  11. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).

    PubMed

    Ben-Zvi, Ilan; Brandt, Benny; Berkun, Yackov; Lidar, Merav; Livneh, Avi

    2012-01-10

    Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average. In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. 29 CFR 1635.12 - Medical information that is not genetic information.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... genetic information. (a) Medical information about a manifested disease, disorder, or pathological..., genetic information about a manifested disease, disorder, or pathological condition is subject to the... 29 Labor 4 2014-07-01 2014-07-01 false Medical information that is not genetic information....

  13. 29 CFR 1635.12 - Medical information that is not genetic information.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... genetic information. (a) Medical information about a manifested disease, disorder, or pathological..., genetic information about a manifested disease, disorder, or pathological condition is subject to the... 29 Labor 4 2013-07-01 2013-07-01 false Medical information that is not genetic information....

  14. 29 CFR 1635.12 - Medical information that is not genetic information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... genetic information. (a) Medical information about a manifested disease, disorder, or pathological..., genetic information about a manifested disease, disorder, or pathological condition is subject to the... 29 Labor 4 2012-07-01 2012-07-01 false Medical information that is not genetic information....

  15. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

    PubMed Central

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Øien, Nancy Christine; Schweiger, Michal R.; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E.; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N.

    2015-01-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients’ phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. PMID:25186178

  16. Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

    PubMed Central

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E.; Heath, Emma; Smedley, Damian P.; Estabel, Jeanne; Sunter, David; DiTommaso, Tia; White, Jacqueline K.; Ramirez-Solis, Ramiro; Smyth, Ian; Steel, Karen P.; Watt, Fiona M.

    2014-01-01

    Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. PMID:24721909

  17. Contrasting patterns of genetic and phenotypic differentiation in two invasive salmonids in the southern hemisphere

    PubMed Central

    Monzón-Argüello, Catalina; Consuegra, Sofia; Gajardo, Gonzalo; Marco-Rius, Francisco; Fowler, Daniel M; DeFaveri, Jacquelin; Garcia de Leaniz, Carlos

    2014-01-01

    Invasion success may be expected to increase with residence time (i.e., time since first introduction) and secondary releases (i.e., those that follow the original introduction), but this has rarely been tested in natural fish populations. We compared genetic and phenotypic divergence in rainbow trout and brown trout in Chile and the Falkland Islands to test the prediction that adaptive divergence, measured as PST/FST, would increase with residence time and secondary releases. We also explored whether interspecific competition between invaders could drive phenotypic divergence. Residence time had no significant effect on genetic diversity, phenotypic divergence, effective population size, or signatures of expansion of invasive trout. In contrast, secondary releases had a major effect on trout invasions, and rainbow trout populations mostly affected by aquaculture escapees showed significant divergence from less affected populations. Coexistence with brown trout had a positive effect on phenotypic divergence of rainbow trout. Our results highlight an important role of secondary releases in shaping fish invasions, but do not support the contention that older invaders are more differentiated than younger ones. They also suggest that exotic trout may not have yet developed local adaptations in these recently invaded habitats, at least with respect to growth-related traits. PMID:25469171

  18. Salt Stress Phenotypes in Listeria monocytogenes Vary by Genetic Lineage and Temperature

    PubMed Central

    den Bakker, Henk C.; Fortes, Esther D.; Boor, Kathryn J.; Wiedmann, Martin

    2010-01-01

    Abstract Listeria monocytogenes can survive and grow under wide-ranging environmental stress conditions encountered both in foods and in the host. The ability of certain L. monocytogenes subtypes to thrive under stress conditions present in specific niches was hypothesized to reflect genetic characteristics and phenotypic capabilities conserved among strains within a subtype. To quantify variations in salt stress phenotypes among 40 strains selected to represent the diversity of the three major L. monocytogenes genetic lineages and to determine if salt stress phenotypes were associated with genetic relatedness, we measured growth under salt stress at both 7°C and 37°C. At 7°C, in brain–heart infusion with 6% NaCl, average growth rates among the lineages were similar. A comparison of doubling times after exposure to salt stress at 7°C or 37°C indicated that growth at 7°C provided crossprotection to subsequent salt stress for strains in lineages I and II. At 37°C, in brain–heart infusion with 6% NaCl, lineage I and III strains grew significantly faster (p < 0.0001) than lineage II strains. Under salt stress at 37°C, differences in growth parameters were significantly (p < 0.005) associated with genetic relatedness of the strains. Compatible solute uptake is part of the L. monocytogenes salt stress response, but growth differences between the lineages were not related to differences in transcript levels of osmolyte transporter-encoding genes betL, gbuA, oppA, and opuCA. The combination of phylogenetic and phenotypic data suggests that L. monocytogenes lineage I and III strains, which are most commonly associated with human and animal disease, may be better adapted to osmotic stress at 37°C, conditions that are present in the host gastrointestinal tract. PMID:20707723

  19. Phenotypic Screens Identify Parasite Genetic Factors Associated with Malarial Fever Response in Plasmodium falciparum piggyBac Mutants

    PubMed Central

    Thomas, Phaedra; Sedillo, Jennifer; Oberstaller, Jenna; Li, Suzanne; Zhang, Min; Singh, Naresh; Wang, Chengqi C. Q.; Udenze, Kenneth; Jiang, Rays H. Y.

    2016-01-01

    ABSTRACT Malaria remains one of the most devastating parasitic diseases worldwide, with 90% of the malaria deaths in Africa in 2013 attributable to Plasmodium falciparum. The clinical symptoms of malaria include cycles of fever, corresponding to parasite rupture from red blood cells every 48 h. Parasite pathways involved in the parasite’s ability to survive the host fever response, and indeed, the functions of ~40% of P. falciparum genes as a whole, are still largely unknown. Here, we evaluated the potential of scalable forward-genetic screening methods to identify genes involved in the host fever response. We performed a phenotypic screen for genes linked to the parasite response to febrile temperatures by utilizing a selection of single-disruption P. falciparum mutants generated via random piggyBac transposon mutagenesis in a previous study. We identified several mutants presenting significant phenotypes in febrile response screens compared to the wild type, indicating possible roles for the disrupted genes in this process. We present these initial studies as proof that forward genetics can be used to gain insight into critical factors associated with parasite biology. IMPORTANCE Though the P. falciparum genome sequence has been available for many years, ~40% of its genes do not have informative annotations, as they show no detectable homology to those of studied organisms. More still have not been evaluated via genetic methods. Scalable forward-genetic approaches that allow interrogation of gene function without any pre-existing knowledge are needed to hasten understanding of parasite biology, which will expedite the identification of drug targets and the development of future interventions in the face of spreading resistance to existing frontline drugs. In this work, we describe a new approach to pursue forward-genetic phenotypic screens for P. falciparum to identify factors associated with virulence. Future large-scale phenotypic screens developed to

  20. Measures for interoperability of phenotypic data: minimum information requirements and formatting.

    PubMed

    Ćwiek-Kupczyńska, Hanna; Altmann, Thomas; Arend, Daniel; Arnaud, Elizabeth; Chen, Dijun; Cornut, Guillaume; Fiorani, Fabio; Frohmberg, Wojciech; Junker, Astrid; Klukas, Christian; Lange, Matthias; Mazurek, Cezary; Nafissi, Anahita; Neveu, Pascal; van Oeveren, Jan; Pommier, Cyril; Poorter, Hendrik; Rocca-Serra, Philippe; Sansone, Susanna-Assunta; Scholz, Uwe; van Schriek, Marco; Seren, Ümit; Usadel, Björn; Weise, Stephan; Kersey, Paul; Krajewski, Paweł

    2016-01-01

    Plant phenotypic data shrouds a wealth of information which, when accurately analysed and linked to other data types, brings to light the knowledge about the mechanisms of life. As phenotyping is a field of research comprising manifold, diverse and time-consuming experiments, the findings can be fostered by reusing and combining existing datasets. Their correct interpretation, and thus replicability, comparability and interoperability, is possible provided that the collected observations are equipped with an adequate set of metadata. So far there have been no common standards governing phenotypic data description, which hampered data exchange and reuse. In this paper we propose the guidelines for proper handling of the information about plant phenotyping experiments, in terms of both the recommended content of the description and its formatting. We provide a document called "Minimum Information About a Plant Phenotyping Experiment", which specifies what information about each experiment should be given, and a Phenotyping Configuration for the ISA-Tab format, which allows to practically organise this information within a dataset. We provide examples of ISA-Tab-formatted phenotypic data, and a general description of a few systems where the recommendations have been implemented. Acceptance of the rules described in this paper by the plant phenotyping community will help to achieve findable, accessible, interoperable and reusable data.

  1. Data from a survey of Clostridium perfringens and Clostridium difficile shedding by dogs and cats in the Madrid region (Spain), including phenotypic and genetic characteristics of recovered isolates.

    PubMed

    Álvarez-Pérez, Sergio; Blanco, José L; Harmanus, Celine; Kuijper, Ed J; García, Marta E

    2017-10-01

    This article contains information related to a recent survey of the prevalence of fecal shedding of Clostridium perfringens and C. difficile by dogs and cats attended in veterinary clinics located in the Madrid region (Spain). Specifically, we provide detailed information about the clinics that participated in the survey, the demographic and clinic characteristics of recruited animals and the genetic and phenotypic characteristics (including antimicrobial susceptibility data), of recovered bacterial isolates.

  2. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification

    PubMed Central

    Bezerra, Ana R.; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G.; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R.; Santos, Manuel A. S.

    2013-01-01

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research. PMID:23776239

  3. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification.

    PubMed

    Bezerra, Ana R; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R; Santos, Manuel A S

    2013-07-02

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.

  4. Structural mapping: how to study the genetic architecture of a phenotypic trait through its formation mechanism.

    PubMed

    Tong, Chunfa; Shen, Lianying; Lv, Yafei; Wang, Zhong; Wang, Xiaoling; Feng, Sisi; Li, Xin; Sui, Yihan; Pang, Xiaoming; Wu, Rongling

    2014-01-01

    Traditional approaches for genetic mapping are to simply associate the genotypes of a quantitative trait locus (QTL) with the phenotypic variation of a complex trait. A more mechanistic strategy has emerged to dissect the trait phenotype into its structural components and map specific QTLs that control the mechanistic and structural formation of a complex trait. We describe and assess such a strategy, called structural mapping, by integrating the internal structural basis of trait formation into a QTL mapping framework. Electrical impedance spectroscopy (EIS) has been instrumental for describing the structural components of a phenotypic trait and their interactions. By building robust mathematical models on circuit EIS data and embedding these models within a mixture model-based likelihood for QTL mapping, structural mapping implements the EM algorithm to obtain maximum likelihood estimates of QTL genotype-specific EIS parameters. The uniqueness of structural mapping is to make it possible to test a number of hypotheses about the pattern of the genetic control of structural components. We validated structural mapping by analyzing an EIS data collected for QTL mapping of frost hardiness in a controlled cross of jujube trees. The statistical properties of parameter estimates were examined by simulation studies. Structural mapping can be a powerful alternative for genetic mapping of complex traits by taking account into the biological and physical mechanisms underlying their formation.

  5. Genetic variation for phenotypically invariant traits detected in teosinte: implications for the evolution of novel forms.

    PubMed

    Lauter, Nick; Doebley, John

    2002-01-01

    How new discrete states of morphological traits evolve is poorly understood. One possibility is that single-gene changes underlie the evolution of new discrete character states and that evolution is dependent on the occurrence of new single-gene mutations. Another possibility is that multiple-gene changes are required to elevate an individual or population above a threshold required to produce the new character state. A prediction of the latter model is that genetic variation for the traits should exist in natural populations in the absence of phenotypic variation. To test this idea, we studied traits that are phenotypically invariant within teosinte and for which teosinte is discretely different from its near relative, maize. By employing a QTL mapping strategy to analyze the progeny of a testcross between an F(1) of two teosintes and a maize inbred line, we identified cryptic genetic variation in teosinte for traits that are invariant in teosinte. We argue that such cryptic genetic variation can contribute to the evolution of novelty when reconfigured to exceed the threshold necessary for phenotypic expression or by acting to modify or stabilize the effects of major mutations.

  6. Bioclimatic, ecological, and phenotypic intermediacy and high genetic admixture in a natural hybrid of octoploid strawberries.

    PubMed

    Salamone, Isabella; Govindarajulu, Rajanikanth; Falk, Stacey; Parks, Matthew; Liston, Aaron; Ashman, Tia-Lynn

    2013-05-01

    Hybrid zones provide "natural laboratories" for understanding the processes of selection, reinforcement, and speciation. We sought to gain insight into the degree of introgression and the extent of ecological-phenotypic intermediacy in the natural hybrid strawberry, Fragaria × ananassa subsp. cuneifolia. • We used whole-plastome sequencing to identify parental species-specific (Fragaria chiloensis and F. virginiana) chloroplast single-nucleotide polymorphisms and combined the use of these with nuclear microsatellite markers to genetically characterize the hybrid zone. We assessed the potential role of selection in the observed geographic patterns by bioclimatically characterizing the niche of the hybrid populations and phenotypically characterizing hybrid individuals of known genomic constitution. • Significant admixture and little overall maternal bias in chloroplast or nuclear genomes suggest a high degree of interfertility among the parental and hybrid species and point to a long history of backcrossing and genetic mixing in the hybrid zone. Even though hybrids were phenotypically intermediate to the parental species, there was a discernible fingerprint of the parental genotype within hybrid individuals. Thus, although the pattern of introgression observed suggests geographic limitations to gene flow, it may be reinforced by selection for specific parental traits in the bioclimatically intermediate habitat occupied by the hybrid. • This work uncovered the genetic complexity underlying the hybrid zone of the wild relatives of the cultivated strawberry. It lays the foundation for experimental dissection of the causes of genomic introgression and nuclear-cytoplasmic disassociation, and for understanding other parts of Fragaria evolutionary history.

  7. Estimate of genetic gain in popcorn after cycles of phenotypic recurrent selection.

    PubMed

    Ematné, H J; Nunes, J A R; Dias, K O G; Prado, P E R; Souza, J C

    2016-05-20

    Popcorn is widely consumed in Brazil, yet there are few breeding programs for this crop. Recurrent selection (RS) is a viable breeding alternative for popcorn; however, the gains achieved must be frequently checked. The aim of this study was to assess the effect of selection for grain type (round and pointed) after four cycles of phenotypic RS on the main agronomic traits of popcorn, to estimate the genetic gain achieved for the trait of expansion volume (EV), and to obtain estimates of phenotypic correlations for the main traits of the crop in the UFLA E and UFLA R populations. The zero, one, two, and three cycles of the UFLA E and UFLA R populations, the fourth cycle, and the controls IAC-112 and IAC-125 were used. The experiments were conducted at the experimental farm of Universidade Federal de Lavras (UFLA; Environment 1) and at the experimental area of the Genetics and Plant Breeding Sector of the Department of Biology at UFLA (Environment 2) in the 2010/11 crop season. Nine agronomic traits were evaluated, including EV and grain yield (GY). The UFLA R and UFLA E populations showed similar behavior for all evaluated traits. The type of grain did not affect the genetic gain for EV, which was 5 and 3.7% in each cycle carried out in the UFLA E and UFLA R population, respectively. Phenotypic selection carried out during recombination for EV is an effective method for increasing expression of the trait. EV and GY did not show a linear association.

  8. Distinct subspecies or phenotypic plasticity? Genetic and morphological differentiation of mountain honey bees in East Africa

    PubMed Central

    Gruber, Karl; Schöning, Caspar; Otte, Marianne; Kinuthia, Wanja; Hasselmann, Martin

    2013-01-01

    Identifying the forces shaping intraspecific phenotypic and genotypic divergence are of key importance in evolutionary biology. Phenotypic divergence may result from local adaptation or, especially in species with strong gene flow, from pronounced phenotypic plasticity. Here, we examine morphological and genetic divergence among populations of the western honey bee Apis mellifera in the topographically heterogeneous East African region. The currently accepted “mountain refugia hypothesis” states that populations living in disjunct montane forests belong to a different lineage than those in savanna habitats surrounding these forests. We obtained microsatellite data, mitochondrial sequences, and morphometric data from worker honey bees collected from feral colonies in three montane forests and corresponding neighboring savanna regions in Kenya. Honey bee colonies from montane forests showed distinct worker morphology compared with colonies in savanna areas. Mitochondrial sequence data did not support the existence of the two currently accepted subspecies. Furthermore, analyses of the microsatellite data with a Bayesian clustering method did not support the existence of two source populations as it would be expected under the mountain refugia scenario. Our findings suggest that phenotypic plasticity rather than distinct ancestry is the leading cause behind the phenotypic divergence observed between montane forest and savanna honey bees. Our study thus corroborates the idea that high gene flow may select for increased plasticity. PMID:24223262

  9. The evolution of interacting phenotypes: genetics and evolution of social dominance.

    PubMed

    Moore, Allen J; Haynes, Kenneth F; Preziosi, Richard F; Moore, Patricia J

    2002-12-01

    Although the argument over genetic influences on social dominance is contentious, genetic models of interacting phenotypes provide a theoretical framework for heritable effects on, and therefore evolution of, social behavior. Here we adapt the interacting phenotype model to show how social dominance can evolve. Our model makes a number of predictions: rapid evolution of behavior, strong correlated responses in associated traits (such as a badge of status), and, because context is important for social dominance, integrated evolution of both dominant and subordinate behavior reflecting direct and indirect genetic effects and social selection. We also describe the results of empirical work, artificial selection based on social status within a hierarchy in the cockroach Nauphoeta cinerea, that we used to test the predictions of our model. There was little change within selection lines in the expression of agonistic behavior, but by just generation 7 of selection, in comparisons between lines, high-line males consistently dominated low and control males, while low-line males were consistently subordinate to high-line and control males. There was a strong correlated response to selection in the pheromonal badge of status. Some correlated responses to selection differed among replicate lines, with the compound that makes males subordinate changed in one replicate, while the compound that confers dominance was altered in the other. Overall, our results are consistent with predictions from models of interacting phenotypes: social dominance is influenced by additive genetic variation, can evolve as a result of social selection, and evolution of social interactions appears to be rapid. Finally, different responses in the replicates allowed us to test very specific predictions regarding the role of the social pheromone in N. cinerea, highlighting the value of artificial selection experiments as a tool in evolutionary behavioral genetic studies.

  10. Local versus Generalized Phenotypes in Two Sympatric Aurelia Species: Understanding Jellyfish Ecology Using Genetics and Morphometrics.

    PubMed

    Chiaverano, Luciano M; Bayha, Keith W; Graham, William M

    2016-01-01

    For individuals living in environmentally heterogeneous environments, a key component for adaptation and persistence is the extent of phenotypic differentiation in response to local environmental conditions. In order to determine the extent of environmentally induced morphological variation in a natural population distributed along environmental gradients, it is necessary to account for potential genetic differences contributing to morphological differentiation. In this study, we set out to quantify geographic morphological variation in the moon jellyfish Aurelia exposed at the extremes of a latitudinal environmental gradient in the Gulf of Mexico (GoM). We used morphological data based on 28 characters, and genetic data taken from mitochondrial cytochrome oxidase I (COI) and nuclear internal transcribed spacer 1 (ITS-1). Molecular analyses revealed the presence of two genetically distinct species of Aurelia co-occurring in the GoM: Aurelia sp. 9 and Aurelia c.f. sp. 2, named for its divergence from (for COI) and similarity to (for ITS-1) Aurelia sp. 2 (Brazil). Neither species exhibited significant population genetic structure between the Northern and the Southeastern Gulf of Mexico; however, they differed greatly in the degree of geographic morphological variation. The morphology of Aurelia sp. 9 exhibited ecophenotypic plasticity and varied significantly between locations, while morphology of Aurelia c.f. sp. 2 was geographically invariant (i.e., canalized). The plastic, generalist medusae of Aurelia sp. 9 are likely able to produce environmentally-induced, "optimal" phenotypes that confer high relative fitness in different environments. In contrast, the non-plastic generalist individuals of Aurelia c.f. sp. 2 likely produce environmentally-independent phenotypes that provide the highest fitness across environments. These findings suggest the two Aurelia lineages co-occurring in the GoM were likely exposed to different past environmental conditions (i

  11. Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility.

    PubMed

    Cole, J B; Null, D J; VanRaden, P M

    2016-09-01

    Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of 18 recessive haplotypes in Ayrshire (n=1), Brown Swiss (n=5), Holstein (n=10), and Jersey (n=2) cattle on milk, fat, and protein yields, somatic cell score (SCS), single-trait productive life (PL), daughter pregnancy rate (DPR), heifer conception rate (HCR), and cow conception rate (CCR). The haplotypes evaluated were Ayrshire haplotype 1, Brown Swiss haplotypes 1 and 2, spinal dysmyelination, spinal muscular atrophy, Weaver Syndrome, brachyspina, Holstein cholesterol deficiency, Holstein haplotypes 1 to 5, bovine leukocyte adhesion deficiency, complex vertebral malformation, mulefoot (syndactyly), and Jersey haplotypes 1 and 2. When causal variants are unknown and tests are based only on single nucleotide polymorphism haplotypes, it can sometimes be difficult to accurately determine carrier status. For example, 2 Holstein haplotypes for cholesterol deficiency have the same single nucleotide polymorphism genotype, but only one of them carries the causative mutation. Genotyped daughters of carrier bulls included in the analysis ranged from 8 for Weaver Syndrome to 17,869 for Holstein haplotype 3. Lactation records preadjusted for nongenetic factors and direct genomic values (DGV) were used to estimate phenotypic and genetic effects of recessive haplotypes, respectively. We found no phenotypic or genetic differences between carriers and noncarriers of Ayrshire or Brown Swiss defects. Several associations were noted for Holstein haplotypes, including fat and HCR for Holstein haplotype 0 carriers; milk, protein, SCS, PL, and fertility for Holstein haplotype 1; protein, PL, CCR, and HCR for Holstein haplotype 2; milk, protein, and fertility for Holstein haplotype 4; and protein yield and DPR for Holstein haplotype 5. There were no differences among bovine leukocyte adhesion deficiency carriers, but complex vertebral malformation affected fat yield and mulefoot

  12. Uncertainty in the Information Provided during Genetic Counseling.

    ERIC Educational Resources Information Center

    van Zuuren, F. J.; van Schie, E. C. M.; van Baaren, N. K.

    1997-01-01

    Clients seek genetic counseling to become informed, make better decisions, and to be reassured. Genetic knowledge, however, involves uncertainty. Genetic information conveyed in 30 counseling sessions was studied for its predictability, controllability and novelty (unexpected findings). The interrelationship of unpredictability, uncontrollability,…

  13. Information capacity of genetic regulatory elements

    NASA Astrophysics Data System (ADS)

    Tkačik, Gašper; Callan, Curtis G., Jr.; Bialek, William

    2008-07-01

    Changes in a cell’s external or internal conditions are usually reflected in the concentrations of the relevant transcription factors. These proteins in turn modulate the expression levels of the genes under their control and sometimes need to perform nontrivial computations that integrate several inputs and affect multiple genes. At the same time, the activities of the regulated genes would fluctuate even if the inputs were held fixed, as a consequence of the intrinsic noise in the system, and such noise must fundamentally limit the reliability of any genetic computation. Here we use information theory to formalize the notion of information transmission in simple genetic regulatory elements in the presence of physically realistic noise sources. The dependence of this “channel capacity” on noise parameters, cooperativity and cost of making signaling molecules is explored systematically. We find that, in the range of parameters probed by recent in vivo measurements, capacities higher than one bit should be achievable. It is of course generally accepted that gene regulatory elements must, in order to function properly, have a capacity of at least one bit. The central point of our analysis is the demonstration that simple physical models of noisy gene transcription, with realistic parameters, can indeed achieve this capacity: it was not self-evident that this should be so. We also demonstrate that capacities significantly greater than one bit are possible, so that transcriptional regulation need not be limited to simple “on-off” components. The question whether real systems actually exploit this richer possibility is beyond the scope of this investigation.

  14. The distribution of genetic variance across phenotypic space and the response to selection.

    PubMed

    Blows, Mark W; McGuigan, Katrina

    2015-05-01

    The role of adaptation in biological invasions will depend on the availability of genetic variation for traits under selection in the new environment. Although genetic variation is present for most traits in most populations, selection is expected to act on combinations of traits, not individual traits in isolation. The distribution of genetic variance across trait combinations can be characterized by the empirical spectral distribution of the genetic variance-covariance (G) matrix. Empirical spectral distributions of G from a range of trait types and taxa all exhibit a characteristic shape; some trait combinations have large levels of genetic variance, while others have very little genetic variance. In this study, we review what is known about the empirical spectral distribution of G and show how it predicts the response to selection across phenotypic space. In particular, trait combinations that form a nearly null genetic subspace with little genetic variance respond only inconsistently to selection. We go on to set out a framework for understanding how the empirical spectral distribution of G may differ from the random expectations that have been developed under random matrix theory (RMT). Using a data set containing a large number of gene expression traits, we illustrate how hypotheses concerning the distribution of multivariate genetic variance can be tested using RMT methods. We suggest that the relative alignment between novel selection pressures during invasion and the nearly null genetic subspace is likely to be an important component of the success or failure of invasion, and for the likelihood of rapid adaptation in small populations in general.

  15. Genetic structure of a foundation species: scaling community phenotypes from the individual to the region.

    PubMed

    Bangert, R K; Lonsdorf, E V; Wimp, G M; Shuster, S M; Fischer, D; Schweitzer, J A; Allan, G J; Bailey, J K; Whitham, T G

    2008-02-01

    Understanding the local and regional patterns of species distributions has been a major goal of ecological and evolutionary research. The notion that these patterns can be understood through simple quantitative rules is attractive, but while numerous scaling laws exist (e.g., metabolic, fractals), we are aware of no studies that have placed individual traits and community structure together within a genetics based scaling framework. We document the potential for a genetic basis to the scaling of ecological communities, largely based upon our long-term studies of poplars (Populus spp.). The genetic structure and diversity of these foundation species affects riparian ecosystems and determines a much larger community of dependent organisms. Three examples illustrate these ideas. First, there is a strong genetic basis to phytochemistry and tree architecture (both above- and belowground), which can affect diverse organisms and ecosystem processes. Second, empirical studies in the wild show that the local patterns of genetics based community structure scale up to western North America. At multiple spatial scales the arthropod community phenotype is related to the genetic distance among plants that these arthropods depend upon for survival. Third, we suggest that the familiar species-area curve, in which species richness is a function of area, is also a function of genetic diversity. We find that arthropod species richness is closely correlated with the genetic marker diversity and trait variance suggesting a genetic component to these curves. Finally, we discuss how genetic variation can interact with environmental variation to affect community attributes across geographic scales along with conservation implications.

  16. Egg shell quality in Japanese quail: characteristics, heritabilities and genetic and phenotypic relationships.

    PubMed

    Narinc, D; Aygun, A; Karaman, E; Aksoy, T

    2015-07-01

    The objective of the present study was to estimate heritabilities as well as genetic and phenotypic correlations for egg weight, specific gravity, shape index, shell ratio, egg shell strength, egg length, egg width and shell weight in Japanese quail eggs. External egg quality traits were measured on 5864 eggs of 934 female quails from a dam line selected for two generations. Within the Bayesian framework, using Gibbs Sampling algorithm, a multivariate animal model was applied to estimate heritabilities and genetic correlations for external egg quality traits. The heritability estimates for external egg quality traits were moderate to high and ranged from 0.29 to 0.81. The heritability estimates for egg and shell weight of 0.81 and 0.76 were fairly high. The genetic and phenotypic correlations between egg shell strength with specific gravity, shell ratio and shell weight ranging from 0.55 to 0.79 were relatively high. It can be concluded that it is possible to determine egg shell quality using the egg specific gravity values utilizing its high heritability and fairly high positive correlation with most of the egg shell quality traits. As a result, egg specific gravity may be the choice of selection criterion rather than other external egg traits for genetic improvement of egg shell quality in Japanese quails.

  17. Genetic assimilation and the postcolonization erosion of phenotypic plasticity in island tiger snakes.

    PubMed

    Aubret, Fabien; Shine, Richard

    2009-12-01

    In 1942, C.H. Waddington [1] suggested that colonizing populations could initially succeed by flexibly altering their characteristics (phenotypic plasticity; [2-4]) in fitness-inducing traits, but selective forces would rapidly eliminate that plasticity to result in a canalized trait [1, 5, 6]. Waddington termed this process "genetic assimilation"[1, 7]. Despite the potential importance of genetic assimilation to evolutionary changes in founder populations [8-10], empirical evidence on this topic is rare, possibly because it happens on short timescales and is therefore difficult to detect except under unusual circumstances [11, 12]. We exploited a mosaic of snake populations isolated (or introduced) on islands from less than 30 years ago to more than 9000 years ago and exposed to selection for increased head size (i.e., ability to ingest large prey [13-16]). Here we show that a larger head size is achieved by plasticity in "young" populations and by genetic canalization in "older" populations. Island tiger snakes (Notechis scutatus) thus show clear empirical evidence of genetic assimilation, with the elaboration of an adaptive trait shifting from phenotypically plastic expression through to canalization within a few thousand years.

  18. Prevalence, heritability and genetic correlations of congenital sensorineural deafness and pigmentation phenotypes in the Border Collie.

    PubMed

    De Risio, Luisa; Lewis, Tom; Freeman, Julia; de Stefani, Alberta; Matiasek, Lara; Blott, Sarah

    2011-06-01

    The objectives of this study were to estimate prevalence, heritability and genetic correlations of congenital sensorineural deafness (CSD) and pigmentation phenotypes in the Border Collie. Entire litters of Border Collies that presented to the Animal Health Trust (1994-2008) for assessment of hearing status by brain stem auditory evoked response (BAER) at 4-10 weeks of age were included. Heritability and genetic correlations were estimated using residual maximum likelihood (REML). Of 4143 puppies that met the inclusion criteria, 97.6% had normal hearing status, 2.0% were unilaterally deaf and 0.4% were bilaterally deaf. Heritability of deafness as a trichotomous trait (normal/unilaterally deaf/bilaterally deaf) was estimated at 0.42 using multivariate analysis. Genetic correlations of deafness with iris colour and merle coat colour were 0.58 and 0.26, respectively. These results indicate that there is a significant genetic effect on CSD in Border Collies and that some of the genes determining deafness also influence pigmentation phenotypes.

  19. Recent developments in statistical methods for detecting genetic loci affecting phenotypic variability.

    PubMed

    Rönnegård, Lars; Valdar, William

    2012-07-24

    A number of recent works have introduced statistical methods for detecting genetic loci that affect phenotypic variability, which we refer to as variability-controlling quantitative trait loci (vQTL). These are genetic variants whose allelic state predicts how much phenotype values will vary about their expected means. Such loci are of great potential interest in both human and non-human genetic studies, one reason being that a detected vQTL could represent a previously undetected interaction with other genes or environmental factors. The simultaneous publication of these new methods in different journals has in many cases precluded opportunity for comparison. We survey some of these methods, the respective trade-offs they imply, and the connections between them. The methods fall into three main groups: classical non-parametric, fully parametric, and semi-parametric two-stage approximations. Choosing between alternatives involves balancing the need for robustness, flexibility, and speed. For each method, we identify important assumptions and limitations, including those of practical importance, such as their scope for including covariates and random effects. We show in simulations that both parametric methods and their semi-parametric approximations can give elevated false positive rates when they ignore mean-variance relationships intrinsic to the data generation process. We conclude that choice of method depends on the trait distribution, the need to include non-genetic covariates, and the population size and structure, coupled with a critical evaluation of how these fit with the assumptions of the statistical model.

  20. Genetic and virulence-phenotype characterization of serotypes 2 and 9 of Streptococcus suis swine isolates.

    PubMed

    Blume, Verena; Luque, Inmaculada; Vela, Ana I; Borge, Carmen; Maldonado, Alfonso; Domínguez, Lucas; Tarradas, Carmen; Fernández-Garayzábal, José F

    2009-09-01

    The aim of this study was to analyze the genetic characteristics and virulence phenotypes of Streptococcus suis, specifically, in clinical isolates of serotypes 2 and 9 (n = 195), obtained from diverse geographical areas across Spain. Pulsed-field gel electrophoresis (PFGE) typing identified 97 genetic profiles, 68% of which were represented by single isolates, indicative of a substantial genetic diversity among the S. suis isolates analyzed. Five PFGE profiles accounted for 33.3% of the isolates and were isolated from 38% of the herds in nine different provinces, indicative of the bacterium's widespread distribution in the Spanish swine population. Representative isolates of the most prevalent PFGE profiles of both serotypes were subjected to multilocus sequence typing (MLST) analysis. The results indicated that serotypes 2 and 9 have distinct genetic backgrounds. Serotype 2 isolates belong to the ST1 complex, a highly successful clone that has spread over most European countries. In accordance with isolates of this complex, most serotype 2 isolates also expressed the phenotype MRP(+)EF(+)SLY(+). Serotype 9 isolates belong to the ST61 complex, which is distantly related to the widespread European ST87 clone. Also, in contrast to most isolates of the European ST87 clone, which express the large variant MRP*, the majority of serotype 9 isolates (97.9%) did not express the protein.

  1. Speciation in the highlands of Mexico: genetic and phenotypic divergence in the Mexican jay (Aphelocoma ultramarina).

    PubMed

    McCormack, J E; Peterson, A T; Bonaccorso, E; Smith, T B

    2008-05-01

    The pine-oak woodlands of the Mexican highlands harbour significant biological diversity, yet little is known about the evolutionary history of organisms inhabiting this region. We assessed genetic and phenotypic differentiation in 482 individuals representing 27 populations of the Mexican jay (Aphelocoma ultramarina) - a widespread bird species of the Mexican highlands - to test whether populations in the central and northern Mexican sierras display discrete breaks between groups, which would be consistent with a role for the different mountain chains in divergence and speciation. We found abrupt breaks in mitochondrial DNA (mtDNA; ND2 and control region) delineating four major genetic groups found in the Sierra Madre Occidental, Sierra Madre Oriental, southern Central Plateau (Bajio), and Transvolcanic Belt. These mtDNA groups were largely corroborated by data from nuclear microsatellites and phenotypic data, except that clades from the Central Plateau and Sierra Madre Oriental showed clinal change in these data sets. Uncertainty about the mutation rate for our mitochondrial markers warrants considerable caution with regard to estimating divergence times, but the major genetic groups appear to have split before the most extreme period of glacial cycling that marked the last 0.7 million years and after Mexico's period of major mountain formation. The fact that some genetic breaks do not coincide with well-known geographic barriers suggests a role for ecology in divergence and speciation, and we discuss implications for taxonomy and conservation.

  2. Discovering Pair-Wise Genetic Interactions: An Information Theory-Based Approach

    PubMed Central

    Ignac, Tomasz M.; Skupin, Alexander; Sakhanenko, Nikita A.; Galas, David J.

    2014-01-01

    Phenotypic variation, including that which underlies health and disease in humans, results in part from multiple interactions among both genetic variation and environmental factors. While diseases or phenotypes caused by single gene variants can be identified by established association methods and family-based approaches, complex phenotypic traits resulting from multi-gene interactions remain very difficult to characterize. Here we describe a new method based on information theory, and demonstrate how it improves on previous approaches to identifying genetic interactions, including both synthetic and modifier kinds of interactions. We apply our measure, called interaction distance, to previously analyzed data sets of yeast sporulation efficiency, lipid related mouse data and several human disease models to characterize the method. We show how the interaction distance can reveal novel gene interaction candidates in experimental and simulated data sets, and outperforms other measures in several circumstances. The method also allows us to optimize case/control sample composition for clinical studies. PMID:24670935

  3. Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

    PubMed

    Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Robert D; Chapman, Sherita N; Cole, John W; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J; Kleindorfer, Dawn O; Labovitz, Daniel L; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S; McArdle, Patrick F; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M; Rhodes, David; Rich, Stephen S; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M; Rundek, Tatjana; Sacco, Ralph L; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B; Meschia, James F

    2014-12-01

    NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke. © 2014 American Heart Association, Inc.

  4. Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer.

    PubMed

    Capela, Carlos; Dossou, Ange Dodji; Silva-Gomes, Rita; Sopoh, Ghislain Emmanuel; Makoutode, Michel; Menino, João Filipe; Fraga, Alexandra Gabriel; Cunha, Cristina; Carvalho, Agostinho; Rodrigues, Fernando; Pedrosa, Jorge

    2016-04-01

    Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.

  5. [Angelman syndrome: physical characteristics and behavioural phenotype in 37 patients with confirmed genetic diagnosis].

    PubMed

    Galván-Manso, M; Campistol, J; Monros, E; Póo, P; Vernet, A M; Pineda, M; Sans, A; Colomer, J; Conill, J J; Sanmartí, F X

    Angelman syndrome (AS) is characterised by mental retardation, ataxic gait, epilepsy, absence of language and a special series of physical traits behavioural phenotype. Its incidence is estimated as one in every 20,000 individuals. On the basis of discoveries made in molecular biology, patients can be classified as belonging to five types: deletion, paternal uniparental disomy (UPD), imprinting defects, mutation of the UBE3A ubiquitin protein ligase gene and unidentified mechanism (15% 20% of patients). Some studies report significant correlations between the phenotype and the genetic cause. We reviewed, retrospectively, 37 patients suffering from AS with a positive genetic study and who had been controlled for at least two years in the Neurological Service at the Hospital Sant Joan de D u. Data was collected on physical characteristics, behavioural phenotype, type of communication, sleep disorders and the medication they needed, as well as epilepsy, start age, types of seizures, medication, schooling and social integration. 87% of cases were due to de novo deletion, 8% were caused by UPD, and 5% had their origins in imprinting defects. The average age of diagnosis was 6.5 years. The sleep disorders present in 48% of the patients required medication in 67% of cases, and 95% presented epilepsy. The most frequent seizures were myoclonic, tonic clonic and atonic. The electroencephalogram (EEG) was the characteristic found in the AS in 68%. The most effective treatment was afforded by valproate and clonazepam. As regards the phenotype, no differences were found according to the genetic alteration. The most effective treatment for the sleep disorders was melatonin. Epilepsy was an almost constant finding in our series, as was cognitive affectation. Lastly, it must be pointed out that educational and socio occupational integration is difficult for patients suffering from AS.

  6. Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer

    PubMed Central

    Capela, Carlos; Dossou, Ange Dodji; Silva-Gomes, Rita; Sopoh, Ghislain Emmanuel; Makoutode, Michel; Menino, João Filipe; Fraga, Alexandra Gabriel; Cunha, Cristina; Carvalho, Agostinho; Rodrigues, Fernando; Pedrosa, Jorge

    2016-01-01

    Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes. PMID:27128681

  7. Genetic and phenotypic parameters for carcass and meat quality traits in commercial crossbred pigs.

    PubMed

    Miar, Y; Plastow, G S; Moore, S S; Manafiazar, G; Charagu, P; Kemp, R A; Van Haandel, B; Huisman, A E; Zhang, C Y; McKay, R M; Bruce, H L; Wang, Z

    2014-07-01

    Pork quality and carcass characteristics are now being integrated into swine breeding objectives because of their economic value. Understanding the genetic basis for these traits is necessary for this to be accomplished. The objective of this study was to estimate phenotypic and genetic parameters for carcass and meat quality traits in 2 Canadian swine populations. Data from a genomic selection study aimed at improving meat quality with a mating system involving hybrid Landrace × Large White and Duroc pigs were used to estimate heritabilities and phenotypic and genetic correlations among them. Data on 2,100 commercial crossbred pigs for meat quality and carcass traits were recorded with pedigrees compromising 9,439 animals over 15 generations. Significant fixed effects (company, sex, and slaughter batch), covariates (cold carcass weight and slaughter age), and random additive and common litter effects were fitted in the models. A series of pairwise bivariate analyses were implemented in ASReml to estimate phenotypic and genetic parameters. Heritability estimates (±SE) for carcass traits were moderate to high and ranged from 0.22 ± 0.08 for longissimus dorsi muscle area to 0.63 ± 0.04 for trimmed ham weight, except for firmness, which was low. Heritability estimates (±SE) for meat quality traits varied from 0.10 ± 0.04 to 0.39 ± 0.06 for the Minolta b* of ham quadriceps femoris muscle and shear force, respectively. Generally, most of the genetic correlations were significant (P < 0.05) and ranged from low (0.18 ± 0.07) to high (-0.97 ± 0.35). There were high negative genetic correlations between drip loss with pH and shear force and a positive correlation with cooking loss. Genetic correlations between carcass weight (both hot and cold) with carcass marbling were highly positive. It was concluded that selection for increasing primal and subprimal cut weights with better pork quality may be possible. Furthermore, the use of pH is confirmed as an indicator

  8. Regulating genetic information--exploring the options in legal theory.

    PubMed

    2014-12-01

    Ground-breaking genetic discoveries and technological advances have introduced a new world of genetic exploration, and technological advances have facilitated the discovery of the genetic basis of a myriad of diseases. Genetic testing promises to potentially revolutionise health care and offer the potential ofpersonalised medicine. Genetic technology may also offer the means to detect potential future disabilities. In light of rapid advances in genetic science and technology, questions arise as to whether an appropriate framework exists to protect the interests of individuals, prevent the misuse of genetic information by interested third parties, and also to encourage further advances in genetic science. In consideration of rapidly advancing genetic technologies and the ethical and legal concerns that arise, this article examines the regulation of genetic information, primarily from a theoretical perspective. It explores the preferable mode of regulation and choice of regulatory frameworks in legal theory, including non-discrimination, privacy and property.

  9. [Modern evolutional developmental biology: mechanical and molecular genetic or phenotypic approaches?].

    PubMed

    Vorob'eva, É I

    2010-01-01

    Heightened interest in the evolutionary problems of developmental biology in the 1980s was due to the success of molecular genetics and disappointment in the synthetic theory of evolution, where the chapters of embryology and developmental biology seem to have been left out. Modern evo-devo, which turned out to be antipodean to the methodology of the synthetic theory of evolution, propagandized in the development of evolutionary problems only the mechanical and molecular genetic approach to the evolution of ontogenesis, based on cellular and intercellular interactions. The phonotypical approach to the evaluation of evolutionary occurrences in ontogenesis, which aids in the joining of the genetic and epigenetic levels of research, the theory of natural selection, the nomogenetic conception, and the problem of the wholeness of the organism in onto- and phylogenesis may be against this. The phenotypic approach to ontogenesis is methodologically the most perspective for evolutionary developmental biology.

  10. Natural Genetic Variation for Growth and Development Revealed by High-Throughput Phenotyping in Arabidopsis thaliana

    PubMed Central

    Zhang, Xu; Hause, Ronald J.; Borevitz, Justin O.

    2012-01-01

    Leaf growth and development determines a plant’s capacity for photosynthesis and carbon fixation. These morphological traits are the integration of genetic and environmental factors through time. Yet fine dissection of the developmental genetic basis of leaf expansion throughout a growing season is difficult, due to the complexity of the trait and the need for real time measurement. In this study, we developed a time-lapse image analysis approach, which traces leaf expansion under seasonal light variation. Three growth traits, rosette leaf area, circular area, and their ratio as compactness, were measured and normalized on a linear timescale to control for developmental heterogeneity. We found high heritability for all growth traits that changed over time. Our study highlights a cost-effective, high-throughput phenotyping approach that facilitates the dissection of genetic basis of plant shoot growth and development under dynamic environmental conditions. PMID:22384379

  11. Using the Collaborative Cross to Study the Role of Genetic Diversity in Cancer-Related Phenotypes.

    PubMed

    Reilly, Karlyne M

    2016-03-01

    Human populations are genetically diverse and often a single mouse model can only represent a small subset of the human population. Studying genetic diversity directly can improve the predictive value of mouse models of cancer biology and research on the effects of carcinogens and therapeutics in humans. The collaborative cross is a panel of inbred mouse lines that captures 90% of the genetic diversity of the Mus musculus strain and can help identify regions of the genome that are responsible for variation in cancer phenotypes across the population. The appropriate procedure will depend on the mouse model used; here, three mouse cross designs are described as examples. © 2016 Cold Spring Harbor Laboratory Press.

  12. Natural Genetic Variation for Growth and Development Revealed by High-Throughput Phenotyping in Arabidopsis thaliana.

    PubMed

    Zhang, Xu; Hause, Ronald J; Borevitz, Justin O

    2012-01-01

    Leaf growth and development determines a plant's capacity for photosynthesis and carbon fixation. These morphological traits are the integration of genetic and environmental factors through time. Yet fine dissection of the developmental genetic basis of leaf expansion throughout a growing season is difficult, due to the complexity of the trait and the need for real time measurement. In this study, we developed a time-lapse image analysis approach, which traces leaf expansion under seasonal light variation. Three growth traits, rosette leaf area, circular area, and their ratio as compactness, were measured and normalized on a linear timescale to control for developmental heterogeneity. We found high heritability for all growth traits that changed over time. Our study highlights a cost-effective, high-throughput phenotyping approach that facilitates the dissection of genetic basis of plant shoot growth and development under dynamic environmental conditions.

  13. Computational approaches for the genetic and phenotypic characterization of a Saccharomyces cerevisiae wine yeast collection.

    PubMed

    Franco-Duarte, R; Umek, L; Zupan, B; Schuller, D

    2009-12-01

    Within this study, we have used a set of computational techniques to relate the genotypes and phenotypes of natural populations of Saccharomyces cerevisiae, using allelic information from 11 microsatellite loci and results from 24 phenotypic tests. A group of 103 strains was obtained from a larger S. cerevisiae winemaking strain collection by clustering with self-organizing maps. These strains were further characterized regarding their allelic combinations for 11 microsatellites and analysed in phenotypic screens that included taxonomic criteria (carbon and nitrogen assimilation tests, growth at different temperatures) and tests with biotechnological relevance (ethanol resistance, H(2)S or aromatic precursors formation). Phenotypic variability was rather high and each strain showed a unique phenotypic profile. The results, expressed as optical density (A(640)) after 22 h of growth, were in agreement with taxonomic data, although with some exceptions, since few strains were capable of consuming arabinose and ribose to a small extent. Based on microsatellite allelic information, naïve Bayesian classifier correctly assigned (AUC = 0.81, p < 10(-8)) most of the strains to the vineyard from where they were isolated, despite their close location (50-100 km). We also identified subgroups of strains with similar values of a phenotypic feature and microsatellite allelic pattern (AUC > 0.75). Subgroups were found for strains with low ethanol resistance, growth at 30 degrees C and growth in media containing galactose, raffinose or urea. The results demonstrate that computational approaches can be used to establish genotype-phenotype relations and to make predictions about a strain's biotechnological potential.

  14. Personality as an intermediate phenotype for genetic dissection of alcohol use disorder.

    PubMed

    Oreland, Lars; Lagravinese, Gianvito; Toffoletto, Simone; Nilsson, Kent W; Harro, Jaanus; Robert Cloninger, C; Comasco, Erika

    2017-01-04

    Genetic and environmental interactive influences on predisposition to develop alcohol use disorder (AUD) account for the high heterogeneity among AUD patients and make research on the risk and resiliency factors complicated. Several attempts have been made to identify the genetic basis of AUD; however, only few genetic polymorphisms have consistently been associated with AUD. Intermediate phenotypes are expected to be in-between proxies of basic neuronal biological processes and nosological symptoms of AUD. Personality is likely to be a top candidate intermediate phenotype for the dissection of the genetic underpinnings of different subtypes of AUD. To date, 38 studies have investigated personality traits, commonly assessed by the Cloninger's Tridimensional Personality Questionnaire (TPQ) or Temperament and Character Inventory (TCI), in relation to polymorphisms of candidate genes of neurotransmitter systems in alcohol-dependent patients. Particular attention has been given to the functional polymorphism of the serotonin transporter gene (5-HTTLPR), however, leading to contradictory results, whereas results with polymorphisms in other candidate monoaminergic genes (e.g., tryptophan hydroxylase, serotonin receptors, monoamine oxidases, dopamine receptors and transporter) are sparse. Only one genome-wide association study has been performed so far and identified the ABLIM1 gene of relevance for novelty seeking, harm avoidance and reward dependence in alcohol-dependent patients. Studies investigating genetic factors together with personality could help to define more homogenous subgroups of AUD patients and facilitate treatment strategies. This review also urges the scientific community to combine genetic data with psychobiological and environmental data to further dissect the link between personality and AUD.

  15. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    DOE PAGES

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; ...

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatialmore » distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.« less

  16. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    SciTech Connect

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege  G.; Helland, Åslaug; Rye, Inga  H.; Borresen-Dale, Anne -Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin  L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  17. Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.

    PubMed

    Männel, Claudia; Meyer, Lars; Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger; Friederici, Angela D

    2015-10-01

    Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype.

  18. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    PubMed

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc.

  19. Striking Phenotypic Variation yet Low Genetic Differentiation in Sympatric Lake Trout (Salvelinus namaycush)

    PubMed Central

    Coon, Andrew; Carson, Robert; Debes, Paul V.

    2016-01-01

    The study of population differentiation in the context of ecological speciation is commonly assessed using populations with obvious discreteness. Fewer studies have examined diversifying populations with occasional adaptive variation and minor reproductive isolation, so factors impeding or facilitating the progress of early stage differentiation are less understood. We detected non-random genetic structuring in lake trout (Salvelinus namaycush) inhabiting a large, pristine, postglacial lake (Mistassini Lake, Canada), with up to five discernible genetic clusters having distinctions in body shape, size, colouration and head shape. However, genetic differentiation was low (FST = 0.017) and genetic clustering was largely incongruent between several population- and individual-based clustering approaches. Genotype- and phenotype-environment associations with spatial habitat, depth and fish community structure (competitors and prey) were either inconsistent or weak. Striking morphological variation was often more continuous within than among defined genetic clusters. Low genetic differentiation was a consequence of relatively high contemporary gene flow despite large effective population sizes, not migration-drift disequilibrium. Our results suggest a highly plastic propensity for occupying multiple habitat niches in lake trout and a low cost of morphological plasticity, which may constrain the speed and extent of adaptive divergence. We discuss how factors relating to niche conservatism in this species may also influence how plasticity affects adaptive divergence, even where ample ecological opportunity apparently exists. PMID:27680019

  20. Striking Phenotypic Variation yet Low Genetic Differentiation in Sympatric Lake Trout (Salvelinus namaycush).

    PubMed

    Marin, Kia; Coon, Andrew; Carson, Robert; Debes, Paul V; Fraser, Dylan J

    The study of population differentiation in the context of ecological speciation is commonly assessed using populations with obvious discreteness. Fewer studies have examined diversifying populations with occasional adaptive variation and minor reproductive isolation, so factors impeding or facilitating the progress of early stage differentiation are less understood. We detected non-random genetic structuring in lake trout (Salvelinus namaycush) inhabiting a large, pristine, postglacial lake (Mistassini Lake, Canada), with up to five discernible genetic clusters having distinctions in body shape, size, colouration and head shape. However, genetic differentiation was low (FST = 0.017) and genetic clustering was largely incongruent between several population- and individual-based clustering approaches. Genotype- and phenotype-environment associations with spatial habitat, depth and fish community structure (competitors and prey) were either inconsistent or weak. Striking morphological variation was often more continuous within than among defined genetic clusters. Low genetic differentiation was a consequence of relatively high contemporary gene flow despite large effective population sizes, not migration-drift disequilibrium. Our results suggest a highly plastic propensity for occupying multiple habitat niches in lake trout and a low cost of morphological plasticity, which may constrain the speed and extent of adaptive divergence. We discuss how factors relating to niche conservatism in this species may also influence how plasticity affects adaptive divergence, even where ample ecological opportunity apparently exists.

  1. Metabolome 2.0: quantitative genetics and network biology of metabolic phenotypes.

    PubMed

    Dumas, Marc-Emmanuel

    2012-10-01

    The characterization of the metabolome has rapidly evolved over two decades, from early developments in analytical chemistry to systems biology. Metabolites and small molecules are not independent; they are organized in biochemical pathways and in a wider metabolic network, which is itself dependent on various genetic and signaling networks for its regulation. Recent advances in genomics, transcriptomics, proteomics and metabolomics have been matched by the development of publicly available repositories, which have helped shaping a new generation of integrative studies using metabolite measurements in molecular epidemiology and genetic studies. Although the environment influences metabolism, the identification of the genetic determinants of metabolic phenotypes (metabotypes) was made possible by the development of metabotype quantitative trait locus (mQTL) mapping and metabolomic genome-wide association studies (mGWAS) in a rigorous statistical genetics framework, deriving associations between metabolite concentrations and genetic polymorphisms. However, given the complexity of the biomolecular events involved in the regulation of metabolic patterns, alternative network biology approaches have also been recently introduced, such as integrated metabolome and interactome mapping (iMIM). This unprecedented convergence of metabolic biochemistry, quantitative genetics and network biology already has had a strong impact on the role of the metabolome in biomedical sciences, and this review gives a foretaste of its anticipated successes in eventually delivering personalized medicine.

  2. Genetic basis of persistent red blood cell microcytosis in the Chinese unexplained by phenotypical testing.

    PubMed

    So, Chi-Chiu; Liu, Ada K; Tsang, Mandy H; Ngai, Donna Y; Leung, Kin-Sang; Chan, Amy Y

    2015-01-01

    Hypochromic microcytic anaemia is the hallmark phenotype of thalassaemia. Current phenotypical tests do not provide a diagnosis in a small proportion of patients with red blood cell microcytosis. We aim to evaluate the genetic basis of red cell microcytosis in these cases in our Chinese population. We identified from a large cohort of 1684 unselected requests for thalassaemia testing 23 Chinese subjects who had unexplained microcytosis after phenotypical iron and haemoglobin studies. In 18 of these subjects with available DNA, extensive genotypical analysis of the α and β globin gene cluster was performed, including gap-PCR, multiplex amplification-refractory mutation system, Sanger sequencing and multiplex ligation-dependent probe amplification. Occult single and double α globin gene (HBA1, HBA2) deletions and α thalassaemic haemoglobinopathies (Haemoglobin Quong Sze, Haemoglobin Constant Spring) were the genetic basis for the microcytosis. Occult β globin gene (HBB) mutations and δ globin gene (HBD) abnormalities masking β thalassaemia are not seen. A cost-effective genotyping approach for the detection of these occult globin gene mutations can be proposed. The identification of these mutations is important for making a diagnosis and for the provision of accurate genetic counselling. (This paper adds to our understanding of the genetic basis of red blood cell microcytosis in clinical practice, and it provides a cost-effective approach for genotyping in diagnostic laboratories). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Genetic Analysis of the Pathogenic Molecular Sub-phenotype Interferon Alpha Identifies Multiple Novel Loci Involved in Systemic Lupus Erythematosus

    PubMed Central

    Kariuki, Silvia N.; Ghodke-Puranik, Yogita; Dorschner, Jessica M.; Chrabot, Beverly S.; Kelly, Jennifer A.; Tsao, Betty P.; Kimberly, Robert P.; Alarcón-Riquelme, Marta E.; Jacob, Chaim O.; Criswell, Lindsey A.; Sivils, Kathy L.; Langefeld, Carl D.; Harley, John B.; Skol, Andrew D.; Niewold, Timothy B.

    2014-01-01

    Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=1.24 × 10−7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease. PMID:25338677

  4. Breed-Specific Hematological Phenotypes in the Dog: A Natural Resource for the Genetic Dissection of Hematological Parameters in a Mammalian Species

    PubMed Central

    Szladovits, Balazs; Davison, Lucy J.; Garden, Oliver A.

    2013-01-01

    Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition. PMID:24282579

  5. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis.

    PubMed

    Hendrickx, Wouter; Simeone, Ines; Anjum, Samreen; Mokrab, Younes; Bertucci, François; Finetti, Pascal; Curigliano, Giuseppe; Seliger, Barbara; Cerulo, Luigi; Tomei, Sara; Delogu, Lucia Gemma; Maccalli, Cristina; Wang, Ena; Miller, Lance D; Marincola, Francesco M; Ceccarelli, Michele; Bedognetti, Davide

    2017-01-01

    Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity.

  6. [Phenotypes and genetic mechanisms of resistance to macrolides and lincosamides in viridans group streptococci].

    PubMed

    Artiles Campelo, F; Horcajada Herrera, I; Alamo Antúnez, I; Cãnas Pedrosa, A; Lafarga Capuz, B

    2007-09-01

    Viridans group streptococci (VGS) are part of the oropharyngeal, intestinal and genital flora, but they may cause endocarditis and bacteremia in susceptible patients. Penicillin- and macrolide-resistant strains are increasing every year. The aim of this study was to investigate genetic mechanisms of resistance to macrolides in clinically relevant isolates. We identified 85 isolates from January 2004 to June 2006. Susceptibility to penicillin, cefotaxime, erythromycin, clindamycin and gentamycin was determined. A resistance phenotype was assigned according to the disk approximation test (erythromycin-clindamycin). The mechanism of resistance was determined by PCR for the following genes: ermB, ermA, ermC, ermA (TR) and mefA/E. We identified 51 isolates belonging to Streptococcus anginosus species, most of which were obtained from abdominal abscesses, and 34 isolates belonging to other species, most of which were obtained from blood cultures. The macrolide resistance rate was 28.2% (24/85). The MLS(B) phenotype was observed in 66.7% of the isolates, primarily in the S. anginosus group. The M phenotype was predominant in S. mitis and S. oralis. Isolates that expressed the constitutive MLS(B) phenotype carried the ermB gene, and those that expressed the inducible MLSB phenotype carried the ermA gene. Isolates that expressed the M phenotype carried the mefA/E gene. There was coresistance with penicillin in 20.8% (5/24) of the isolates. Coresistance with penicillin was low. These results suggest that screening for macrolide resistance in VGS would be desirable because of the potential transmission of resistance genes to other pathogenic streptococci.

  7. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis

    PubMed Central

    Simeone, Ines; Anjum, Samreen; Mokrab, Younes; Bertucci, François; Finetti, Pascal; Curigliano, Giuseppe; Cerulo, Luigi; Tomei, Sara; Delogu, Lucia Gemma; Maccalli, Cristina; Miller, Lance D.; Ceccarelli, Michele

    2017-01-01

    ABSTRACT Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. PMID:28344865

  8. HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease.

    PubMed Central

    Mearin, M L; Biemond, I; Peña, A S; Polanco, I; Vazquez, C; Schreuder, G T; de Vries, R R; van Rood, J J

    1983-01-01

    The DR-locus controlled B-cell antigens were studied in 163 unrelated Spanish coeliac children and 68 families of this group, nine of them with more than one coeliac patient, to obtain more information about the association between these antigens and coeliac disease. The results show that the most common coeliac phenotypes are DR3/DR7, DR7/DR5, DR3/other DR, and DR3/DR3. The family study confirmed the segregation of the disease with the above mentioned phenotypes. In eight of the nine multiple case families, all coeliac children shared both HLA-DR antigens. These findings make it unlikely that a single dominant gene linked to HLA-DR controls the susceptibility to coeliac disease. The phenotypes in the patients were not distributed according to the Hardy-Weinberg equilibrium. Thus, a model based on one recessive susceptibility gene linked to HLA-DR is not probable either. The complexity of the genetics of coeliac disease and some of the features shared with the HLA-DR pattern in juvenile insulin-dependent diabetes are discussed. PMID:6602084

  9. Grocery Store Genetics: A PCR-Based Genetics Lab that Links Genotype to Phenotype

    ERIC Educational Resources Information Center

    Briju, Betsy J.; Wyatt, Sarah E.

    2015-01-01

    Instructors often present Mendelian genetics and molecular biology separately. As a result, students often fail to connect the two topics in a tangible manner. We have adopted a simple experiment to help link these two important topics in a basic biology course, using red and white onions bought from a local grocery store. A lack of red coloration…

  10. Grocery Store Genetics: A PCR-Based Genetics Lab that Links Genotype to Phenotype

    ERIC Educational Resources Information Center

    Briju, Betsy J.; Wyatt, Sarah E.

    2015-01-01

    Instructors often present Mendelian genetics and molecular biology separately. As a result, students often fail to connect the two topics in a tangible manner. We have adopted a simple experiment to help link these two important topics in a basic biology course, using red and white onions bought from a local grocery store. A lack of red coloration…

  11. Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

    PubMed

    Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E; Kayser, Manfred

    2017-02-27

    Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

  12. The genetic diversity and phenotypic characterisation of Streptococcus agalactiae isolates from Rio de Janeiro, Brazil.

    PubMed

    Corrêa, Ana Beatriz de Almeida; Silva, Lígia Guedes da; Pinto, Tatiana de Castro Abreu; Oliveira, Ivi Cristina Menezes de; Fernandes, Flávio Gimenis; Costa, Natalia Silva da; Mattos, Marcos Corrêa de; Fracalanzza, Sergio Eduardo Longo; Benchetrit, Leslie Claude

    2011-12-01

    Streptococcus agalactiae isolates are more common among pregnant women, neonates and nonpregnant adults with underlying diseases compared to other demographic groups. In this study, we evaluate the genetic and phenotypic diversity in S. agalactiae strains from Rio de Janeiro (RJ) that were isolated from asymptomatic carriers. We analysed these S. agalactiae strains using pulsed-field gel electrophoresis (PFGE), serotyping and antimicrobial susceptibility testing, as well as by determining the macrolide resistance phenotype, and detecting the presence of the ermA/B, mefA/E and lnuB genes. The serotypes Ia, II, III and V were the most prevalent serotypes observed. The 60 strains analysed were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampin and tetracycline was observed. Among the erythromycin and/or clindamycin resistant strains, the ermA, ermB and mefA/E genes were detected and the constitutive macrolides, lincosamides and streptogramin B-type resistance was the most prevalent phenotype observed. The lnuB gene was not detected in any of the strains studied. We found 56 PFGE electrophoretic profiles and only 22 of them were allocated in polymorphism patterns. This work presents data on the genetic diversity and prevalent capsular serotypes among RJ isolates. Approximately 85% of these strains came from pregnant women; therefore, these data may be helpful in developing future prophylaxis and treatment strategies for neonatal syndromes in RJ.

  13. [Molecular genetic basis for para-Bombay phenotypes in two cases].

    PubMed

    He, Yang-Ming; Xu, Xian-Guo; Zhu, Fa-Ming; Yan, Li-Xing

    2007-06-01

    This study was purposed to investigate the molecular genetics basis for para-Bombay phenotype. The para-Bombay phenotype of two probands was identified by routine serological techniques. The full coding region of alpha (1, 2) fucosyltransferase gene (FUT1 and FUT2) in the probands was amplified by polymerase chain reaction and the amplified fragments were directly sequenced, meanwhile the mutations of FUT1 were also identified by TOPO TA cloning sequence method. The results indicated that two heterozygous mutations were detected by directly sequencing in two probands: AG deletion at position 547 - 552 and C to T mutation at position 658. Two different mutations were confirmed to be true compound heterozygotes with each mutation on a separate homologous chromosome by TOPO TA cloning sequence method. AG deletion at position 547 - 552 caused a reading frame shift and a premature stop codon. C658T mutation resulted in Arg-->Cys at amino acid position 220. It is suggested that the FUT1 mutation of two probands are compound heterozygous mutation with different chromosomes, which are named h1h3 and may be the genetics basis of para-Bombay phenotype.

  14. Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour

    PubMed Central

    Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H.; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R.; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E.; Kayser, Manfred

    2017-01-01

    Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing. PMID:28240252

  15. The Loci of repeated evolution: a catalog of genetic hotspots of phenotypic variation.

    PubMed

    Martin, Arnaud; Orgogozo, Virginie

    2013-05-01

    What is the nature of the genetic changes underlying phenotypic evolution? We have catalogued 1008 alleles described in the literature that cause phenotypic differences among animals, plants, and yeasts. Surprisingly, evolution of similar traits in distinct lineages often involves mutations in the same gene ("gene reuse"). This compilation yields three important qualitative implications about repeated evolution. First, the apparent evolution of similar traits by gene reuse can be traced back to two alternatives, either several independent causative mutations or a single original mutational event followed by sorting processes. Second, hotspots of evolution-defined as the repeated occurrence of de novo mutations at orthologous loci and causing similar phenotypic variation-are omnipresent in the literature with more than 100 examples covering various levels of analysis, including numerous gain-of-function events. Finally, several alleles of large effect have been shown to result from the aggregation of multiple small-effect mutations at the same hotspot locus, thus reconciling micromutationist theories of adaptation with the empirical observation of large-effect variants. Although data heterogeneity and experimental biases prevented us from extracting quantitative trends, our synthesis highlights the existence of genetic paths of least resistance leading to viable evolutionary change. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  16. Identification of genetic loci underlying the phenotypic constructs of autism spectrum disorders Running head: Genetic loci for latent factors in ASD

    PubMed Central

    Liu, Xiao-Qing; Georgiades, Stelios; Duku, Eric; Thompson, Ann; Devlin, Bernie; Cook, Edwin H.; Wijsman, Ellen M.; Paterson, Andrew D.; Szatmari, Peter

    2012-01-01

    Objective To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors. Method Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from the Autism Genome Project (AGP) phase I (1,236 ASD subjects from 618 families); the second was from the AGP phase II (804 unrelated ASD subjects). Variables derived from the factor analysis were then used as quantitative traits in genome-wide variance components linkage analyses. Results Six factors, joint attention, social interaction and communication, non-verbal communication, repetitive sensory-motor behaviour, peer interaction, and compulsion/restricted interests, were retained for both datasets. There was good agreement between the factor loading patterns from the two datasets. All factors showed familial aggregation. Suggestive evidence for linkage was obtained for the joint attention factor on 11q23. Genome-wide significant evidence for linkage was obtained for the repetitive sensory-motor behaviour factor on 19q13.3. Conclusions This study demonstrates that the underlying phenotypic constructs based on the ADI-R algorithm items are replicable in independent datasets; and the empirically derived factors are suitable and informative in genetic studies of ASD. PMID:21703496

  17. Strain-specific nuclear genetic background differentially affects mitochondria-related phenotypes in Saccharomyces cerevisiae.

    PubMed

    Montanari, Arianna; Francisci, Silvia; Fazzi D'Orsi, Mario; Bianchi, Michele Maria

    2014-06-01

    In the course of our studies on mitochondrial defects, we have observed important phenotypic variations in Saccharomyces cerevisiae strains suggesting that a better characterization of the genetic variability will be essential to define the relationship between the mitochondrial efficiency and the presence of different nuclear backgrounds. In this manuscript, we have extended the study of such relations by comparing phenotypic assays related to mitochondrial functions of three wild-type laboratory strains. In addition to the phenotypic variability among the wild-type strains, important differences have been observed among strains bearing identical mitochondrial tRNA mutations that could be related only to the different nuclear background of the cells. Results showed that strains exhibited an intrinsic variability in the severity of the effects of the mitochondrial mutations and that specific strains might be used preferentially to evaluate the phenotypic effect of mitochondrial mutations on carbon metabolism, stress responses, and mitochondrial DNA stability. In particular, while W303-1B and MCC123 strains should be used to study the effect of severe mitochondrial tRNA mutations, D273-10B/A1 strain is rather suitable for studying the effects of milder mutations.

  18. Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

    PubMed

    Rice, Gillian I; Kitabayashi, Naoki; Barth, Magalie; Briggs, Tracy A; Burton, Annabel C E; Carpanelli, Maria Luisa; Cerisola, Alfredo M; Colson, Cindy; Dale, Russell C; Danti, Federica Rachele; Darin, Niklas; De Azua, Begoña; De Giorgis, Valentina; De Goede, Christian G L; Desguerre, Isabelle; De Laet, Corinne; Eslahi, Atieh; Fahey, Michael C; Fallon, Penny; Fay, Alex; Fazzi, Elisa; Gorman, Mark P; Gowrinathan, Nirmala Rani; Hully, Marie; Kurian, Manju A; Leboucq, Nicolas; Lin, Jean-Pierre S-M; Lines, Matthew A; Mar, Soe S; Maroofian, Reza; Martí-Sanchez, Laura; McCullagh, Gary; Mojarrad, Majid; Narayanan, Vinodh; Orcesi, Simona; Ortigoza-Escobar, Juan Dario; Pérez-Dueñas, Belén; Petit, Florence; Ramsey, Keri M; Rasmussen, Magnhild; Rivier, François; Rodríguez-Pombo, Pilar; Roubertie, Agathe; Stödberg, Tommy I; Toosi, Mehran Beiraghi; Toutain, Annick; Uettwiller, Florence; Ulrick, Nicole; Vanderver, Adeline; Waldman, Amy; Livingston, John H; Crow, Yanick J

    2017-04-10

    We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

  19. Genetic and phenotypic evidence of the Salmonella enterica serotype Enteritidis human-animal interface in Chile.

    PubMed

    Retamal, Patricio; Fresno, Marcela; Dougnac, Catherine; Gutierrez, Sindy; Gornall, Vanessa; Vidal, Roberto; Vernal, Rolando; Pujol, Myriam; Barreto, Marlen; González-Acuña, Daniel; Abalos, Pedro

    2015-01-01

    Salmonella enterica serotype Enteritidis is a worldwide zoonotic agent that has been recognized as a very important food-borne bacterial pathogen, mainly associated with consumption of poultry products. The aim of this work was to determine genotypic and phenotypic evidence of S. Enteritidis transmission among seabirds, poultry and humans in Chile. Genotyping was performed using PCR-based virulotyping, pulse-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Pathogenicity-associated phenotypes were determined with survival to free radicals, acidic pH, starvation, antimicrobial resistance, and survival within human dendritic cells. As result of PCR and PFGE assays, some isolates from the three hosts showed identical genotypic patterns, and through MLST it was determined that all of them belong to sequence type 11. Phenotypic assays show diversity of bacterial responses among isolates. When results were analyzed according to bacterial host, statistical differences were identified in starvation and dendritic cells survival assays. In addition, isolates from seabirds showed the highest rates of resistance to gentamycin, tetracycline, and ampicillin. Overall, the very close genetic and phenotypic traits shown by isolates from humans, poultry, and seabirds suggest the inter-species transmission of S. Enteritidis bacteria between hosts, likely through anthropogenic environmental contamination that determines infection of seabirds with bacteria that are potentially pathogenic for other susceptible organism, including humans.

  20. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes.

    PubMed

    Zhang, Qihong; Seo, Seongjin; Bugge, Kevin; Stone, Edwin M; Sheffield, Val C

    2012-05-01

    There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet-Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7(-/-) mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect.

  1. The genetic inheritance of the blue-eyed white phenotype in alpacas (Vicugna pacos).

    PubMed

    Jackling, Felicity C; Johnson, Warren E; Appleton, Belinda R

    2014-01-01

    White-spotting patterns in mammals can be caused by mutations in the gene KIT, whose protein is necessary for the normal migration and survival of melanocytes from the neural crest. The alpaca (Vicugna pacos) blue-eyed white (BEW) phenotype is characterized by 2 blue eyes and a solid white coat over the whole body. Breeders hypothesize that the BEW phenotype in alpacas is caused by the combination of the gene causing gray fleece and a white-spotting gene. We performed an association study using KIT flanking and intragenic markers with 40 unrelated alpacas, of which 17 were BEW. Two microsatellite alleles at KIT-related markers were significantly associated (P < 0.0001) with the BEW phenotype (bew1 and bew2). In a larger cohort of 171 related individuals, we identify an abundance of an allele (bew1) in gray animals and the occurrence of bew2 homozygotes that are solid white with pigmented eyes. Association tests accounting for population structure and familial relatedness are consistent with a proposed model where these alleles are in linkage disequilibrium with a mutation or mutations that contribute to the BEW phenotype and to individual differences in fleece color. © The American Genetic Association. 2012. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. A Novel Knowledge-Driven Systems Biology Approach for Phenotype Prediction upon Genetic Intervention

    PubMed Central

    Chang, Rui; Shoemaker, Robert; Wang, Wei

    2011-01-01

    Deciphering the biological networks underlying complex phenotypic traits, e.g., human disease is undoubtedly crucial to understand the underlying molecular mechanisms and to develop effective therapeutics. Due to the network complexity and the relatively small number of available experiments, data-driven modeling is a great challenge for deducing the functions of genes/ proteins in the network and in phenotype formation. We propose a novel knowledge-driven systems biology method that utilizes qualitative knowledge to construct a Dynamic Bayesian network (DBN) to represent the biological network underlying a specific phenotype. Edges in this network depict physical interactions between genes and/or proteins. A qualitative knowledge model first translates typical molecular interactions into constraints when resolving the DBN structure and parameters. Therefore, the uncertainty of the network is restricted to a subset of models which are consistent with the qualitative knowledge. All models satisfying the constraints are considered as candidates for the underlying network. These consistent models are used to perform quantitative inference. By in silico inference, we can predict phenotypic traits upon genetic interventions and perturbing in the network. We applied our method to analyze the puzzling mechanism of breast cancer cell proliferation network and we accurately predicted cancer cell growth rate upon manipulating (anti)cancerous marker genes/proteins. PMID:21282866

  3. Genetic and phenotypic evidence of the Salmonella enterica serotype Enteritidis human-animal interface in Chile

    PubMed Central

    Retamal, Patricio; Fresno, Marcela; Dougnac, Catherine; Gutierrez, Sindy; Gornall, Vanessa; Vidal, Roberto; Vernal, Rolando; Pujol, Myriam; Barreto, Marlen; González-Acuña, Daniel; Abalos, Pedro

    2015-01-01

    Salmonella enterica serotype Enteritidis is a worldwide zoonotic agent that has been recognized as a very important food-borne bacterial pathogen, mainly associated with consumption of poultry products. The aim of this work was to determine genotypic and phenotypic evidence of S. Enteritidis transmission among seabirds, poultry and humans in Chile. Genotyping was performed using PCR-based virulotyping, pulse-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Pathogenicity-associated phenotypes were determined with survival to free radicals, acidic pH, starvation, antimicrobial resistance, and survival within human dendritic cells. As result of PCR and PFGE assays, some isolates from the three hosts showed identical genotypic patterns, and through MLST it was determined that all of them belong to sequence type 11. Phenotypic assays show diversity of bacterial responses among isolates. When results were analyzed according to bacterial host, statistical differences were identified in starvation and dendritic cells survival assays. In addition, isolates from seabirds showed the highest rates of resistance to gentamycin, tetracycline, and ampicillin. Overall, the very close genetic and phenotypic traits shown by isolates from humans, poultry, and seabirds suggest the inter-species transmission of S. Enteritidis bacteria between hosts, likely through anthropogenic environmental contamination that determines infection of seabirds with bacteria that are potentially pathogenic for other susceptible organism, including humans. PMID:26029196

  4. Regulating genetic privacy in the online health information era.

    PubMed

    Magnusson, Roger S

    2002-01-01

    As the clinical implications of the genetic components of disease come to be better understood, there is likely to be a significant increase in the volume of genetic information held within clinical records. As patient health care records, in turn, come on-line as part of broader health information networks, there is likely to be considerable pressure in favour of special laws protecting genetic privacy. This paper reviews some of the privacy challenges posed by electronic health records, some government initiatives in this area, and notes the impact that developments in genetic testing will have upon the 'genetic content' of e-health records. Despite the sensitivity of genetic information, the paper argues against a policy of 'genetic exceptionalism', and its implications for genetic privacy laws.

  5. Genetic and Phenotypic Characterization of Manufacturing Seeds for a Tetravalent Dengue Vaccine (DENVax)

    PubMed Central

    Huang, Claire Y.-H.; Kinney, Richard M.; Livengood, Jill A.; Bolling, Bethany; Arguello, John J.; Luy, Betty E.; Silengo, Shawn J.; Boroughs, Karen L.; Stovall, Janae L.; Kalanidhi, Akundi P.; Brault, Aaron C.; Osorio, Jorge E.; Stinchcomb, Dan T.

    2013-01-01

    Background We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses. These viruses, containing the pre-membrane (prM) and envelope (E) genes of dengue serotypes 1–4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. Methodology/Principal Findings After deriving vaccine viruses from RNA-transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai) Aedes aegypti mosquito vectors. Conclusion/Significance All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia. PMID:23738026

  6. Human Tuberculosis II. M. tuberculosis Mechanisms of Genetic and Phenotypic Resistance to Anti-Tuberculosis Drugs.

    PubMed

    Sgaragli, Giampietro; Frosini, Maria

    2016-01-01

    The great progress of knowledge of both M. tuberculosis physiology and how human host and bacilli interact has provided fertile ground for improving diagnosis and cure of TB infection. Once M. tuberculosis has infected humans, it elaborates strategies for evading the risk to killing by the cells of the host immune system and by the anti-tuberculosis (anti-TB) agents employed to cure infection. These strategies give rise to a bacterial multidrug resistance (MDR) status. This stems firstly from genetic mutations targeting a constellation of drug-processing mechanisms that still need full identification, as drug efflux pumps and drug activating/ inactivating enzymes (genetic resistance). Secondly, from the bacterial adaptation to stressful environmental conditions by adopting a temporary dormancy state lasting for decades and characterized by indifference to anti-TB drugs (phenotypic resistance or tolerance). The clarification of the strategies elaborated for surviving by M. tuberculosis has brought to the identification in the last few years of a number of mycobacterial molecular targets worth to exploitation for the development of novel and powerful anti-TB drugs. These targets include drug-efflux pump systems, considered partly responsible for genetic multi-drug resistance, and several enzymes and pump systems, as well, that sustain the metabolic adaptations of M. tuberculosis in the host and give rise to its phenotypic drug resistance.

  7. Approaches for the Identification of Genetic Modifiers of Nutrient Dependent Phenotypes: Examples from Folate

    PubMed Central

    Zinck, John W. R.; MacFarlane, Amanda J.

    2014-01-01

    By combining the sciences of nutrition, bioinformatics, genomics, population genetics, and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene–nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome-wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene–nutrient interaction studies, the association of genetic polymorphisms with disease expression, and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focused on specific examples from investigations of the interactions of folate, B-vitamin consumption, and polymorphisms in the genes of B-vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status. PMID:25988111

  8. Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster

    PubMed Central

    Iyer, Janani; Wang, Qingyu; Le, Thanh; Pizzo, Lucilla; Grönke, Sebastian; Ambegaokar, Surendra S.; Imai, Yuzuru; Srivastava, Ashutosh; Troisí, Beatriz Llamusí; Mardon, Graeme; Artero, Ruben; Jackson, George R.; Isaacs, Adrian M.; Partridge, Linda; Lu, Bingwei; Kumar, Justin P.; Girirajan, Santhosh

    2016-01-01

    About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (http://flynotyper.sourceforge.net), to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes. Flynotyper utilizes a series of image processing operations to automatically detect the fly eye and the individual ommatidium, and calculates a phenotypic score as a measure of the disorderliness of ommatidial arrangement in the fly eye. As a proof of principle, we tested our method by analyzing the defects due to eye-specific knockdown of Drosophila orthologs of 12 neurodevelopmental genes to accurately document differential sensitivities of these genes to dosage alteration. We also evaluated eye images from six independent studies assessing the effect of overexpression of repeats, candidates from peptide library screens, and modifiers of neurotoxicity and developmental processes on eye morphology, and show strong concordance with the original assessment. We further demonstrate the utility of this method by analyzing 16 modifiers of sine oculis obtained from two genome-wide deficiency screens of Drosophila and accurately quantifying the effect of its enhancers and suppressors during eye development. Our method will complement existing assays for eye phenotypes, and increase the accuracy of studies that use fly eyes for functional evaluation of genes and genetic interactions. PMID:26994292

  9. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    PubMed

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  10. Rapid phenotyping of knockout mice to identify genetic determinants of bone strength

    PubMed Central

    Freudenthal, Bernard; Logan, John; Croucher, Peter I

    2016-01-01

    The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease. PMID:27535945

  11. Rapid phenotyping of knockout mice to identify genetic determinants of bone strength.

    PubMed

    Freudenthal, Bernard; Logan, John; Croucher, Peter I; Williams, Graham R; Bassett, J H Duncan

    2016-10-01

    The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease. © 2016 Society for Endocrinology.

  12. Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes

    PubMed Central

    Lees, John A.; Vehkala, Minna; Välimäki, Niko; Harris, Simon R.; Chewapreecha, Claire; Croucher, Nicholas J.; Marttinen, Pekka; Davies, Mark R.; Steer, Andrew C.; Tong, Steven Y. C.; Honkela, Antti; Parkhill, Julian; Bentley, Stephen D.; Corander, Jukka

    2016-01-01

    Bacterial genomes vary extensively in terms of both gene content and gene sequence. This plasticity hampers the use of traditional SNP-based methods for identifying all genetic associations with phenotypic variation. Here we introduce a computationally scalable and widely applicable statistical method (SEER) for the identification of sequence elements that are significantly enriched in a phenotype of interest. SEER is applicable to tens of thousands of genomes by counting variable-length k-mers using a distributed string-mining algorithm. Robust options are provided for association analysis that also correct for the clonal population structure of bacteria. Using large collections of genomes of the major human pathogens Streptococcus pneumoniae and Streptococcus pyogenes, SEER identifies relevant previously characterized resistance determinants for several antibiotics and discovers potential novel factors related to the invasiveness of S. pyogenes. We thus demonstrate that our method can answer important biologically and medically relevant questions. PMID:27633831

  13. The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype.

    PubMed

    Kere, Juha

    2014-09-19

    Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or reading disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.

  14. Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes.

    PubMed

    Bonny, Olivier; Bochud, Murielle

    2014-09-01

    Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  15. A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

    PubMed Central

    Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J.; Hus, Vanessa; Murtha, Michael T.; Lowe, Jennifer K.; Willsey, A. Jeremy; Moreno-De-Luca, Daniel; Yu, Timothy W.; Fombonne, Eric; Geschwind, Daniel; Grice, Dorothy E.; Ledbetter, David H.; Mane, Shrikant M.; Martin, Donna M.; Morrow, Eric M.; Walsh, Christopher A.; Sutcliffe, James S.; Martin, Christa Lese; Beaudet, Arthur L.; Lord, Catherine; State, Matthew W.; Cook, Edwin H.; Devlin, Bernie

    2014-01-01

    Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD. PMID:25534755

  16. Insights in connecting phenotypes in bacteria to coevolutionary information

    NASA Astrophysics Data System (ADS)

    Cheng, Ryan; Morcos, Faruck; Hayes, Ryan; Helm, Rodney; Levine, Herbert; Onuchic, Jose

    It has long been known that protein sequences are far from random. These sequences have been evolutionarily selected to maintain their ability to fold into stable, three-dimensional folded structures as well as their ability to form macromolecular assemblies, perform catalytic functions, etc. For these reasons, there exist quantifiable mutational patterns in the collection of sequence data for a protein family arising from the need to maintain favorable residue-residue interactions to facilitate folding as well as cellular function. Here, we focus on studying the correlated mutational patterns that give rise to interaction specificity in bacterial two-component signaling (TCS) systems. TCS proteins have evolved to be able to preferentially bind and transfer a phosphate group to their signaling partner while avoiding phosphotransfer with non-partners. We infer a Potts model Hamiltonian governing the correlated mutational patterns that are observed in the sequence data of TCS partners and apply this model to recently published in vivo mutational data. Our findings further support the notion that statistical models built from sequence data can be used to predict bacterial phenotypes as well as engineer interaction specificity between non-partner TCS proteins. This research has been supported by the NSF INSPIRE Award (MCB-1241332) and by the CTBP sponsored by the NSF (Grant PHY- 1427654).

  17. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta.

    PubMed

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-08-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.

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

    PubMed

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

    2017-07-17

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

  19. Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

    PubMed Central

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-01-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype–phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population. PMID:25944380

  20. Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial.

    PubMed

    Godino, Job G; van Sluijs, Esther M F; Marteau, Theresa M; Sutton, Stephen; Sharp, Stephen J; Griffin, Simon J

    2016-11-01

    Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, n = 190) or in combination with a genetic (n = 189) or a phenotypic (n = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI -2.07 to 3.77, p = 0.57); phenotypic risk group versus control group 1.32 (95% CI -1.61 to 4.25, p = 0.38); and genetic risk group versus phenotypic risk group -0.47 (95% CI -3.40 to 2.46, p = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and

  1. Estimating genetic and phenotypic parameters of cellular immune-associated traits in dairy cows.

    PubMed

    Denholm, Scott J; McNeilly, Tom N; Banos, Georgios; Coffey, Mike P; Russell, George C; Bagnall, Ainsley; Mitchell, Mairi C; Wall, Eileen

    2017-04-01

    Data collected from an experimental Holstein-Friesian research herd were used to determine genetic and phenotypic parameters of innate and adaptive cellular immune-associated traits. Relationships between immune-associated traits and production, health, and fertility traits were also investigated. Repeated blood leukocyte records were analyzed in 546 cows for 9 cellular immune-associated traits, including percent T cell subsets, B cells, NK cells, and granulocytes. Variance components were estimated by univariate analysis. Heritability estimates were obtained for all 9 traits, the highest of which were observed in the T cell subsets percent CD4(+), percent CD8(+), CD4(+):CD8(+) ratio, and percent NKp46(+) cells (0.46, 0.41, 0.43 and 0.42, respectively), with between-individual variation accounting for 59 to 81% of total phenotypic variance. Associations between immune-associated traits and production, health, and fertility traits were investigated with bivariate analyses. Strong genetic correlations were observed between percent NKp46(+) and stillbirth rate (0.61), and lameness episodes and percent CD8(+) (-0.51). Regarding production traits, the strongest relationships were between CD4(+):CD8(+) ratio and weight phenotypes (-0.52 for live weight; -0.51 for empty body weight). Associations between feed conversion traits and immune-associated traits were also observed. Our results provide evidence that cellular immune-associated traits are heritable and repeatable, and the noticeable variation between animals would permit selection for altered trait values, particularly in the case of the T cell subsets. The associations we observed between immune-associated, health, fertility, and production traits suggest that genetic selection for cellular immune-associated traits could provide a useful tool in improving animal health, fitness, and fertility.

  2. Genetic and phenotypic characterization of a Japanese wild-derived DOB/Oda rat strain.

    PubMed

    Kuramoto, Takashi; Inoue, Satoko; Neoda, Yuki; Yamasaki, Ken-ichi; Hashimoto, Ryoko; Mashimo, Tomoji; Oda, Sen-ichi; Serikawa, Tadao

    2013-08-01

    Wild-derived rat strains can provide novel genome resources that are not available in standard laboratory strains. Genetic backgrounds of wild-derived strains can facilitate effective genetic linkage analyses and often modulate the expression of mutant phenotypes. Here we describe the development and characterization of a new inbred rat strain, DOB/Oda, from wild rats (Rattus norvegicus) captured in Shitara, Aichi, Japan. Phenotype analysis of 109 parameters revealed that the DOB/Oda rats had small body weight, preference for darkness, and high locomotor activity compared with the rat strains in the National BioResource Project for the Rat (NBRP-Rat) database. Genome analysis with 357 SSLP markers identified DOB/Oda-specific alleles in 70 markers. The percentage of SSLP markers that showed polymorphism between the DOB/Oda strain and any of 132 laboratory strains from NBRP-Rat varied from 89 to 95 %. The polymorphic rate (average of the values of the percentage) for the DOB/Oda strain was 91.6 %, much higher than the rates for available wild-derived strains such as the Brown Norway rat. A phylogenic tree constructed with DOB/Oda and all the strains in NBRP-Rat showed that the DOB/Oda strain localized within the wild rat groups, apparently separate from the laboratory strains. Together, these findings indicated that the DOB/Oda rat has a unique genome that is not available in the laboratory strains. Therefore, the new DOB/Oda strain will provide an important genome resource that will be useful for designing genetic experiments and for the discovery of genes that modulate mutant phenotypes.

  3. Rapid Evolution of Phenotypic Plasticity and Shifting Thresholds of Genetic Assimilation in the Nematode Caenorhabditis remanei

    PubMed Central

    Sikkink, Kristin L.; Reynolds, Rose M.; Ituarte, Catherine M.; Cresko, William A.; Phillips, Patrick C.

    2014-01-01

    Many organisms can acclimate to new environments through phenotypic plasticity, a complex trait that can be heritable, subject to selection, and evolve. However, the rate and genetic basis of plasticity evolution remain largely unknown. We experimentally evolved outbred populations of the nematode Caenorhabditis remanei under an acute heat shock during early larval development. When raised in a nonstressful environment, ancestral populations were highly sensitive to a 36.8° heat shock and exhibited high mortality. However, initial exposure to a nonlethal high temperature environment resulted in significantly reduced mortality during heat shock (hormesis). Lines selected for heat shock resistance rapidly evolved the capacity to withstand heat shock in the native environment without any initial exposure to high temperatures, and early exposure to high temperatures did not lead to further increases in heat resistance. This loss of plasticity would appear to have resulted from the genetic assimilation of the heat induction response in the noninducing environment. However, analyses of transcriptional variation via RNA-sequencing from the selected populations revealed no global changes in gene regulation correlated with the observed changes in heat stress resistance. Instead, assays of the phenotypic response across a broader range of temperatures revealed that the induced plasticity was not fixed across environments, but rather the threshold for the response was shifted to higher temperatures over evolutionary time. These results demonstrate that apparent genetic assimilation can result from shifting thresholds of induction across environments and that analysis of the broader environmental context is critically important for understanding the evolution of phenotypic plasticity. PMID:24727288

  4. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1-centenarians in Okinawa.

    PubMed

    Willcox, Bradley J; Willcox, Donald Craig; Suzuki, Makoto

    2016-11-12

    A study of elderly Okinawans has been carried out by the Okinawa Centenarian Study (OCS) research group for over four decades. The OCS began in 1975 as a population-based study of centenarians (99-year-olds and older) and other selected elderly persons residing in the main island of the Japanese prefecture of Okinawa. As of 2015, over 1000 centenarians have been examined. By several measures of health and longevity the Okinawans can claim to be the world's healthiest and longest-lived people. In this paper we explore the demographic, phenotypic, and genetic characteristics of this fascinating population.

  5. Structural and Genetic Assessment of the ABCA4-Associated Optical Gap Phenotype

    PubMed Central

    Nõupuu, Kalev; Lee, Winston; Zernant, Jana; Tsang, Stephen H.; Allikmets, Rando

    2014-01-01

    Purpose. To investigate the developmental stages and genetic etiology of the optical gap phenotype in recessive Stargardt disease (STGD1). Methods. Single and longitudinal data points from 15 patients, including four sibling pairs, exhibiting an optical gap phenotype on spectral-domain optical coherence tomography (SD-OCT) with confirmed disease-causing ABCA4 alleles were retrospectively analyzed. Fundus images with corresponding SD-OCT scans were collected with a confocal scanning laser ophthalmoscope. Structural phenotypes were assigned to three developmental stages according to SD-OCT. The ABCA4 gene was screened in all patients. Results. At least two disease-causing ABCA4 variants where identified in each patient; all except one (91%) were compound heterozygous for the p.G1961E mutation. All patients exhibited structural findings on SD-OCT that grouped into three progressive developmental stages over several years. Stage 1 was characterized by mild disruptions of the ellipsoid zone (EZ) band over the fovea. Stage 2 was a progressive expansion of the EZ band loss resulting in an empty lesion devoid of photoreceptors. Stage 3 observed a structural collapse of the inner retinal layers into the optical gap space leading to involvement and atrophy of the RPE thereafter. Conclusions. The optical gap phenotype in STGD1 can be structurally divided into three progressive stages spanning several years. This particular phenotype also appears to be highly associated with the p.G1961E mutation of ABCA4. Taken together, it appears that a focal loss of photoreceptors sequentially precedes RPE dysfunction in the early development of ABCA4-associated optical gap lesions. PMID:25301883

  6. Iterative combination of national phenotype, genotype, pedigree, and foreign information

    USDA-ARS?s Scientific Manuscript database

    Single step methods can combine all sources of information into accurate rankings for animals with and without genotypes. Equations that require inverting the genomic relationship matrix G work well with limited numbers of animals, but equivalent models without inversion are needed as numbers increa...

  7. Predicting brain structure in population-based samples with biologically informed genetic scores for schizophrenia.

    PubMed

    Van der Auwera, Sandra; Wittfeld, Katharina; Shumskaya, Elena; Bralten, Janita; Zwiers, Marcel P; Onnink, A Marten H; Usberti, Niccolo; Hertel, Johannes; Völzke, Henry; Völker, Uwe; Hosten, Norbert; Franke, Barbara; Grabe, Hans J

    2017-04-01

    Schizophrenia is associated with brain structural abnormalities including gray and white matter volume reductions. Whether these alterations are caused by genetic risk variants for schizophrenia is unclear. Previous attempts to detect associations between polygenic factors for schizophrenia and structural brain phenotypes in healthy subjects have been negative or remain non-replicated. In this study, we used genetic risk scores that were based on the accumulated effect of selected risk variants for schizophrenia belonging to specific biological systems like synaptic function, neurodevelopment, calcium signaling, and glutamatergic neurotransmission. We hypothesized that this "biologically informed" approach would provide the missing link between genetic risk for schizophrenia and brain structural phenotypes. We applied whole-brain voxel-based morphometry (VBM) analyses in two population-based target samples and subsequent regions of interest (ROIs) analyses in an independent replication sample (total N = 2725). No consistent association between the genetic scores and brain volumes were observed in the investigated samples. These results suggest that in healthy subjects with a higher genetic risk for schizophrenia additional factors apart from common genetic variants (e.g., infection, trauma, rare genetic variants, or gene-gene interactions) are required to induce structural abnormalities of the brain. Further studies are recommended to test for possible gene-gene or gene-environment effects. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Towards Systems Genetic Analyses in Barley: Integration of Phenotypic, Expression and Genotype Data into GeneNetwork

    USDA-ARS?s Scientific Manuscript database

    A typical genetical genomics experiment results in three separate data sets: genotype, gene expression, and higher-order phenotypic data. Used in concert, these data sets provide the opportunity to perform genetic analysis at a systems level. The predictive power of these experiments is largely d...

  9. Genetic Causes of Phenotypic Adaptation to the Second Fermentation of Sparkling Wines in Saccharomyces cerevisiae

    PubMed Central

    Martí-Raga, Maria; Peltier, Emilien; Mas, Albert; Beltran, Gemma; Marullo, Philippe

    2016-01-01

    Hybridization is known to improve complex traits due to heterosis and phenotypic robustness. However, these phenomena have been rarely explained at the molecular level. Here, the genetic determinism of Saccharomyces cerevisiae fermentation performance was investigated using a QTL mapping approach on an F1-progeny population. Three main QTL were detected, with positive alleles coming from both parental strains. The heterosis effect found in the hybrid was partially explained by three loci showing pseudooverdominance and dominance effects. The molecular dissection of those QTL revealed that the adaptation to second fermentation is related to pH, lipid, or osmotic regulation. Our results suggest that the stressful conditions of second fermentation have driven the selection of rare genetic variants adapted to maintain yeast cell homeostasis and, in particular, to low pH conditions. PMID:27903630

  10. Prevalence and genetic analysis of phenotypically Vi- negative Salmonella typhi isolates in children from Kathmandu, Nepal.

    PubMed

    Pulickal, Anoop S; Callaghan, Martin J; Kelly, Dominic F; Maskey, Mitu; Mahat, Sandeep; Hamaluba, Mainga; Dongol, Sabina; Adhikari, Neelam; Thorson, Stephen; Basynat, Buddha; Murdoch, David R; Farrar, Jeremy J; Pollard, Andrew J

    2013-08-01

    The Vi capsular polysaccharide (ViPS) protects Salmonella enterica subspecies enterica serotype Typhi (S.Typhi) in vivo by multiple mechanisms. Recent microbiological reports from typhoid endemic countries suggest that acapsulate S.Typhi may occur in nature and contribute to clinical typhoid fever that is indistinguishable from disease caused by capsulate strains. The prevalence and genetic basis of ViPS-negative S.Typhi isolates in children from Kathmandu, Nepal, were tested in 68 isolates. Although 5.9% of isolates tested negative for capsular expression by slide agglutination tests, a novel multiplex PCR assay and individual PCR analyses demonstrated the presence of all 14 genes responsible for the synthesis, transportation and regulation of the ViPS. These data suggest that phenotypically acapsulate S.Typhi may not have a genetic basis for the same.

  11. Phenotypic and genetic evidence for a unifactorial structure of spatial abilities

    PubMed Central

    Rimfeld, Kaili; Shakeshaft, Nicholas G.; Malanchini, Margherita; Rodic, Maja; Selzam, Saskia; Schofield, Kerry; Dale, Philip S.; Kovas, Yulia; Plomin, Robert

    2017-01-01

    Spatial abilities encompass several skills differentiable from general cognitive ability (g). Importantly, spatial abilities have been shown to be significant predictors of many life outcomes, even after controlling for g. To date, no studies have analyzed the genetic architecture of diverse spatial abilities using a multivariate approach. We developed “gamified” measures of diverse putative spatial abilities. The battery of 10 tests was administered online to 1,367 twin pairs (age 19–21) from the UK-representative Twins Early Development Study (TEDS). We show that spatial abilities constitute a single factor, both phenotypically and genetically, even after controlling for g. This spatial ability factor is highly heritable (69%). We draw three conclusions: (i) The high heritability of spatial ability makes it a good target for gene-hunting research; (ii) some genes will be specific to spatial ability, independent of g; and (iii) these genes will be associated with all components of spatial ability. PMID:28223478

  12. Phenotypic and genetic evidence for a unifactorial structure of spatial abilities.

    PubMed

    Rimfeld, Kaili; Shakeshaft, Nicholas G; Malanchini, Margherita; Rodic, Maja; Selzam, Saskia; Schofield, Kerry; Dale, Philip S; Kovas, Yulia; Plomin, Robert

    2017-03-07

    Spatial abilities encompass several skills differentiable from general cognitive ability (g). Importantly, spatial abilities have been shown to be significant predictors of many life outcomes, even after controlling for g. To date, no studies have analyzed the genetic architecture of diverse spatial abilities using a multivariate approach. We developed "gamified" measures of diverse putative spatial abilities. The battery of 10 tests was administered online to 1,367 twin pairs (age 19-21) from the UK-representative Twins Early Development Study (TEDS). We show that spatial abilities constitute a single factor, both phenotypically and genetically, even after controlling for g This spatial ability factor is highly heritable (69%). We draw three conclusions: (i) The high heritability of spatial ability makes it a good target for gene-hunting research; (ii) some genes will be specific to spatial ability, independent of g; and (iii) these genes will be associated with all components of spatial ability.

  13. Genetic Causes of Phenotypic Adaptation to the Second Fermentation of Sparkling Wines in Saccharomyces cerevisiae.

    PubMed

    Martí-Raga, Maria; Peltier, Emilien; Mas, Albert; Beltran, Gemma; Marullo, Philippe

    2017-02-09

    Hybridization is known to improve complex traits due to heterosis and phenotypic robustness. However, these phenomena have been rarely explained at the molecular level. Here, the genetic determinism of Saccharomyces cerevisiae fermentation performance was investigated using a QTL mapping approach on an F1-progeny population. Three main QTL were detected, with positive alleles coming from both parental strains. The heterosis effect found in the hybrid was partially explained by three loci showing pseudooverdominance and dominance effects. The molecular dissection of those QTL revealed that the adaptation to second fermentation is related to pH, lipid, or osmotic regulation. Our results suggest that the stressful conditions of second fermentation have driven the selection of rare genetic variants adapted to maintain yeast cell homeostasis and, in particular, to low pH conditions.

  14. Local versus Generalized Phenotypes in Two Sympatric Aurelia Species: Understanding Jellyfish Ecology Using Genetics and Morphometrics

    PubMed Central

    Chiaverano, Luciano M.; Bayha, Keith W.; Graham, William M.

    2016-01-01

    For individuals living in environmentally heterogeneous environments, a key component for adaptation and persistence is the extent of phenotypic differentiation in response to local environmental conditions. In order to determine the extent of environmentally induced morphological variation in a natural population distributed along environmental gradients, it is necessary to account for potential genetic differences contributing to morphological differentiation. In this study, we set out to quantify geographic morphological variation in the moon jellyfish Aurelia exposed at the extremes of a latitudinal environmental gradient in the Gulf of Mexico (GoM). We used morphological data based on 28 characters, and genetic data taken from mitochondrial cytochrome oxidase I (COI) and nuclear internal transcribed spacer 1 (ITS-1). Molecular analyses revealed the presence of two genetically distinct species of Aurelia co-occurring in the GoM: Aurelia sp. 9 and Aurelia c.f. sp. 2, named for its divergence from (for COI) and similarity to (for ITS-1) Aurelia sp. 2 (Brazil). Neither species exhibited significant population genetic structure between the Northern and the Southeastern Gulf of Mexico; however, they differed greatly in the degree of geographic morphological variation. The morphology of Aurelia sp. 9 exhibited ecophenotypic plasticity and varied significantly between locations, while morphology of Aurelia c.f. sp. 2 was geographically invariant (i.e., canalized). The plastic, generalist medusae of Aurelia sp. 9 are likely able to produce environmentally-induced, “optimal” phenotypes that confer high relative fitness in different environments. In contrast, the non-plastic generalist individuals of Aurelia c.f. sp. 2 likely produce environmentally-independent phenotypes that provide the highest fitness across environments. These findings suggest the two Aurelia lineages co-occurring in the GoM were likely exposed to different past environmental conditions (i

  15. When three traits make a line: evolution of phenotypic plasticity and genetic assimilation through linear reaction norms in stochastic environment