Science.gov

Sample records for human genetic variation

  1. A global reference for human genetic variation

    PubMed Central

    2016-01-01

    The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. PMID:26432245

  2. A global reference for human genetic variation.

    PubMed

    Auton, Adam; Brooks, Lisa D; Durbin, Richard M; Garrison, Erik P; Kang, Hyun Min; Korbel, Jan O; Marchini, Jonathan L; McCarthy, Shane; McVean, Gil A; Abecasis, Gonçalo R

    2015-10-01

    The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

  3. Genetic variation and the de novo assembly of human genomes

    PubMed Central

    Chaisson, Mark J. P.; Wilson, Richard K.; Eichler, Evan E.

    2016-01-01

    The discovery of genetic variation and the assembly of genome sequences are both inextricably linked to advances in DNA-sequencing technology. Short-read massively parallel sequencing has revolutionized our ability to discover genetic variation but is insufficient to generate high-quality genome assemblies or resolve most structural variation. Full resolution of variation is only guaranteed by complete de novo assembly of a genome. Here, we review approaches to genome assembly, the nature of gaps or missing sequences, and biases in the assembly process. We describe the challenges of generating a complete de novo genome assembly using current technologies and the impact that being able to perfectly sequence the genome would have on understanding human disease and evolution. Finally, we summarize recent technological advances that improve both contiguity and accuracy and emphasize the importance of complete de novo assembly as opposed to read mapping as the primary means to understanding the full range of human genetic variation. PMID:26442640

  4. 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.

  5. Genetics of the dentofacial variation in human malocclusion.

    PubMed

    Moreno Uribe, L M; Miller, S F

    2015-04-01

    Malocclusions affect individuals worldwide, resulting in compromised function and esthetics. Understanding the etiological factors contributing to the variation in dentofacial morphology associated with malocclusions is the key to develop novel treatment approaches. Advances in dentofacial phenotyping, which is the comprehensive characterization of hard and soft tissue variation in the craniofacial complex, together with the acquisition of large-scale genomic data have started to unravel genetic mechanisms underlying facial variation. Knowledge on the genetics of human malocclusion is limited even though results attained thus far are encouraging, with promising opportunities for future research. This review summarizes the most common dentofacial variations associated with malocclusions and reviews the current knowledge of the roles of genes in the development of malocclusions. Lastly, this review will describe ways to advance malocclusion research, following examples from the expanding fields of phenomics and genomic medicine, which aim to better patient outcomes.

  6. Genetics of the dentofacial variation in human malocclusion

    PubMed Central

    Moreno Uribe, L. M.; Miller, S. F.

    2015-01-01

    Malocclusions affect individuals worldwide, resulting in compromised function and esthetics. Understanding the etiological factors contributing to the variation in dentofacial morphology associated with malocclusions is the key to develop novel treatment approaches. Advances in dentofacial phenotyping, which is the comprehensive characterization of hard and soft tissue variation in the craniofacial complex, together with the acquisition of large-scale genomic data have started to unravel genetic mechanisms underlying facial variation. Knowledge on the genetics of human malocclusion is limited even though results attained thus far are encouraging, with promising opportunities for future research. This review summarizes the most common dentofacial variations associated with malocclusions and reviews the current knowledge of the roles of genes in the development of malocclusions. Lastly, this review will describe ways to advance malocclusion research, following examples from the expanding fields of phenomics and genomic medicine, which aim to better patient outcomes. PMID:25865537

  7. Genetic and epigenetic variation of human populations: An adaptive tale.

    PubMed

    Quintana-Murci, Lluis

    2016-01-01

    The evolutionary history of modern humans means much more than their demographic past. It includes the way in which humans have had to genetically adapt to the different environments they have encountered-nutritional, climatic or pathogenic-as well as the different epigenetic responses elicited by such environmental cues. Detecting how natural selection has affected human genome variability has proven to be a powerful tool to delineate genes and biological functions having played a key role in human adaptation, a variation which can also be involved in phenotypes of medical relevance. This article reviews several examples that illustrate well how different environmental pressures, particularly those imposed by pathogens and infectious diseases, have shaped the patterns of genetic and epigenetic variability currently observed in human populations.

  8. Human copy number variation and complex genetic disease.

    PubMed

    Girirajan, Santhosh; Campbell, Catarina D; Eichler, Evan E

    2011-01-01

    Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.

  9. Mine, Yours, Ours? Sharing Data on Human Genetic Variation

    PubMed Central

    Montinaro, Francesco; Capocasa, Marco; Sanna, Emanuele; Bisol, Giovanni Destro

    2012-01-01

    The achievement of a robust, effective and responsible form of data sharing is currently regarded as a priority for biological and bio-medical research. Empirical evaluations of data sharing may be regarded as an indispensable first step in the identification of critical aspects and the development of strategies aimed at increasing availability of research data for the scientific community as a whole. Research concerning human genetic variation represents a potential forerunner in the establishment of widespread sharing of primary datasets. However, no specific analysis has been conducted to date in order to ascertain whether the sharing of primary datasets is common-practice in this research field. To this aim, we analyzed a total of 543 mitochondrial and Y chromosomal datasets reported in 508 papers indexed in the Pubmed database from 2008 to 2011. A substantial portion of datasets (21.9%) was found to have been withheld, while neither strong editorial policies nor high impact factor proved to be effective in increasing the sharing rate beyond the current figure of 80.5%. Disaggregating datasets for research fields, we could observe a substantially lower sharing in medical than evolutionary and forensic genetics, more evident for whole mtDNA sequences (15.0% vs 99.6%). The low rate of positive responses to e-mail requests sent to corresponding authors of withheld datasets (28.6%) suggests that sharing should be regarded as a prerequisite for final paper acceptance, while making authors deposit their results in open online databases which provide data quality control seems to provide the best-practice standard. Finally, we estimated that 29.8% to 32.9% of total resources are used to generate withheld datasets, implying that an important portion of research funding does not produce shared knowledge. By making the scientific community and the public aware of this important aspect, we may help popularize a more effective culture of data sharing. PMID:22679483

  10. Human Papillomavirus 18 Genetic Variation and Cervical Cancer Risk Worldwide

    PubMed Central

    Chen, Alyce A.; Gheit, Tarik; Franceschi, Silvia

    2015-01-01

    ABSTRACT Human papillomavirus 18 (HPV18) is the second most carcinogenic HPV type, after HPV16, and it accounts for approximately 12% of squamous cell carcinoma (SCC) as well as 37% of adenocarcinoma (ADC) of the cervix worldwide. We aimed to evaluate the worldwide diversity and carcinogenicity of HPV18 genetic variants by sequencing the entire long control region (LCR) and the E6 open reading frame of 711 HPV18-positive cervical samples from 39 countries, taking advantage of the International Agency for Research on Cancer biobank. A total of 209 unique HPV18 sequence variants were identified that formed three phylogenetic lineages (A, B, and C). A and B lineages each divided into four sublineages, including a newly identified candidate B4 sublineage. The distribution of lineages varied by geographical region, with B and C lineages found principally in Africa. HPV18 (sub)lineages were compared between 453 cancer cases and 236 controls, as well as between 81 ADC and 160 matched SCC cases. In region-stratified analyses, there were no significant differences in the distribution of HPV18 variant lineages between cervical cancer cases and controls or between ADC and SCC. In conclusion, our findings do not support the role of HPV18 (sub)lineages for discriminating cancer risk or explaining why HPV18 is more strongly linked with ADC than SCC. IMPORTANCE This is the largest and most geographically/ethnically diverse study of the genetic variation of HPV18 to date, providing a comprehensive reference for phylogenetic classification of HPV18 sublineages for epidemiological and biological studies. PMID:26269181

  11. Human genetic variation: new challenges and opportunities for doping control.

    PubMed

    Schneider, Angela J; Fedoruk, Matthew N; Rupert, Jim L

    2012-01-01

    Sport celebrates differences in competitors that lead to the often razor-thin margins between victory and defeat. The source of this variation is the interaction between the environment in which the athletes develop and compete and their genetic make-up. However, a darker side of sports may also be genetically influenced: some anti-doping tests are affected by the athlete's genotype. Genetic variation is an issue that anti-doping authorities must address as more is learned about the interaction between genotype and the responses to prohibited practices. To differentiate between naturally occurring deviations in indirect blood and urine markers from those potentially caused by doping, the "biological-passport" program uses intra-individual variability rather than population values to establish an athlete's expected physiological range. The next step in "personalized" doping control may be the inclusion of genetic data, both for the purposes of documenting an athlete's responses to doping agents and doping-control assays as well facilitating athlete and sample identification. Such applications could benefit "clean" athletes but will come at the expense of risks to privacy. This article reviews the instances where genetics has intersected with doping control, and briefly discusses the potential role, and ethical implications, of genotyping in the struggle to eliminate illicit ergogenic practices.

  12. GENETIC ASSOCIATION ANALYSIS OF COPY NUMBER VARIATION (CNVs) IN HUMAN DISEASE PATHOGENESIS

    PubMed Central

    Ionita-Laza, Iuliana; Rogers, Angela J.; Lange, Christoph; Raby, Benjamin A.; Lee, Charles

    2009-01-01

    Structural genetic variation, including copy number variation (CNV), constitutes a substantial fraction of total genetic variability and the importance of structural genetic variants in modulating human disease is increasingly being recognized. Early successes in identifying disease-associated CNVs via a candidate gene approach mandate that future disease association studies need to include structural genetic variation. Such analyses should not rely on previously developed methodologies that were designed to evaluate single nucleotide polymorphisms (SNPs). Instead, development of novel technical, statistical, and epidemiologic methods will be necessary to optimally capture this newly-appreciated form of genetic variation in a meaningful manner. PMID:18822366

  13. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans.

    PubMed

    Verloop, Herman; Dekkers, Olaf M; Peeters, Robin P; Schoones, Jan W; Smit, Johannes W A

    2014-09-01

    Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.

  14. Estimating the Respective Contributions of Human and Viral Genetic Variation to HIV Control

    PubMed Central

    Bartha, István; Brumme, Chanson; Harrigan, Richard

    2017-01-01

    We evaluated the fraction of variation in HIV-1 set point viral load attributable to viral or human genetic factors by using joint host/pathogen genetic data from 541 HIV infected individuals. We show that viral genetic diversity explains 29% of the variation in viral load while host factors explain 8.4%. Using a joint model including both host and viral effects, we estimate a total of 30% heritability, indicating that most of the host effects are reflected in viral sequence variation. PMID:28182649

  15. Genetic variation and effects on human eating behavior.

    PubMed

    de Krom, Mariken; Bauer, Florianne; Collier, David; Adan, R A H; la Fleur, Susanne E

    2009-01-01

    Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living.

  16. Systematic documentation and analysis of human genetic variation using the microattribution approach

    PubMed Central

    Giardine, Belinda; Borg, Joseph; Higgs, Douglas R.; Peterson, Kenneth R.; Maglott, Donna; Basak, A. Nazli; Clark, Barnaby; Faustino, Paula; Felice, Alex E.; Francina, Alain; Gallivan, Monica V. E.; Georgitsi, Marianthi; Gibbons, Richard J.; Giordano, Piero C.; Harteveld, Cornelis L.; Joly, Philippe; Kanavakis, Emmanuel; Kollia, Panagoula; Menzel, Stephan; Miller, Webb; Moradkhani, Kamran; Old, John; Papachatzopoulou, Adamantia; Papadakis, Manoussos N.; Papadopoulos, Petros; Pavlovic, Sonja; Philipsen, Sjaak; Radmilovic, Milena; Riemer, Cathy; Schrijver, Iris; Stojiljkovic, Maja; Thein, Swee Lay; Traeger-Synodinos, Jan; Tully, Ray; Wada, Takahito; Waye, John; Wiemann, Claudia; Zukic, Branka; Chui, David H. K.; Wajcman, Henri; Hardison, Ross C.; Patrinos, George P.

    2013-01-01

    We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to these disorders, and then implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories 1. A total of 1,941 unique genetic variants in 37 genes, encoding globins (HBA2, HBA1, HBG2, HBG1, HBD, HBB) and other erythroid proteins (ALOX5AP, AQP9, ARG2, ASS1, ATRX, BCL11A, CNTNAP2, CSNK2A1, EPAS1, ERCC2, FLT1, GATA1, GPM6B, HAO2, HBS1L, KDR, KL, KLF1, MAP2K1, MAP3K5, MAP3K7, MYB, NOS1, NOS2, NOS3, NOX3, NUP133, PDE7B, SMAD3, SMAD6, and TOX) are currently documented in these databases with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants and now provides a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The large repository of previously reported data, together with more recent data, acquired by microattribution, demonstrates how the comprehensive documentation of human variation will provide key insights into normal biological processes and how these are perturbed in human genetic disease. Using the microattribution process set out here, datasets which took decades to accumulate for the globin genes could be assembled rapidly for other genes and disease systems. The principles established here for the globin gene system will serve as a model for other systems and the analysis of other common and/or complex human genetic diseases. PMID:21423179

  17. Identification of species and genetic variation in Taenia isolates from human and swine of North India.

    PubMed

    Singh, Satyendra K; Prasad, Kashi N; Singh, Aloukick K; Gupta, Kamlesh K; Chauhan, Ranjeet S; Singh, Amrita; Singh, Avinash; Rai, Ravi P; Pati, Binod K

    2016-10-01

    Taenia solium is the major cause of taeniasis and cysticercosis/neurocysticercosis (NCC) in the developing countries including India, but the existence of other Taenia species and genetic variation have not been studied in India. So, we studied the existence of different Taenia species, and sequence variation in Taenia isolates from human (proglottids and cysticerci) and swine (cysticerci) in North India. Amplification of cytochrome c oxidase subunit 1 gene (cox1) was done by polymerase chain reaction (PCR) followed by sequencing and phylogenetic analysis. We identified two species of Taenia i.e. T. solium and Taenia asiatica in our isolates. T. solium isolates showed similarity with Asian genotype and nucleotide variations from 0.25 to 1.01 %, whereas T. asiatica displayed nucleotide variations ranged from 0.25 to 0.5 %. These findings displayed the minimal genetic variations in North Indian isolates of T. solium and T. asiatica.

  18. Human Genetic Variation. Grades 9-12. NIH Curriculum Supplement Series.

    ERIC Educational Resources Information Center

    Biological Sciences Curriculum Study, Colorado Springs.

    This curriculum supplement guide brings the latest medical discoveries to classrooms. This module focuses on the objectives of introducing students to the genetic variations of human beings, and developing an understanding of the relationship between biomedical research and personal and public health. This module includes five major sections: (1)…

  19. Rare structural genetic variation in human prion diseases.

    PubMed

    Lukic, Ana; Uphill, James; Brown, Craig A; Beck, John; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E; Collinge, John; Mead, Simon

    2015-05-01

    Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

  20. A comparison of worldwide phonemic and genetic variation in human populations.

    PubMed

    Creanza, Nicole; Ruhlen, Merritt; Pemberton, Trevor J; Rosenberg, Noah A; Feldman, Marcus W; Ramachandran, Sohini

    2015-02-03

    Worldwide patterns of genetic variation are driven by human demographic history. Here, we test whether this demographic history has left similar signatures on phonemes-sound units that distinguish meaning between words in languages-to those it has left on genes. We analyze, jointly and in parallel, phoneme inventories from 2,082 worldwide languages and microsatellite polymorphisms from 246 worldwide populations. On a global scale, both genetic distance and phonemic distance between populations are significantly correlated with geographic distance. Geographically close language pairs share significantly more phonemes than distant language pairs, whether or not the languages are closely related. The regional geographic axes of greatest phonemic differentiation correspond to axes of genetic differentiation, suggesting that there is a relationship between human dispersal and linguistic variation. However, the geographic distribution of phoneme inventory sizes does not follow the predictions of a serial founder effect during human expansion out of Africa. Furthermore, although geographically isolated populations lose genetic diversity via genetic drift, phonemes are not subject to drift in the same way: within a given geographic radius, languages that are relatively isolated exhibit more variance in number of phonemes than languages with many neighbors. This finding suggests that relatively isolated languages are more susceptible to phonemic change than languages with many neighbors. Within a language family, phoneme evolution along genetic, geographic, or cognate-based linguistic trees predicts similar ancestral phoneme states to those predicted from ancient sources. More genetic sampling could further elucidate the relative roles of vertical and horizontal transmission in phoneme evolution.

  1. Genetic variation in lipid desaturases and its impact on the development of human disease

    PubMed Central

    2010-01-01

    Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management. PMID:20565855

  2. Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome.

    PubMed

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui; Kim, Su Yeon; Korneliussen, Thorfinn; Vinckenbosch, Nicolas; Tian, Geng; Huerta-Sanchez, Emilia; Feder, Alison F; Grarup, Niels; Jørgensen, Torben; Jiang, Tao; Witte, Daniel R; Sandbæk, Annelli; Hellmann, Ines; Lauritzen, Torsten; Hansen, Torben; Pedersen, Oluf; Wang, Jun; Nielsen, Rasmus

    2011-10-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

  3. A comparison of worldwide phonemic and genetic variation in human populations

    PubMed Central

    Creanza, Nicole; Ruhlen, Merritt; Pemberton, Trevor J.; Rosenberg, Noah A.; Feldman, Marcus W.; Ramachandran, Sohini

    2015-01-01

    Worldwide patterns of genetic variation are driven by human demographic history. Here, we test whether this demographic history has left similar signatures on phonemes—sound units that distinguish meaning between words in languages—to those it has left on genes. We analyze, jointly and in parallel, phoneme inventories from 2,082 worldwide languages and microsatellite polymorphisms from 246 worldwide populations. On a global scale, both genetic distance and phonemic distance between populations are significantly correlated with geographic distance. Geographically close language pairs share significantly more phonemes than distant language pairs, whether or not the languages are closely related. The regional geographic axes of greatest phonemic differentiation correspond to axes of genetic differentiation, suggesting that there is a relationship between human dispersal and linguistic variation. However, the geographic distribution of phoneme inventory sizes does not follow the predictions of a serial founder effect during human expansion out of Africa. Furthermore, although geographically isolated populations lose genetic diversity via genetic drift, phonemes are not subject to drift in the same way: within a given geographic radius, languages that are relatively isolated exhibit more variance in number of phonemes than languages with many neighbors. This finding suggests that relatively isolated languages are more susceptible to phonemic change than languages with many neighbors. Within a language family, phoneme evolution along genetic, geographic, or cognate-based linguistic trees predicts similar ancestral phoneme states to those predicted from ancient sources. More genetic sampling could further elucidate the relative roles of vertical and horizontal transmission in phoneme evolution. PMID:25605893

  4. Human genomic variation

    PubMed Central

    Disotell, Todd R

    2000-01-01

    The recent completion and assembly of the first draft of the human genome, which combines samples from several ethnically diverse males and females, provides preliminary data on the extent of human genetic variation. PMID:11178257

  5. Genetic background drives transcriptional variation in human induced pluripotent stem cells.

    PubMed

    Rouhani, Foad; Kumasaka, Natsuhiko; de Brito, Miguel Cardoso; Bradley, Allan; Vallier, Ludovic; Gaffney, Daniel

    2014-06-01

    Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor.

  6. Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

    PubMed

    Chen, Lu; Ge, Bing; Casale, Francesco Paolo; Vasquez, Louella; Kwan, Tony; Garrido-Martín, Diego; Watt, Stephen; Yan, Ying; Kundu, Kousik; Ecker, Simone; Datta, Avik; Richardson, David; Burden, Frances; Mead, Daniel; Mann, Alice L; Fernandez, Jose Maria; Rowlston, Sophia; Wilder, Steven P; Farrow, Samantha; Shao, Xiaojian; Lambourne, John J; Redensek, Adriana; Albers, Cornelis A; Amstislavskiy, Vyacheslav; Ashford, Sofie; Berentsen, Kim; Bomba, Lorenzo; Bourque, Guillaume; Bujold, David; Busche, Stephan; Caron, Maxime; Chen, Shu-Huang; Cheung, Warren; Delaneau, Oliver; Dermitzakis, Emmanouil T; Elding, Heather; Colgiu, Irina; Bagger, Frederik O; Flicek, Paul; Habibi, Ehsan; Iotchkova, Valentina; Janssen-Megens, Eva; Kim, Bowon; Lehrach, Hans; Lowy, Ernesto; Mandoli, Amit; Matarese, Filomena; Maurano, Matthew T; Morris, John A; Pancaldi, Vera; Pourfarzad, Farzin; Rehnstrom, Karola; Rendon, Augusto; Risch, Thomas; Sharifi, Nilofar; Simon, Marie-Michelle; Sultan, Marc; Valencia, Alfonso; Walter, Klaudia; Wang, Shuang-Yin; Frontini, Mattia; Antonarakis, Stylianos E; Clarke, Laura; Yaspo, Marie-Laure; Beck, Stephan; Guigo, Roderic; Rico, Daniel; Martens, Joost H A; Ouwehand, Willem H; Kuijpers, Taco W; Paul, Dirk S; Stunnenberg, Hendrik G; Stegle, Oliver; Downes, Kate; Pastinen, Tomi; Soranzo, Nicole

    2016-11-17

    Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.

  7. Republished: Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime

    PubMed Central

    Forsberg, Lars Anders; Absher, Devin; Dumanski, Jan Piotr

    2013-01-01

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders. PMID:23781115

  8. Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime

    PubMed Central

    Forsberg, Lars Anders; Absher, Devin; Dumanski, Jan Piotr

    2013-01-01

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders. PMID:23172682

  9. Impact of Human Management on the Genetic Variation of Wild Pepper, Capsicum annuum var. glabriusculum

    PubMed Central

    González-Jara, Pablo; Moreno-Letelier, Alejandra; Fraile, Aurora; Piñero, Daniel; García-Arenal, Fernando

    2011-01-01

    Management of wild peppers in Mexico has occurred for a long time without clear phenotypic signs of domestication. However, pre-domestication management could have implications for the population's genetic richness. To test this hypothesis we analysed 27 wild (W), let standing (LS) and cultivated (C) populations, plus 7 samples from local markets (LM), with nine polymorphic microsatellite markers. Two hundred and fifty two alleles were identified, averaging 28 per locus. Allele number was higher in W, and 15 and 40% less in LS and C populations, respectively. Genetic variation had a significant population structure. In W populations, structure was associated with ecological and geographic areas according to isolation by distance. When LM and C populations where included in the analysis, differentiation was no longer apparent. Most LM were related to distant populations from Sierra Madre Oriental, which represents their probable origin. Historical demography shows a recent decline in all W populations. Thus, pre-domestication human management is associated with a significant reduction of genetic diversity and with a loss of differentiation suggesting movement among regions by man. Measures to conserve wild and managed populations should be implemented to maintain the source and the architecture of genetic variation in this important crop relative. PMID:22163053

  10. Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality.

    PubMed

    Buckholtz, J W; Callicott, J H; Kolachana, B; Hariri, A R; Goldberg, T E; Genderson, M; Egan, M F; Mattay, V S; Weinberger, D R; Meyer-Lindenberg, A

    2008-03-01

    Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

  11. Population Genetic Inference from Personal Genome Data: Impact of Ancestry and Admixture on Human Genomic Variation

    PubMed Central

    Kidd, Jeffrey M.; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D.; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F.; Peckham, Heather E.; Omberg, Larsson; Bormann Chung, Christina A.; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G.; Russell, Archie; Reynolds, Andy; Clark, Andrew G.; Reese, Martin G.; Lincoln, Stephen E.; Butte, Atul J.; De La Vega, Francisco M.; Bustamante, Carlos D.

    2012-01-01

    Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas—70% of the European ancestry in today’s African Americans dates back to European gene flow happening only 7–8 generations ago. PMID:23040495

  12. Genetic Variations in Human Glutathione Transferase Enzymes: Significance for Pharmacology and Toxicology

    PubMed Central

    Josephy, P. David

    2010-01-01

    Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione. While many GST-catalyzed transformations result in the detoxication of xenobiotics, a few substrates, such as dihaloalkanes, undergo bioactivation to reactive intermediates. Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy. This review presents a discussion of the biochemistry of GSTs, the sources—both genetic and environmental—of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs. PMID:20981235

  13. Analysis of protein-coding genetic variation in 60,706 humans

    PubMed Central

    Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V; Samocha, Kaitlin E; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl B; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack A; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David M; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose C; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin M; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah M; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark J

    2016-01-01

    Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes. PMID:27535533

  14. Analysis of protein-coding genetic variation in 60,706 humans.

    PubMed

    Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V; Samocha, Kaitlin E; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl B; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack A; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David M; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose C; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin M; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah M; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark J; MacArthur, Daniel G

    2016-08-18

    Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

  15. ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

    PubMed Central

    2009-01-01

    Background Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. Methods One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. Results We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. Conclusion In summary, our screen indicates that ALDH1A2 genetic

  16. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase.

    PubMed Central

    Clark, A G; Weiss, K M; Nickerson, D A; Taylor, S L; Buchanan, A; Stengård, J; Salomaa, V; Vartiainen, E; Perola, M; Boerwinkle, E; Sing, C F

    1998-01-01

    Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed. PMID:9683608

  17. Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration

    PubMed Central

    Hu, Sile; Zhou, Hang; Guo, Jing; Jin, Li; Tang, Kun

    2013-01-01

    Human facial morphology is a combination of many complex traits. Little is known about the genetic basis of common facial morphological variation. Existing association studies have largely used simple landmark-distances as surrogates for the complex morphological phenotypes of the face. However, this can result in decreased statistical power and unclear inference of shape changes. In this study, we applied a new image registration approach that automatically identified the salient landmarks and aligned the sample faces using high density pixel points. Based on this high density registration, three different phenotype data schemes were used to test the association between the common facial morphological variation and 10 candidate SNPs, and their performances were compared. The first scheme used traditional landmark-distances; the second relied on the geometric analysis of 15 landmarks and the third used geometric analysis of a dense registration of ∼30,000 3D points. We found that the two geometric approaches were highly consistent in their detection of morphological changes. The geometric method using dense registration further demonstrated superiority in the fine inference of shape changes and 3D face modeling. Several candidate SNPs showed potential associations with different facial features. In particular, one SNP, a known risk factor of non-syndromic cleft lips/palates, rs642961 in the IRF6 gene, was validated to strongly predict normal lip shape variation in female Han Chinese. This study further demonstrated that dense face registration may substantially improve the detection and characterization of genetic association in common facial variation. PMID:24339768

  18. Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

    PubMed Central

    Siegelmann-Danieli, N; Buetow, K H

    1999-01-01

    The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat polymorphism at intron 4 of the Cyp19 gene revealed the presence of six common and two rare alleles. Contingency table analysis revealed a significant difference in allelic distribution between cases and controls (χ2 5df = 13.52, P = 0.019). The allele measuring 171 bp was over-represented in cases; of 14 individuals homozygous for this allele, 13 were cases. These individuals had a higher incidence of cancer in family members and an earlier age at diagnosis than other cases. In sequencing Cyp19's coding exons and regulatory regions, we discovered a perfect association between a silent polymorphism (G→A at Val80) and the high-risk genotype. Our conclusion is that constitutional genetic variation at the Cyp19 locus is associated with the risk of developing breast cancer, with the 171-bp allele serving as the high-risk allele. © 1999 Cancer Research Campaign PMID:10027313

  19. An integrated map of genetic variation from 1,092 human genomes

    PubMed Central

    2012-01-01

    Summary Through characterising the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help understand the genetic contribution to disease. We describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methodologies to integrate information across multiple algorithms and diverse data sources we provide a validated haplotype map of 38 million SNPs, 1.4 million indels and over 14 thousand larger deletions. We show that individuals from different populations carry different profiles of rare and common variants and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways and that each individual harbours hundreds of rare non-coding variants at conserved sites, such as transcription-factor-motif disrupting changes. This resource, which captures up to 98% of accessible SNPs at a frequency of 1% in populations of medical genetics focus, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations. PMID:23128226

  20. Genetic engineering compared to natural genetic variations.

    PubMed

    Arber, Werner

    2010-11-30

    By comparing strategies of genetic alterations introduced in genetic engineering with spontaneously occurring genetic variation, we have come to conclude that both processes depend on several distinct and specific molecular mechanisms. These mechanisms can be attributed, with regard to their evolutionary impact, to three different strategies of genetic variation. These are local nucleotide sequence changes, intragenomic rearrangement of DNA segments and the acquisition of a foreign DNA segment by horizontal gene transfer. Both the strategies followed in genetic engineering and the amounts of DNA sequences thereby involved are identical to, or at least very comparable with, those involved in natural genetic variation. Therefore, conjectural risks of genetic engineering must be of the same order as those for natural biological evolution and for conventional breeding methods. These risks are known to be quite low. There is no scientific reason to assume special long-term risks for GM crops. For future agricultural developments, a road map is designed that can be expected to lead, by a combination of genetic engineering and conventional plant breeding, to crops that can insure food security and eliminate malnutrition and hunger for the entire human population on our planet. Public-private partnerships should be formed with the mission to reach the set goals in the coming decades.

  1. Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells.

    PubMed

    Giani, Felix C; Fiorini, Claudia; Wakabayashi, Aoi; Ludwig, Leif S; Salem, Rany M; Jobaliya, Chintan D; Regan, Stephanie N; Ulirsch, Jacob C; Liang, Ge; Steinberg-Shemer, Orna; Guo, Michael H; Esko, Tõnu; Tong, Wei; Brugnara, Carlo; Hirschhorn, Joel N; Weiss, Mitchell J; Zon, Leonard I; Chou, Stella T; French, Deborah L; Musunuru, Kiran; Sankaran, Vijay G

    2016-01-07

    Multipotent and pluripotent stem cells are potential sources for cell and tissue replacement therapies. For example, stem cell-derived red blood cells (RBCs) are a potential alternative to donated blood, but yield and quality remain a challenge. Here, we show that application of insight from human population genetic studies can enhance RBC production from stem cells. The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation. Our findings therefore highlight the potential for combining human genome variation studies with genome editing approaches to improve cell and tissue production for regenerative medicine.

  2. An integrated map of genetic variation from 1,092 human genomes.

    PubMed

    Abecasis, Goncalo R; Auton, Adam; Brooks, Lisa D; DePristo, Mark A; Durbin, Richard M; Handsaker, Robert E; Kang, Hyun Min; Marth, Gabor T; McVean, Gil A

    2012-11-01

    By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

  3. Genetic variation and population structure in the endangered Hermann's tortoise: the roles of geography and human-mediated processes.

    PubMed

    Perez, Melanie; Livoreil, Barbara; Mantovani, Sara; Boisselier, Marie-Catherine; Crestanello, Barbara; Abdelkrim, Jawad; Bonillo, Céline; Goutner, Vassilis; Lambourdière, Josie; Pierpaoli, Massimo; Sterijovski, Bogoljub; Tomovic, Ljiljana; Vilaça, Sibelle T; Mazzotti, Stefano; Bertorelle, Giorgio

    2014-01-01

    The Hermann's tortoise (Testudo hermanni) is an endangered land tortoise distributed in disjoint populations across Mediterranean Europe. We investigated its genetic variation by typing 1 mitochondrial locus and 9 nuclear microsatellites in approximately 300 individuals from 22 localities. Our goal was to understand the relative impact of natural and human-mediated processes in shaping the genetic structure and to identify the genetic priorities for the conservation of this species. We found that 1) all geographic areas are highly differentiated, mainly as a function of their distance but with a clear genetic discontinuity (F st values larger than 0.4) between the Eastern and the Western subspecies; 2) the contact zone between subspecies is located farthest to the west than previously believed, and it probably coincides with the delta of the largest Italian river; 3) extinction events due to climatic conditions in the Upper Palaeolithic and subsequent human-mediated translocations in the Neolithic possibly explain the unexpected similarity among Spain, Sicily, and Corsica. For conservation purposes, the large majority of genetic pools appears native although hybridization among subspecies, related to extensive 20th century trade of tortoises across Europe, is observed in Spain and some Italian samples. Most populations do not seem at immediate risk of low genetic variation, except the French population, which has very low nuclear genetic diversity (heterozygosity = 0.25) and where 50 out of 51 sampled animals shared the same mitochondrial sequence. In general, restocking and reintroduction plans should carefully consider the genetic background of the individuals.

  4. Human Genetic Variation and Yellow Fever Mortality during 19th Century U.S. Epidemics

    PubMed Central

    2014-01-01

    ABSTRACT We calculated the incidence, mortality, and case fatality rates for Caucasians and non-Caucasians during 19th century yellow fever (YF) epidemics in the United States and determined statistical significance for differences in the rates in different populations. We evaluated nongenetic host factors, including socioeconomic, environmental, cultural, demographic, and acquired immunity status that could have influenced these differences. While differences in incidence rates were not significant between Caucasians and non-Caucasians, differences in mortality and case fatality rates were statistically significant for all epidemics tested (P < 0.01). Caucasians diagnosed with YF were 6.8 times more likely to succumb than non-Caucasians with the disease. No other major causes of death during the 19th century demonstrated a similar mortality skew toward Caucasians. Nongenetic host factors were examined and could not explain these large differences. We propose that the remarkably lower case mortality rates for individuals of non-Caucasian ancestry is the result of human genetic variation in loci encoding innate immune mediators. PMID:24895309

  5. Genetic Variation in Human Vitamin C Transporter Genes in Common Complex Diseases123

    PubMed Central

    Shaghaghi, Mandana Amir; Kloss, Olena

    2016-01-01

    Adequate plasma, cellular, and tissue vitamin C concentrations are required for maintaining optimal health through suppression of oxidative stress and optimizing functions of certain enzymes that require vitamin C as a cofactor. Polymorphisms in the vitamin C transporter genes, compromising genes encoding sodium-dependent ascorbate transport proteins, and also genes encoding facilitative transporters of dehydroascorbic acid, are associated with plasma and tissue cellular ascorbate status and hence cellular redox balance. This review summarizes our current knowledge of the links between variations in vitamin C transporter genes and common chronic diseases. We conclude that emerging genetic knowledge has a good likelihood of defining future personalized dietary recommendations and interventions; however, further validations through biological studies as well as controlled dietary trials are required to identify predictive and actionable genetic biomarkers. We further advocate the need to consider genetic variation of vitamin C transporters in future clinical and epidemiologic studies on common complex diseases. PMID:26980812

  6. Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation.

    PubMed

    Buse, J B; Yasuda, K; Lay, T P; Seo, T S; Olson, A L; Pessin, J E; Karam, J H; Seino, S; Bell, G I

    1992-11-01

    Four overlapping DNA fragments spanning 32 kb containing the human GLUT4 facilitative glucose-transporter gene were isolated and characterized. The sequence of the GLUT4 gene (approximately 6.3 kb) and 2.0 kb of the promoter region was determined. The sequence of the promoter revealed potential binding sites for transcription factors known to regulate gene expression in muscle cells and adipocytes. However, transfection of constructs including 2 kb of the GLUT4 promoter fused to the bacterial CAT gene into 3T3-L1 adipocytes displayed only weak promoter activity. Because insulin resistance plays a prominent role in the development of NIDDM, genetic variation in the sequence of GLUT4 also was evaluated. Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR. The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA. SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus. In addition to the silent substitution in the codon for Asn130 (AAC or AAT) and a Val383 (GTC)-->Ile(ATC) replacement described previously, two new variants were identified. One was a T-->A substitution in intron 1 that was found in 1 of 36 NIDDM patients who were typed for this variant. The second was a Ile385(ATT)-->Thr(ACT) replacement that occurred in 1 normal individual and was not found in any of 676 other normal and diabetic subjects. A large and racially diverse group of normal and diabetic individuals also was screened for the Ile383 polymorphism. It occurred in both diabetic and nondiabetic subjects. There is no indication from our data that these polymorphisms are associated with NIDDM.

  7. Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs.

    PubMed

    Hightower, C Makena; Zhang, Kuixing; Miramontes-González, José P; Rao, Fangwen; Wei, Zhiyun; Schork, Andrew J; Nievergelt, Caroline M; Biswas, Nilima; Mahata, Manjula; Elkelis, Nina; Taupenot, Laurent; Stridsberg, Mats; Ziegler, Michael G; O'Connor, Daniel T

    2013-12-01

    The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p = 3.19E-16, at 65.2 ± 5.0% of trait variance), sharing significant (p < 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p < 0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.

  8. Human genetics

    SciTech Connect

    Carlson, E.A.

    1984-01-01

    This text provides full and balanced coverage of the concepts requisite for a thorough understanding of human genetics. Applications to both the individual and society are integrated throughout the lively and personal narrative, and the essential principles of heredity are clearly presented to prepare students for informed participation in public controversies. High-interest, controversial topics, including recombinant DNA technology, oncogenes, embryo transfer, environmental mutagens and carcinogens, IQ testing, and eugenics encourage understanding of important social issues.

  9. Genomic and network patterns of schizophrenia genetic variation in human evolutionary accelerated regions.

    PubMed

    Xu, Ke; Schadt, Eric E; Pollard, Katherine S; Roussos, Panos; Dudley, Joel T

    2015-05-01

    The population persistence of schizophrenia despite associated reductions in fitness and fecundity suggests that the genetic basis of schizophrenia has a complex evolutionary history. A recent meta-analysis of schizophrenia genome-wide association studies offers novel opportunities for assessment of the evolutionary trajectories of schizophrenia-associated loci. In this study, we hypothesize that components of the genetic architecture of schizophrenia are attributable to human lineage-specific evolution. Our results suggest that schizophrenia-associated loci enrich in genes near previously identified human accelerated regions (HARs). Specifically, we find that genes near HARs conserved in nonhuman primates (pHARs) are enriched for schizophrenia-associated loci, and that pHAR-associated schizophrenia genes are under stronger selective pressure than other schizophrenia genes and other pHAR-associated genes. We further evaluate pHAR-associated schizophrenia genes in regulatory network contexts to investigate associated molecular functions and mechanisms. We find that pHAR-associated schizophrenia genes significantly enrich in a GABA-related coexpression module that was previously found to be differentially regulated in schizophrenia affected individuals versus healthy controls. In another two independent networks constructed from gene expression profiles from prefrontal cortex samples, we find that pHAR-associated schizophrenia genes are located in more central positions and their average path lengths to the other nodes are significantly shorter than those of other schizophrenia genes. Together, our results suggest that HARs are associated with potentially important functional roles in the genetic architecture of schizophrenia.

  10. Genetic variation in Tunisia in the context of human diversity worldwide

    PubMed Central

    Cherni, Lotfi; Pakstis, Andrew J.; Boussetta, Sami; Elkamel, Sarra; Frigi, Sabeh; Khodjet‐El‐Khil, Houssein; Barton, Alison; Haigh, Eva; Speed, William C.; Ben Ammar Elgaaied, Amel; Kidd, Judith R.

    2016-01-01

    ABSTRACT Objectives North Africa has a complex demographic history of migrations from within Africa, Europe, and the Middle East. However, population genetic studies, especially for autosomal genetic markers, are few relative to other world regions. We examined autosomal markers for eight Tunisian and Libyan populations in order to place them in a global context. Materials and Methods Data were collected by TaqMan on 399 autosomal single nucleotide polymorphisms on 331 individuals from Tunisia and Libya. These data were combined with data on the same SNPs previously typed on 2585 individuals from 57 populations from around the world. Where meaningful, close by SNPs were combined into multiallelic haplotypes. Data were evaluated by clustering, principal components, and population tree analyses. For a subset of 102 SNPs, data from the literature on seven additional North African populations were included in analyses. Results Average heterozygosity of the North African populations is high relative to our global samples, consistent with a complex demographic history. The Tunisian and Libyan samples form a discrete cluster in the global and regional views and can be separated from sub‐Sahara, Middle East, and Europe. Within Tunisia the Nebeur and Smar are outlier groups. Across North Africa, pervasive East‐West geographical patterns were not found. Discussion Known historical migrations and invasions did not displace or homogenize the genetic variation in the region but rather enriched it. Even a small region like Tunisia contains considerable genetic diversity. Future studies across North Africa have the potential to increase our understanding of the historical demographic factors influencing the region. Am J Phys Anthropol 161:62–71, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc. PMID:27192181

  11. Human genetics of the Kula Ring: Y-chromosome and mitochondrial DNA variation in the Massim of Papua New Guinea

    PubMed Central

    van Oven, Mannis; Brauer, Silke; Choi, Ying; Ensing, Joe; Schiefenhövel, Wulf; Stoneking, Mark; Kayser, Manfred

    2014-01-01

    The island region at the southeastern-most tip of New Guinea and its inhabitants known as Massim are well known for a unique traditional inter-island trading system, called Kula or Kula Ring. To characterize the Massim genetically, and to evaluate the influence of the Kula Ring on patterns of human genetic variation, we analyzed paternally inherited Y-chromosome (NRY) and maternally inherited mitochondrial (mt) DNA polymorphisms in >400 individuals from this region. We found that the nearly exclusively Austronesian-speaking Massim people harbor genetic ancestry components of both Asian (AS) and Near Oceanian (NO) origin, with a proportionally larger NO NRY component versus a larger AS mtDNA component. This is similar to previous observations in other Austronesian-speaking populations from Near and Remote Oceania and suggests sex-biased genetic admixture between Asians and Near Oceanians before the occupation of Remote Oceania, in line with the Slow Boat from Asia hypothesis on the expansion of Austronesians into the Pacific. Contrary to linguistic expectations, Rossel Islanders, the only Papuan speakers of the Massim, showed a lower amount of NO genetic ancestry than their Austronesian-speaking Massim neighbors. For the islands traditionally involved in the Kula Ring, a significant correlation between inter-island travelling distances and genetic distances was observed for mtDNA, but not for NRY, suggesting more male- than female-mediated gene flow. As traditionally only males take part in the Kula voyages, this finding may indicate a genetic signature of the Kula Ring, serving as another example of how cultural tradition has shaped human genetic diversity. PMID:24619143

  12. Combined examination of sequence and copy number variations in human deafness genes improves diagnosis for cases of genetic deafness

    PubMed Central

    2014-01-01

    Background Copy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. Many CNVs have been associated with either resistance to diseases or identified as the cause of diseases. Currently little is known about the role of CNVs in causing deafness. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. Here we detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing. Methods Coding regions of the deafness genes were captured by a hybridization-based method and processed through the standard next-generation sequencing (NGS) protocol using the Illumina platform. Samples hybridized together in the same reaction were analyzed to obtain CNVs. A read depth based method was used to measure CNVs at the resolution of a single exon. Results were validated by the quantitative PCR (qPCR) based method. Results Among 79 sporadic cases clinically diagnosed with sensorineural hearing loss, we identified previously-reported disease-causing sequence mutations in 16 cases. In addition, we identified a total of 97 CNVs (72 CNV gains and 25 CNV losses) in 27 deafness genes. The CNVs included homozygous deletions which may directly give rise to deleterious effects on protein functions known to be essential for hearing, as well as heterozygous deletions and CNV gains compounded with sequence mutations in deafness genes that could potentially harm gene functions. Conclusions We studied how CNVs in known deafness genes may result in deafness. Data provided here served as a basis to explain how CNVs disrupt normal functions of deafness genes. These results may significantly expand our understanding about how various types of genetic mutations cause deafness in humans. PMID:25342930

  13. Genetic Variation in Cardiomyopathy and Cardiovascular Disorders.

    PubMed

    McNally, Elizabeth M; Puckelwartz, Megan J

    2015-01-01

    With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.

  14. Genetic, environmental and epigenetic influences on variation in human tooth number, size and shape.

    PubMed

    Townsend, Grant; Bockmann, Michelle; Hughes, Toby; Brook, Alan

    2012-01-01

    The aim of this review is to highlight some key recent developments in studies of tooth number, size and shape that are providing better insights into the roles of genetic, environmental and epigenetic factors in the process of dental development. Advances in molecular genetics are helping to clarify how epigenetic factors influence the spatial and temporal regulation of the complex processes involved in odontogenesis. At the phenotypic level, the development of sophisticated systems for image analysis is enabling new dental phenotypes to be defined. The 2D and 3D data that are generated by these imaging systems can then be analysed with mathematical approaches, such as geometric morphometric analysis. By gathering phenotypic data and DNA from twins, it is now possible to use 'genome-wide' association studies and the monozygotic co-twin design to identify important genes in odontogenesis and also to clarify how epigenetic and environmental factors can affect this process. Given that many of the common dental anomalies affecting the human dentition are interrelated, apparently reflecting pleiotropic genetic effects, the discoveries and new directions described in this paper should have important implications for clinical dental practice in the future.

  15. Genetic variation in brain-derived neurotrophic factor and human fear conditioning.

    PubMed

    Hajcak, G; Castille, C; Olvet, D M; Dunning, J P; Roohi, J; Hatchwell, E

    2009-02-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS +/- 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning--evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

  16. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    PubMed

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  17. A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

    PubMed Central

    Richter, Sylvia; Gorny, Xenia; Marco-Pallares, Josep; Krämer, Ulrike M.; Machts, Judith; Barman, Adriana; Bernstein, Hans-Gert; Schüle, Rebecca; Schöls, Ludger; Rodriguez-Fornells, Antoni; Reissner, Carsten; Wüstenberg, Torsten; Heinze, Hans-Jochen; Gundelfinger, Eckart D.; Düzel, Emrah; Münte, Thomas F.; Seidenbecher, Constanze I.; Schott, Björn H.

    2011-01-01

    The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing. PMID:22232585

  18. FAAH genetic variation enhances fronto-amygdala function in mouse and human.

    PubMed

    Dincheva, Iva; Drysdale, Andrew T; Hartley, Catherine A; Johnson, David C; Jing, Deqiang; King, Elizabeth C; Ra, Stephen; Gray, J Megan; Yang, Ruirong; DeGruccio, Ann Marie; Huang, Chienchun; Cravatt, Benjamin F; Glatt, Charles E; Hill, Matthew N; Casey, B J; Lee, Francis S

    2015-03-03

    Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

  19. FAAH genetic variation enhances fronto-amygdala function in mouse and human

    PubMed Central

    Dincheva, Iva; Drysdale, Andrew T.; Hartley, Catherine A.; Johnson, David C.; Jing, Deqiang; King, Elizabeth C.; Ra, Stephen; Gray, Megan; Yang, Ruirong; DeGruccio, Ann Marie; Huang, Chienchun; Cravatt, Benjamin F.; Glatt, Charles E.; Hill, Matthew N.; Casey, B. J.; Lee, Francis S.

    2015-01-01

    Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human. PMID:25731744

  20. Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations

    SciTech Connect

    Eichler, E.E.; Nelson, D.L.

    1996-07-12

    In an attempt to understand the allelic diversity and mutability of the human FMR1 CGG repeat, we have analyzed the AGG substructure of this locus within six genetically-closed populations (Mbuti pygmy, Baka pygmy, R. surui, Karitiana, Mayan, and Hutterite). Most alleles (61/92 or 66%) possessed two AGG interspersions occurring with a periodicity of one AGG every nine or ten CGG repeats, indicating that this pattern is highly conserved in all human populations. Significant differences in allele distribution were observed among the populations for rare variants possessing fewer or more AGG interruptions than the canonical FMR1 CGG repeat sequence. Comparisons of expected heterozygosity of the FMR1 CGG repeat locus with 30 other microsatellite loci, demonstrated remarkably similar levels of polymorphism within each population, suggesting that most FMR1 CGG repeat alleles mutate at rates indistinguishable from other microsatellite loci. A single allele (1 out of 92) was identified with a large uninterrupted tract of pure repeats (42 pure CGG triplets). Retrospective pedigree analysis indicated that this allele had been transmitted unstably. Although such alleles mutate rapidly and likely represent evolving premutations, our analysis suggests that in spite of the estimated frequency of their occurrence, these unstable alleles do not significantly alter the expected heterozygosity of the FMR1 CGG repeat in the human population. 45 refs., 1 fig., 2 tabs.

  1. Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort.

    PubMed

    Vockley, Christopher M; Guo, Cong; Majoros, William H; Nodzenski, Michael; Scholtens, Denise M; Hayes, M Geoffrey; Lowe, William L; Reddy, Timothy E

    2015-08-01

    We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses.

  2. Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort

    PubMed Central

    Vockley, Christopher M.; Guo, Cong; Majoros, William H.; Nodzenski, Michael; Scholtens, Denise M.; Hayes, M. Geoffrey; Lowe, William L.; Reddy, Timothy E.

    2015-01-01

    We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses. PMID:26084464

  3. Classic Weinstein: tetrad analysis, genetic variation and achiasmate segregation in Drosophila and humans.

    PubMed Central

    Zwick, M E; Cutler, D J; Langley, C H

    1999-01-01

    A maximum-likelihood method for the estimation of tetrad frequencies from single-spore data is presented. The multilocus exchange with interference and viability (MEIV) model incorporates a clearly defined model of exchange, interference, and viability whose parameters define a multinomial distribution for single-spore data. Maximum-likelihood analysis of the MEIV model (MEIVLA) allows point estimation of tetrad frequencies and determination of confidence intervals. We employ MEIVLA to determine tetrad frequencies among 15 X chromosomes sampled at random from Drosophila melanogaster natural populations in Africa and North America. Significant variation in the frequency of nonexchange, or E(0) tetrads, is observed within both natural populations. Because most nondisjunction arises from E(0) tetrads, this observation is quite unexpected given both the prevalence and the deleterious consequences of nondisjunction in D. melanogaster. Use of MEIVLA is also demonstrated by reanalyzing a recently published human chromosome 21 dataset. Analysis of simulated datasets demonstrates that MEIVLA is superior to previous methods of tetrad frequency estimation and is particularly well suited to analyze samples where the E(0) tetrad frequency is low and sample sizes are small, conditions likely to be met in most samples from human populations. We discuss the implications of our analysis for determining whether an achiasmate system exists in humans to ensure the proper segregation of E(0) tetrads. PMID:10430587

  4. Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

    PubMed

    Homburger, Julian R; Green, Eric M; Caleshu, Colleen; Sunitha, Margaret S; Taylor, Rebecca E; Ruppel, Kathleen M; Metpally, Raghu Prasad Rao; Colan, Steven D; Michels, Michelle; Day, Sharlene M; Olivotto, Iacopo; Bustamante, Carlos D; Dewey, Frederick E; Ho, Carolyn Y; Spudich, James A; Ashley, Euan A

    2016-06-14

    Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.

  5. Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

    PubMed Central

    Homburger, Julian R.; Green, Eric M.; Caleshu, Colleen; Sunitha, Margaret S.; Taylor, Rebecca E.; Ruppel, Kathleen M.; Metpally, Raghu Prasad Rao; Colan, Steven D.; Michels, Michelle; Day, Sharlene M.; Olivotto, Iacopo; Bustamante, Carlos D.; Dewey, Frederick E.; Ho, Carolyn Y.; Spudich, James A.; Ashley, Euan A.

    2016-01-01

    Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease. PMID:27247418

  6. Human genetic variation in the Sierra de Gredos mountain (central Spain): study of several polymorphisms.

    PubMed

    Moral, P; Sandiumenge, T; Vives, S; Lutken, N; Ortega, F; Marrodan, M D; Fuster, V

    1996-01-01

    The variation in the third component of human complement (C3) and orosomucoid (ORM1) serum proteins, and 6-phosphogluconate dehydrogenase (6PGD), adenosine deaminase (ADA), esterase D (ESD), and acid phosphatase (ACP1) red cell enzymes was examined in two samples from autochthonous populations living on either side of the Sierra de Gredos range in Central Spain. These results support only a moderate differentiation between Gredos subpopulations, which is discussed in relation to other Iberian Peninsula groups. Allele frequencies in Gredos show a remarkable heterogeneity as contrasted with other Iberian populations for most of the markers examined; relatively high C3*S, ORM1*F, ADA*1, ESD*2, and ACP1*C gene frequencies are characteristics of Gredos samples. This differentiation was more marked for the Northern Gredos population and could be related to the geographical peculiarities of this region.

  7. Genetic Variation among Major Human Geographic Groups Supports a Peculiar Evolutionary Trend in PAX9

    PubMed Central

    Paixão-Côrtes, Vanessa R.; Meyer, Diogo; Pereira, Tiago V.; Mazières, Stéphane; Elion, Jacques; Krishnamoorthy, Rajagopal; Zago, Marco A.; Silva, Wilson A.; Salzano, Francisco M.; Bortolini, Maria Cátira

    2011-01-01

    A total of 172 persons from nine South Amerindian, three African and one Eskimo populations were studied in relation to the Paired box gene 9 (PAX9) exon 3 (138 base pairs) as well as its 5′and 3′flanking intronic segments (232 bp and 220 bp, respectively) and integrated with the information available for the same genetic region from individuals of different geographical origins. Nine mutations were scored in exon 3 and six in its flanking regions; four of them are new South American tribe-specific singletons. Exon3 nucleotide diversity is several orders of magnitude higher than its intronic regions. Additionally, a set of variants in the PAX9 and 101 other genes related with dentition can define at least some dental morphological differences between Sub-Saharan Africans and non-Africans, probably associated with adaptations after the modern human exodus from Africa. Exon 3 of PAX9 could be a good molecular example of how evolvability works. PMID:21298044

  8. Global analysis of genetic variation in human arsenic (+ 3 oxidation state) methyltransferase (AS3MT)

    SciTech Connect

    Fujihara, Junko; Soejima, Mikiko; Yasuda, Toshihiro; Koda, Yoshiro; Agusa, Tetsuro; Kunito, Takashi; Tongu, Miki; Yamada, Takaya; Takeshita, Haruo

    2010-03-15

    Human arsenic (+ 3 oxidation state) methyltransferase (AS3MT) is known to catalyze the methylation of arsenite. The objective of this study was to investigate the diversity of the AS3MT gene at the global level. The distribution of 18 single nucleotide polymorphisms (SNPs) in AS3MT was performed in 827 individuals from 10 populations (Japanese, Korean, Chinese, Mongolian, Tibetans, Sri Lankan Tamils, Sri Lankan Sinhalese, Nepal Tamangs, Ovambo, and Ghanaian). In the African populations, the A allele in A6144T was not observed; the allele frequencies of C35587 were much lower than those in other populations; the allele frequencies of A37616 and C37950 were relatively higher than those in other populations. Among Asian populations, Mongolians showed a different genotype distribution pattern. A lower C3963 and T6144 frequencies were observed, and, in the C37616A and T37950C polymorphism, the Mongolian population showed higher A37616 and C37950 allele frequencies than other Asian populations, similarly to the African populations. A total of 66 haplotypes were observed in the Ovambo, 48, in the Ghanaian, 99, in the Japanese, 103, in the Korean, 103, in the South Chinese, 20, in the Sri Lankan Tamil, 12, in the Sri Lankan Sinhalese, 21, in the Nepal Tamang, 50, in the Tibetan, and 45, in the Mongolian populations. The D' values between the SNP pairs were extremely high in the Sri Lankan Sinhalese population. Relatively higher D' values were observed in Mongolian and Sri Lankan Tamil populations. Network analysis showed two clusters that may have different origins, African and Asians (Chinese and/or Japanese). The present study is the first to demonstrate the existence of genetic heterogeneity in a world wide distribution of 18 SNPs in AS3MT.

  9. A brief history of genetic variation analysis.

    PubMed

    Ahmadian, Afshin; Lundeberg, Joakim

    2002-05-01

    As the human genome sequence is determined, there is an emerging need for the analysis of human sequence variations as genetic markers in diagnosis, linkage and association studies, cancer research, and pharmacogenomics. There are several different techniques and approaches for detecting these genetic variations, and here we review some of these techniques and their application fields. However, all the techniques have advantages and disadvantages, andfactors such as laboratory instrumentation, personnel experience, required accuracy, required throughput, and cost often have to be taken into account before selecting a method.

  10. Genetic Variation Within Adrenergic Pathways Determines In Vivo Effects of Presynaptic Stimulation in Humans

    PubMed Central

    Fung, Maple M.; Nguyen, Carie; Mehtani, Parag; Salem, Rany M.; Perez, Brandon; Thomas, Brenda; Das, Madhusudan; Schork, Nicholas J.; Mahata, Sushil K.; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Background Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. Methods and Results To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase β-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype. Conclusions Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may

  11. Genetic Variation of the Alpha Subunit of the Epithelial Na+ Channels Influences Exhaled Na+ in Healthy Humans

    PubMed Central

    Foxx-Lupo, William T.; Wheatley, Courtney M.; Baker, Sarah E.; Cassuto, Nicholas A.; Delamere, Nicholas A.; Snyder, Eric M.

    2011-01-01

    Epithelial Na+ Channels (ENaC) are located on alveolar cells and are important in β2-adrenergic receptor-mediated lung fluid clearance through the removal of Na+ from the alveolar airspace. Previous work has demonstrated that genetic variation of the alpha subunit of ENaC at amino acid 663 is important in channel function: cells with the genotype resulting in alanine at amino acid 663 (A663) demonstrate attenuated function when compared to genotypes with at least one allele encoding threonine (T663, AT/TT). We sought to determine the influence of genetic variation at position 663 of ENaC on exhaled Na+ in healthy humans. Exhaled Na+ was measured in 18 AA and 13 AT/TT subjects (age=27±8 vs. 30±10yrs., ht.=174±12 vs. 171±10cm., wt=68±12 vs. 73±14kg., BMI=22±3 vs. 25±4kg/m2, mean±SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90 minutes following the administration of a nebulized β2-agonist (albuterol sulfate, 2.5mg diluted in 3ml normal saline). The AA group had a higher baseline level of exhaled Na+ and a greater response to β2-agonist stimulation (baseline= 3.1±1.8 vs. 2.3±1.5mmol/l; 30min-post= 2.1±0.7 vs. 2.2±0.8mmol/l; 60min-post= 2.0±0.5 vs. 2.3±1.0mmol/l; 90min-post= 1.8±0.8 vs. 2.6±1.5mmol/l, mean±SD, for AA and AT/TT, respectively, p<0.05). The results are consistent with the notion that genetic variation of ENaC influences β2-adrenergic receptor stimulated Na+ clearance in the lungs, as there was a significant reduction in exhaled Na+ over time in the AA group. PMID:21889619

  12. Alternate circulation and genetic variation of human respiratory syncytial virus genotypes in Chengdu, West China, 2009-2014.

    PubMed

    Hu, Pengwei; Zheng, Tianli; Chen, Jiayi; Zhou, Tao; Chen, Yuhang; Xu, Xin; Pei, Xiaofang

    2017-01-01

    Human respiratory syncytial virus (HRSV) is a major pathogen that causes worldwide seasonal epidemic disease in infants due to its genetic variations. However, published information on the molecular epidemiology of HRSV was never reported particularly in Chengdu of West China. During five consecutive seasons (from 2009 to 2014), 433 (23.7%) of 1827 samples from hospitalized patients were identified as HRSV positive. Epidemiological characteristics of HRSV revealed that subtype A viruses (62.7%) prevailed in the first three epidemic seasons and faded in the next two seasons, while subtype B viruses (37.3%) kept circulating in five epidemic periods. According to the phylogenetic analysis of glycoprotein (G) gene, five HRSV genotypes NA1, ON1, BA9, BA-C, and CB1 were found in Chengdu. The predominant circulating genotype changed from NA1 in the period of 2010-2012 to BA9 of 2013-2014. The newly emerging ON1 was first reported in West China in October 2013. The early genotypes BA-C and CB1 were replaced by the prevailing BA9 after the third epidemic peak. Genetic mutations in glycosylation sites of G protein were found in HRSV variants, suggesting the virus is able to escape the immune recognition and attack. This study elucidated the local HRSV epidemic was associated with the alternate circulation of multiple genotypes and with the change of glycosylation sites of G protein. J. Med. Virol. 89:32-40, 2017. © 2016 Wiley Periodicals, Inc.

  13. Genetic sources of population epigenomic variation.

    PubMed

    Taudt, Aaron; Colomé-Tatché, Maria; Johannes, Frank

    2016-06-01

    The field of epigenomics has rapidly progressed from the study of individual reference epigenomes to surveying epigenomic variation in populations. Recent studies in a number of species, from yeast to humans, have begun to dissect the cis- and trans-regulatory genetic mechanisms that shape patterns of population epigenomic variation at the level of single epigenetic marks, as well as at the level of integrated chromatin state maps. We show that this information is paving the way towards a more complete understanding of the heritable basis underlying population epigenomic variation. We also highlight important conceptual challenges when interpreting results from these genetic studies, particularly in plants, in which epigenomic variation can be determined both by genetic and epigenetic inheritance.

  14. Cryptic Genetic Variation in Evolutionary Developmental Genetics.

    PubMed

    Paaby, Annalise B; Gibson, Greg

    2016-06-13

    Evolutionary developmental genetics has traditionally been conducted by two groups: Molecular evolutionists who emphasize divergence between species or higher taxa, and quantitative geneticists who study variation within species. Neither approach really comes to grips with the complexities of evolutionary transitions, particularly in light of the realization from genome-wide association studies that most complex traits fit an infinitesimal architecture, being influenced by thousands of loci. This paper discusses robustness, plasticity and lability, phenomena that we argue potentiate major evolutionary changes and provide a bridge between the conceptual treatments of macro- and micro-evolution. We offer cryptic genetic variation and conditional neutrality as mechanisms by which standing genetic variation can lead to developmental system drift and, sheltered within canalized processes, may facilitate developmental transitions and the evolution of novelty. Synthesis of the two dominant perspectives will require recognition that adaptation, divergence, drift and stability all depend on similar underlying quantitative genetic processes-processes that cannot be fully observed in continuously varying visible traits.

  15. Cryptic Genetic Variation in Evolutionary Developmental Genetics

    PubMed Central

    Paaby, Annalise B.; Gibson, Greg

    2016-01-01

    Evolutionary developmental genetics has traditionally been conducted by two groups: Molecular evolutionists who emphasize divergence between species or higher taxa, and quantitative geneticists who study variation within species. Neither approach really comes to grips with the complexities of evolutionary transitions, particularly in light of the realization from genome-wide association studies that most complex traits fit an infinitesimal architecture, being influenced by thousands of loci. This paper discusses robustness, plasticity and lability, phenomena that we argue potentiate major evolutionary changes and provide a bridge between the conceptual treatments of macro- and micro-evolution. We offer cryptic genetic variation and conditional neutrality as mechanisms by which standing genetic variation can lead to developmental system drift and, sheltered within canalized processes, may facilitate developmental transitions and the evolution of novelty. Synthesis of the two dominant perspectives will require recognition that adaptation, divergence, drift and stability all depend on similar underlying quantitative genetic processes—processes that cannot be fully observed in continuously varying visible traits. PMID:27304973

  16. The human complement factor H: functional roles, genetic variations and disease associations.

    PubMed

    Rodríguez de Córdoba, Santiago; Esparza-Gordillo, Jorge; Goicoechea de Jorge, Elena; Lopez-Trascasa, Margarita; Sánchez-Corral, Pilar

    2004-06-01

    Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease.

  17. Finding the molecular basis of complex genetic variation in humans and mice

    PubMed Central

    Mott, Richard

    2006-01-01

    I survey the state of the art in complex trait analysis, including the use of new experimental and computational technologies and resources becoming available, and the challenges facing us. I also discuss how the prospects of rodent model systems compare with association mapping in humans. PMID:16524828

  18. Genetic variations in the serotonergic system contribute to amygdala volume in humans

    PubMed Central

    Li, Jin; Chen, Chunhui; Wu, Karen; Zhang, Mingxia; Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K.; Dong, Qi

    2015-01-01

    The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63–65% heritability of amygdala structure. To understand the “missing heritability,” we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure. PMID:26500508

  19. Comparing maternal genetic variation across two millennia reveals the demographic history of an ancient human population in southwest Turkey

    PubMed Central

    Ottoni, Claudio; Willet, Rinse; Claeys, Johan; Talloen, Peter; Van de Vijver, Katrien; Chikhi, Lounès; Poblome, Jeroen; Decorte, Ronny

    2016-01-01

    More than two decades of archaeological research at the site of Sagalassos, in southwest Turkey, resulted in the study of the former urban settlement in all its features. Originally settled in late Classical/early Hellenistic times, possibly from the later fifth century BCE onwards, the city of Sagalassos and its surrounding territory saw empires come and go. The Plague of Justinian in the sixth century CE, which is considered to have caused the death of up to a third of the population in Anatolia, and an earthquake in the seventh century CE, which is attested to have devastated many monuments in the city, may have severely affected the contemporary Sagalassos community. Human occupation continued, however, and Byzantine Sagalassos was eventually abandoned around 1200 CE. In order to investigate whether these historical events resulted in demographic changes across time, we compared the mitochondrial DNA variation of two population samples from Sagalassos (Roman and Middle Byzantine) and a modern sample from the nearby town of Ağlasun. Our analyses revealed no genetic discontinuity across two millennia in the region and Bayesian coalescence-based simulations indicated that a major population decline in the area coincided with the final abandonment of Sagalassos, rather than with the Plague of Justinian or the mentioned earthquake. PMID:26998313

  20. Genetic variation in the Cytb gene of human cerebral Taenia solium cysticerci recovered from clinically and radiologically heterogeneous patients with neurocysticercosis.

    PubMed

    Palafox-Fonseca, Héctor; Zúñiga, Gerardo; Bobes, Raúl José; Govezensky, Tzipe; Piñero, Daniel; Texco-Martínez, Laura; Fleury, Agnès; Proaño, Jefferson; Cárdenas, Graciela; Hernández, Marisela; Sciutto, Edda; Fragoso, Gladis

    2013-11-01

    Neurocysticercosis (NC) is a clinically and radiologically heterogeneous parasitic disease caused by the establishment of larval Taenia solium in the human central nervous system. Host and/or parasite variations may be related to this observed heterogeneity. Genetic differences between pig and human-derived T. solium cysticerci have been reported previously. In this study, 28 cysticerci were surgically removed from 12 human NC patients, the mitochondrial gene that encodes cytochrome b was amplified from the cysticerci and genetic variations that may be related to NC heterogeneity were characterised. Nine different haplotypes (Ht), which were clustered in four haplogroups (Hg), were identified. Hg 3 and 4 exhibited a tendency to associate with age and gender, respectively. However, no significant associations were found between NC heterogeneity and the different T. solium cysticerci Ht or Hg. Parasite variants obtained from patients with similar NC clinical or radiological features were genetically closer than those found in groups of patients with a different NC profile when using the Mantel test. Overall, this study establishes the presence of genetic differences in the Cytb gene of T. solium isolated from human cysticerci and suggests that parasite variation could contribute to NC heterogeneity.

  1. Genetic variation in the Cytb gene of human cerebral Taenia solium cysticerci recovered from clinically and radiologically heterogeneous patients with neurocysticercosis

    PubMed Central

    Palafox-Fonseca, Héctor; Zúñiga, Gerardo; Bobes, Raúl José; Govezensky, Tzipe; Piñero, Daniel; Texco-Martínez, Laura; Fleury, Agnès; Proaño, Jefferson; Cárdenas, Graciela; Hernández, Marisela; Sciutto, Edda; Fragoso, Gladis

    2013-01-01

    Neurocysticercosis (NC) is a clinically and radiologically heterogeneous parasitic disease caused by the establishment of larval Taenia solium in the human central nervous system. Host and/or parasite variations may be related to this observed heterogeneity. Genetic differences between pig and human-derived T. solium cysticerci have been reported previously. In this study, 28 cysticerci were surgically removed from 12 human NC patients, the mitochondrial gene that encodes cytochrome b was amplified from the cysticerci and genetic variations that may be related to NC heterogeneity were characterised. Nine different haplotypes (Ht), which were clustered in four haplogroups (Hg), were identified. Hg 3 and 4 exhibited a tendency to associate with age and gender, respectively. However, no significant associations were found between NC heterogeneity and the different T. solium cysticerci Ht or Hg. Parasite variants obtained from patients with similar NC clinical or radiological features were genetically closer than those found in groups of patients with a different NC profile when using the Mantel test. Overall, this study establishes the presence of genetic differences in the Cytb gene of T. solium isolated from human cysticerci and suggests that parasite variation could contribute to NC heterogeneity. PMID:24271046

  2. Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions.

    PubMed

    Izumi, Aiko; Iijima, Yoshimi; Noguchi, Hiroko; Numakawa, Tadahiro; Okada, Takeya; Hori, Hiroaki; Kato, Tadafumi; Tatsumi, Masahiko; Kosuga, Asako; Kamijima, Kunitoshi; Asada, Takashi; Arima, Kunimasa; Saitoh, Osamu; Shiosaka, Sadao; Kunugi, Hiroshi

    2008-12-01

    Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n=439), major depression (n=409), bipolar disorder (n=207), and controls (n=727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n=166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3' regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P=0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P=0.016) and verbal IQ (P<0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.

  3. Genetic variation in cultivated Rheum tanguticum populations

    PubMed Central

    Hu, Yanping; Xie, Xiaolong; Wang, Li; Zhang, Huaigang; Yang, Jian; Li, Yi

    2014-01-01

    To examine whether cultivation reduced genetic variation in the important Chinese medicinal plant Rheum tanguticum, the levels and distribution of genetic variation were investigated using ISSR markers. Fifty-eight R. tanguticum individuals from five cultivated populations were studied. Thirteen primers were used and a total of 320 DNA bands were scored. High levels of genetic diversity were detected in cultivated R. tanguticum (PPB = 82.19, H = 0.2498, HB = 0.3231, I = 0.3812) and could be explained by the outcrossing system, as well as long-lived and human-mediated seed exchanges. Analysis of molecular variance (AMOVA) showed that more genetic variation was found within populations (76.1%) than among them (23.9%). This was supported by the coefficient of gene differentiation (Gst = 0.2742) and Bayesian analysis (θB = 0.1963). The Mantel test revealed no significant correlation between genetic and geographic distances among populations (r = 0.1176, p = 0.3686). UPGMA showed that the five cultivated populations were separated into three clusters, which was in good accordance with the results provided by the Bayesian software STRUCTURE (K = 3). A short domestication history and no artificial selection may be an effective way of maintaining and conserving the gene pools of wild R. tanguticum. PMID:25249777

  4. Methodology for the analysis of rare genetic variation in genome-wide association and re-sequencing studies of complex human traits

    PubMed Central

    Moutsianas, Loukas

    2014-01-01

    Genome-wide association studies have been successful in identifying common variants that impact complex human traits and diseases. However, despite this success, the joint effects of these variants explain only a small proportion of the genetic variance in these phenotypes, leading to speculation that rare genetic variation might account for much of the ‘missing heritability’. Consequently, there has been an exciting period of research and development into the methodology for the analysis of rare genetic variants, typically by considering their joint effects on complex traits within the same functional unit or genomic region. In this review, we describe a general framework for modelling the joint effects of rare genetic variants on complex traits in association studies of unrelated individuals. We summarise a range of widely used association tests that have been developed from this model and provide an overview of the relative performance of these approaches from published simulation studies. PMID:24916163

  5. A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

    PubMed

    Bartha, István; Carlson, Jonathan M; Brumme, Chanson J; McLaren, Paul J; Brumme, Zabrina L; John, Mina; Haas, David W; Martinez-Picado, Javier; Dalmau, Judith; López-Galíndez, Cecilio; Casado, Concepción; Rauch, Andri; Günthard, Huldrych F; Bernasconi, Enos; Vernazza, Pietro; Klimkait, Thomas; Yerly, Sabine; O'Brien, Stephen J; Listgarten, Jennifer; Pfeifer, Nico; Lippert, Christoph; Fusi, Nicolo; Kutalik, Zoltán; Allen, Todd M; Müller, Viktor; Harrigan, P Richard; Heckerman, David; Telenti, Amalio; Fellay, Jacques

    2013-10-29

    HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10(-12)). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the 'intermediate phenotype' nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host-pathogen interaction. DOI:http://dx.doi.org/10.7554/eLife.01123.001.

  6. Human immune system variation

    PubMed Central

    Brodin, Petter; Davis, Mark M.

    2017-01-01

    The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual’s immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases. PMID:27916977

  7. Sex reduces genetic variation: a multidisciplinary review.

    PubMed

    Gorelick, Root; Heng, Henry H Q

    2011-04-01

    For over a century, the paradigm has been that sex invariably increases genetic variation, despite many renowned biologists asserting that sex decreases most genetic variation. Sex is usually perceived as the source of additive genetic variance that drives eukaryotic evolution vis-à-vis adaptation and Fisher's fundamental theorem. However, evidence for sex decreasing genetic variation appears in ecology, paleontology, population genetics, and cancer biology. The common thread among many of these disciplines is that sex acts like a coarse filter, weeding out major changes, such as chromosomal rearrangements (that are almost always deleterious), but letting minor variation, such as changes at the nucleotide or gene level (that are often neutral), flow through the sexual sieve. Sex acts as a constraint on genomic and epigenetic variation, thereby limiting adaptive evolution. The diverse reasons for sex reducing genetic variation (especially at the genome level) and slowing down evolution may provide a sufficient benefit to offset the famed costs of sex.

  8. Genetic variation and its maintenance

    SciTech Connect

    Roberts, D.F.; De Stefano, G.F.

    1986-01-01

    This book contains several papers divided among three sections. The section titles are: Genetic Diversity--Its Dimensions; Genetic Diversity--Its Origin and Maintenance; and Genetic Diversity--Applications and Problems of Complex Characters.

  9. Genetic analysis of TOR complex gene variation with human longevity: a nested case-control study of American men of Japanese ancestry.

    PubMed

    Morris, Brian J; Donlon, Timothy A; He, Qimei; Grove, John S; Masaki, Kamal H; Elliott, Ayako; Willcox, D Craig; Allsopp, Richard; Willcox, Bradley J

    2015-02-01

    The mechanistic target of rapamycin (mTOR) pathway is crucial for life span determination in model organisms. The aim of the present study was to test tagging single-nucleotide polymorphisms that captured most of the genetic variation across key TOR complex 1 (TORC1) and TOR complex 2 (TORC2) genes MTOR, RPTOR, and RICTOR and the important downstream effector gene RPS6KA1 for association with human longevity (defined as attainment of at least 95 years of age) as well as health span phenotypes. Subjects comprised a homogeneous population of American men of Japanese ancestry, well characterized for aging phenotypes and who have been followed for 48 years. The study used a nested case-control design involving 440 subjects aged 95 years and older and 374 controls. It found no association of 6 tagging single-nucleotide polymorphisms for MTOR, 61 for RPTOR, 7 for RICTOR, or 5 for RPS6KA1 with longevity. Of 40 aging-related phenotypes, no significant association with genotype was seen. Thus common genetic variation (minor allele frequency ≥10%) in MTOR, RPTOR, RICTOR, and RPS6KA1 is not associated with extreme old age or aging phenotypes in this population. Further research is needed to assess the potential genetic contribution of other mTOR pathway genes to human longevity, gene expression, upstream and downstream targets, and clinically relevant aging phenotypes.

  10. Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function

    PubMed Central

    Hariri, Ahmad R.; Gorka, Adam; Hyde, Luke W.; Kimak, Mark; Halder, Indrani; Ducci, Francesca; Ferrell, Robert E.; Goldman, David; Manuck, Stephen B.

    2011-01-01

    Background Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. Methods Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. Results Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. Conclusions Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity. PMID:19103437

  11. Population genetic analysis of the DARC locus (Duffy) reveals adaptation from standing variation associated with malaria resistance in humans

    PubMed Central

    Taravella, Angela M.; Bustamante, Carlos D.; Sikora, Martin

    2017-01-01

    The human DARC (Duffy antigen receptor for chemokines) gene encodes a membrane-bound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. We estimate the time to most recent common ancestor (TMRCA) of the most common FY*O haplotype to be 42 kya (95% CI: 34–49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011–0.18), which is among the strongest estimated in the human genome. We estimate the TMRCA of the FY*A mutation in non-Africans to be 57 kya (95% CI: 48–65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and ≠Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause. PMID:28282382

  12. Impact of Genetic Variation on Human CaMKK2 Regulation by Ca2+-Calmodulin and Multisite Phosphorylation

    PubMed Central

    O’Brien, Matthew T.; Oakhill, Jonathan S.; Ling, Naomi X. Y.; Langendorf, Christopher G.; Hoque, Ashfaqul; Dite, Toby A.; Means, Anthony R.; Kemp, Bruce E.; Scott, John W.

    2017-01-01

    The Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity is strongly associated with prostate and hepatic cancers, whereas reduced CaMKK2 activity has been linked to schizophrenia and bipolar disease in humans. Here we report the functional effects of nine rare-variant point mutations that were detected in large-scale human genetic studies and cancer tissues, all of which occur close to two regulatory phosphorylation sites and the catalytic site on human CaMKK2. Four mutations (G87R, R139W, R142W and E268K) cause a marked decrease in Ca2+-independent autonomous activity, however S137L and P138S mutants displayed increased autonomous and Ca2+-CaM stimulated activities. Furthermore, the G87R mutant is defective in Thr85-autophosphorylation dependent autonomous activity, whereas the A329T mutation rendered CaMKK2 virtually insensitive to Ca2+-CaM stimulation. The G87R and R139W mutants behave as dominant-negative inhibitors of CaMKK2 signaling in cells as they block phosphorylation of the downstream substrate AMP-activated protein kinase (AMPK) in response to ionomycin. Our study provides insight into functionally disruptive, rare-variant mutations in human CaMKK2, which have the potential to influence risk and burden of disease associated with aberrant CaMKK2 activity in human populations carrying these variants. PMID:28230171

  13. Genetic Variation among Staphylococcus aureus Strains from Bovine Milk and Their Relevance to Methicillin-Resistant Isolates from Humans

    PubMed Central

    Hata, Eiji; Katsuda, Ken; Kobayashi, Hideki; Uchida, Ikuo; Tanaka, Kiyoshi; Eguchi, Masashi

    2010-01-01

    In genetic analysis of bovine Staphylococcus aureus isolates that are recognized as an important pathogenic bacterium in bovine mastitis, multilocus sequence typing (MLST) showed strong correlation to the results of pulsed-field gel electrophoresis, coa PCR-restriction fragment length polymorphism (RFLP), spa typing, and the coagulase serotyping method. According to MLST results, strains derived from sequence type 97 (ST97) and ST705 were suggested as not only dominant bovine S. aureus lineages in Japan but also pandemic bovine S. aureus lineages. Although both lineages seem to be distantly related to each other by phylogenetic analysis, both had common characteristics, i.e., lukM/lukF′-PV and coagulase serotype VI. These characteristics were very rare among minor bovine strains and human strains and may contribute to the host specificity of these lineages. Four methicillin-resistant S. aureus (MRSA) isolates were first confirmed from bovine milk in Japan; these isolates showed geno- and serotypes that were identical or similar to those of human MRSA isolates in Japan (ST5, staphylococcal cassette chromosome mec type II [SCCmec II], Spa type t002 or t375, and coagulase serotype II, and ST89, SCCmec IIIa, Spa type t5266, and coagulase serotype I). ST5 and ST89 are uncommon among bovine isolates in the world, whereas these STs are common among human MRSA isolates in Japan. PMID:20392913

  14. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis

    PubMed Central

    Wang, Liuyang; Ko, Emily R.; Gilchrist, James J.; Pittman, Kelly J.; Rautanen, Anna; Pirinen, Matti; Thompson, J. Will; Dubois, Laura G.; Langley, Raymond J.; Jaslow, Sarah L.; Salinas, Raul E.; Rouse, D. Clayburn; Moseley, M. Arthur; Mwarumba, Salim; Njuguna, Patricia; Mturi, Neema; Williams, Thomas N.; Scott, J. Anthony G.; Hill, Adrian V. S.; Woods, Christopher W.; Ginsburg, Geoffrey S.; Tsalik, Ephraim L.; Ko, Dennis C.

    2017-01-01

    Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway’s substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting. PMID:28345042

  15. Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa

    PubMed Central

    Pearson-Fuhrhop, Kristin M.; Minton, Brian; Acevedo, Daniel; Shahbaba, Babak; Cramer, Steven C.

    2013-01-01

    Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity

  16. Host Genetic Control of the Microbiome in Humans and Maise or Relating Host Genetic Variation to the Microbiome (2011 JGI User Meeting)

    SciTech Connect

    Ley, Ruth

    2011-03-23

    The U.S. Department of Energy Joint Genome Institute (JGI) invited scientists interested in the application of genomics to bioenergy and environmental issues, as well as all current and prospective users and collaborators, to attend the annual DOE JGI Genomics of Energy & Environment Meeting held March 22-24, 2011 in Walnut Creek, Calif. The emphasis of this meeting was on the genomics of renewable energy strategies, carbon cycling, environmental gene discovery, and engineering of fuel-producing organisms. The meeting features presentations by leading scientists advancing these topics. Ruth Ley of Cornell University gives a presentation on "Relating Host Genetic Variation to the Microbiome" at the 6th annual Genomics of Energy & Environment Meeting on March 23, 2011.

  17. Host Genetic Control of the Microbiome in Humans and Maise or Relating Host Genetic Variation to the Microbiome (2011 JGI User Meeting)

    ScienceCinema

    Ley, Ruth [Cornell University

    2016-07-12

    The U.S. Department of Energy Joint Genome Institute (JGI) invited scientists interested in the application of genomics to bioenergy and environmental issues, as well as all current and prospective users and collaborators, to attend the annual DOE JGI Genomics of Energy & Environment Meeting held March 22-24, 2011 in Walnut Creek, Calif. The emphasis of this meeting was on the genomics of renewable energy strategies, carbon cycling, environmental gene discovery, and engineering of fuel-producing organisms. The meeting features presentations by leading scientists advancing these topics. Ruth Ley of Cornell University gives a presentation on "Relating Host Genetic Variation to the Microbiome" at the 6th annual Genomics of Energy & Environment Meeting on March 23, 2011.

  18. Genetic variation in innate immunity pathways and their potential contribution to the SIRS/CARS debate: evidence from human studies and animal models.

    PubMed

    Kumpf, Oliver; Schumann, Ralf R

    2010-01-01

    The lack of a causal and successful treatment for sepsis has led to a re-evaluation of the condition's pathophysiology. The failure of anti-inflammatory strategies has implied compensatory immunosuppression to play a central part in fatal clinical cases. While searching for novel therapeutic strategies, the question arose whether pro-inflammation (systemic inflammatory response syndrome, SIRS) or anti-inflammation (compensatory anti-inflammatory response syndrome, CARS) are dominant in sepsis, and may be counteracted by therapeutic measures. Here we ask whether in a given organism--man or mouse--the lack of any functional protein involved in this cascade may help in understanding the events. In humans, genetic variations exist, and some of them have functional consequences altering the inflammatory response to pathogens. In mice, knockout animals were created, which may assist us in understanding the SIRS/CARS cascade. Here we summarize data on genetic variations in the TLR- and cytokine system and their influence on course of infectious diseases and sepsis. In addition, we summarize animal experiments and conclude that both cascades may be needed for containing infection. Imbalances in both the pro- and anti-inflammatory system may be harmful. Thus, interventional strategies have to be introduced carefully, and in the future genetic profiling may be needed in order to tailor therapies in the best way.

  19. Patterns of human genetic variation inferred from comparative analysis of allelic mutations in blood group antigen genes.

    PubMed

    Patnaik, Santosh Kumar; Blumenfeld, Olga O

    2011-03-01

    Comparative analysis of allelic variation of a gene sheds light on the pattern and process of its diversification at the population level. Gene families for which a large number of allelic forms have been verified by sequencing provide a useful resource for such studies. In this regard, human blood group-encoding genes are unique in that differences of cell surface traits among individuals and populations can be readily detected by serological screening, and correlation between the variant cell surface phenotype and the genotype is, in most cases, unequivocal. Here, we perform a comprehensive analysis of allelic forms, compiled in the Blood Group Antigen Gene Mutation database, of ABO, RHD/CE, GYPA/B/E and FUT1/2 gene families that encode the ABO, RH, MNS, and H/h blood group system antigens, respectively. These genes are excellent illustrative examples showing distinct mutational patterns among the alleles, and leading to speculation on how their origin may have been driven by recurrent but different molecular mechanisms. We illustrate how alignment of alleles of a gene may provide an additional insight into the DNA variation process and its pathways, and how this approach may serve to catalog alleles of a gene, simplifying the task and content of mutation databases.

  20. Genetic Variations in Vesicoureteral Reflux Sequelae

    PubMed Central

    Hains, David S.; Schwaderer, Andrew L.

    2016-01-01

    Urinary tract infections (UTI) are a common condition in children. Vesicoureteral reflux (VUR) represents a common associated condition with childhood UTI. UTI susceptibility appears to have a genetic component based on family and UTI cohort studies. Targeted analysis of innate immune system genetic variations indicate that these variations are important in UTI susceptibility. In this overview, we discuss how current cohorts and genetic strategies can be implemented to discover new susceptibility loci in patients with UTI. PMID:26848692

  1. Maintenance of genetic variation in human personality: testing evolutionary models by estimating heritability due to common causal variants and investigating the effect of distant inbreeding.

    PubMed

    Verweij, Karin J H; Yang, Jian; Lahti, Jari; Veijola, Juha; Hintsanen, Mirka; Pulkki-Råback, Laura; Heinonen, Kati; Pouta, Anneli; Pesonen, Anu-Katriina; Widen, Elisabeth; Taanila, Anja; Isohanni, Matti; Miettunen, Jouko; Palotie, Aarno; Penke, Lars; Service, Susan K; Heath, Andrew C; Montgomery, Grant W; Raitakari, Olli; Kähönen, Mika; Viikari, Jorma; Räikkönen, Katri; Eriksson, Johan G; Keltikangas-Järvinen, Liisa; Lehtimäki, Terho; Martin, Nicholas G; Järvelin, Marjo-Riitta; Visscher, Peter M; Keller, Matthew C; Zietsch, Brendan P

    2012-10-01

    Personality traits are basic dimensions of behavioral variation, and twin, family, and adoption studies show that around 30% of the between-individual variation is due to genetic variation. There is rapidly growing interest in understanding the evolutionary basis of this genetic variation. Several evolutionary mechanisms could explain how genetic variation is maintained in traits, and each of these makes predictions in terms of the relative contribution of rare and common genetic variants to personality variation, the magnitude of nonadditive genetic influences, and whether personality is affected by inbreeding. Using genome-wide single nucleotide polymorphism (SNP) data from > 8000 individuals, we estimated that little variation in the Cloninger personality dimensions (7.2% on average) is due to the combined effect of common, additive genetic variants across the genome, suggesting that most heritable variation in personality is due to rare variant effects and/or a combination of dominance and epistasis. Furthermore, higher levels of inbreeding were associated with less socially desirable personality trait levels in three of the four personality dimensions. These findings are consistent with genetic variation in personality traits having been maintained by mutation-selection balance.

  2. P450 GENETIC VARIATION: IMPLICATIONS FOR ENVIRONMENTAL AND WORKPLACE EXPOSURE

    EPA Science Inventory

    The Cytochrome P450 array detoxifies many chemicals by catalyzing the conversion of mostly hydrophobic chemicals into more hydrophilic forms that can subsequently be excreted by the body. Human genetic variation in the genes for these enzymes produces wide variations in the abili...

  3. Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function.

    PubMed

    Jørgensen, Stine; Have, Christian Theil; Underwood, Christina Rye; Johansen, Lars Dan; Wellendorph, Petrine; Gjesing, Anette Prior; Jørgensen, Christinna V; Quan, Shi; Rui, Gao; Inoue, Asuka; Linneberg, Allan; Grarup, Niels; Jun, Wang; Pedersen, Oluf; Hansen, Torben; Bräuner-Osborne, Hans

    2017-01-27

    GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers.

  4. Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis

    PubMed Central

    Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas E.; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger. T.; Schipper, Marguerite E. I.; Verheem, André; Wijmenga, Cisca; Gooszen, Hein G.; van Erpecum, Karel J.

    2014-01-01

    Background Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis. Methods Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs. Results In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology. Conclusion We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a

  5. The Genetic Contribution to Phenological Variation

    NASA Astrophysics Data System (ADS)

    Friedman, J. M.; Roelle, J. E.; Cade, B. S.

    2009-12-01

    Variation in phenology is often attributed to a changing climate. However, in wild populations some of the variation in phenology over space and time is a consequence of genetic variation. We used a common garden consisting of paired collections of native and introduced riparian trees sampled along a latitudinal gradient to explore the genetic component of latitudinal phenological variation. The garden in Fort Collins, Colorado (latitude 40.6°N), included 681 native plains cottonwood (Populus deltoides subsp. monilifera) and introduced saltcedar (Tamarix ramosissima, T. chinensis and hybrids) collected from 15 sites at 29.2-47.6°N in the central United States. In the common garden both species showed latitudinal variation in fall, but not spring, leaf phenology, demonstrating that the latitudinal gradient in fall phenology observed in the field reflects both genetic and climatic variation, while the latitudinal gradient in spring phenology observed in the field reflects climatic variation alone. In contrast, cold hardiness showed strong genetic variation in both fall and spring for both species. The latitudinal variation in fall phenology and cold hardiness of saltcedar appears to have evolved through hybridization and natural selection in the 150 years since introduction. We suggest that phenological networks observing wild populations include marked trees replicated in common gardens to distinguish genetic and environmental influences on phenology.

  6. [The Human Genome Project, genetic viability and genetic epidemiology].

    PubMed

    Hagymási, Krisztina; Tulassay, Zsolt

    2005-12-18

    The goal of the Human Genome Project to elucidate the complete sequence of the human genome has been achieved. The aims of the "post-genome" era are explaining the genetic information, characterisation of functional elements encoded in the human genome and mapping the human genetic variability as well. Two unrelated human beings also share 99.9% of their genomic sequence. The difference of 0.1% is the result of genetic polymorphisms: single nucleotide polymorphisms, repetitive sequences and insertion/deletion. The genetic differences, coupled with environmental exposures will determine the phenotypic variation we observe in health or disease. The disease-causing genetic variants can be identified by linkage analysis or association studies. The knowledge of human genome and application of multiple biomarkers will improve our ability to identify individuals at risk, so that preventive interventions can be applied, earlier diagnosis can be made and treatment can be optimized.

  7. Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies

    PubMed Central

    Gluskin, B S; Mickey, B J

    2016-01-01

    The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence disease risk and pharmacological response. Numerous molecular imaging studies have tested whether common genetic variants influence D2 receptor binding potential (BP) in humans, but demonstration of robust effects has been limited by small sample sizes. We performed a systematic search of published human in vivo molecular imaging studies to estimate effect sizes of common genetic variants on striatal D2 receptor BP. We identified 21 studies examining 19 variants in 11 genes. The most commonly studied variant was a single-nucleotide polymorphism in ANKK1 (rs1800497, Glu713Lys, also called ‘Taq1A'). Fixed- and random-effects meta-analyses of this variant (5 studies, 194 subjects total) revealed that striatal BP was significantly and robustly lower among carriers of the minor allele (Lys713) relative to major allele homozygotes. The weighted standardized mean difference was −0.57 under the fixed-effect model (95% confidence interval=(−0.87, −0.27), P=0.0002). The normal relationship between rs1800497 and BP was not apparent among subjects with neuropsychiatric diseases. Significant associations with baseline striatal D2 receptor BP have been reported for four DRD2 variants (rs1079597, rs1076560, rs6277 and rs1799732) and a PER2 repeat polymorphism, but none have yet been tested in more than two independent samples. Our findings resolve apparent discrepancies in the literature and establish that rs1800497 robustly influences striatal D2 receptor availability. This genetic variant is likely to contribute to important individual differences in human striatal function, neuropsychiatric disease risk and pharmacological response. PMID:26926883

  8. Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases.

    PubMed

    Wallace, Douglas C

    2013-07-19

    Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist-selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies.

  9. Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases

    PubMed Central

    Wallace, Douglas C.

    2013-01-01

    Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist–selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies. PMID:23754818

  10. Genetic variation in natural honeybee populations, Apis mellifera capensis

    NASA Astrophysics Data System (ADS)

    Hepburn, Randall; Neumann, Peter; Radloff, Sarah E.

    2004-09-01

    Genetic variation in honeybee, Apis mellifera, populations can be considerably influenced by breeding and commercial introductions, especially in areas with abundant beekeeping. However, in southern Africa apiculture is based on the capture of wild swarms, and queen rearing is virtually absent. Moreover, the introduction of European subspecies constantly failed in the Cape region. We therefore hypothesize a low human impact on genetic variation in populations of Cape honeybees, Apis mellifera capensis. A novel solution to studying genetic variation in honeybee populations based on thelytokous worker reproduction is applied to test this hypothesis. Environmental effects on metrical morphological characters of the phenotype are separated to obtain a genetic residual component. The genetic residuals are then re-calculated as coefficients of genetic variation. Characters measured included hair length on the abdomen, width and length of wax plate, and three wing angles. The data show for the first time that genetic variation in Cape honeybee populations is independent of beekeeping density and probably reflects naturally occurring processes such as gene flow due to topographic and climatic variation on a microscale.

  11. Normal genetic variation of the human foot: part 1: the paradox of normal anatomical alignment in an evolutionary epigenetic context.

    PubMed

    Quinn, Greg

    2012-01-01

    Molecular genetics is changing our understanding of the developmental translation of genotype to phenotype between and within different phylogenetic groups. Together with a growing understanding of our own evolutionary relationships to common ancestors, the epigenetic processes involved enforce a reexamination of what is regarded as a normal foot structure. A revised populationist approach is proposed and supported by paleoanthropologic evidence that reflects a picture of emerging suitability for bipedalism that is driven by natural genetic divergence.

  12. The landscape of human STR variation.

    PubMed

    Willems, Thomas; Gymrek, Melissa; Highnam, Gareth; Mittelman, David; Erlich, Yaniv

    2014-11-01

    Short tandem repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across more than 1000 individuals in Phase 1 of the 1000 Genomes Project. Extensive quality controls show that reliable allelic spectra can be obtained for close to 90% of the STR loci in the genome. We utilize this call set to analyze determinants of STR variation, assess the human reference genome's representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations.

  13. The landscape of human STR variation

    PubMed Central

    Willems, Thomas; Gymrek, Melissa; Highnam, Gareth; Mittelman, David

    2014-01-01

    Short tandem repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across more than 1000 individuals in Phase 1 of the 1000 Genomes Project. Extensive quality controls show that reliable allelic spectra can be obtained for close to 90% of the STR loci in the genome. We utilize this call set to analyze determinants of STR variation, assess the human reference genome’s representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. PMID:25135957

  14. Personalized Medicine and Human Genetic Diversity

    PubMed Central

    Lu, Yi-Fan; Goldstein, David B.; Angrist, Misha; Cavalleri, Gianpiero

    2014-01-01

    Human genetic diversity has long been studied both to understand how genetic variation influences risk of disease and infer aspects of human evolutionary history. In this article, we review historical and contemporary views of human genetic diversity, the rare and common mutations implicated in human disease susceptibility, and the relevance of genetic diversity to personalized medicine. First, we describe the development of thought about diversity through the 20th century and through more modern studies including genome-wide association studies (GWAS) and next-generation sequencing. We introduce several examples, such as sickle cell anemia and Tay–Sachs disease that are caused by rare mutations and are more frequent in certain geographical populations, and common treatment responses that are caused by common variants, such as hepatitis C infection. We conclude with comments about the continued relevance of human genetic diversity in medical genetics and personalized medicine more generally. PMID:25059740

  15. Predictors of Variation in CYP2A6 mRNA, Protein, and Enzyme Activity in a Human Liver Bank: Influence of Genetic and Nongenetic Factors.

    PubMed

    Tanner, Julie-Anne; Prasad, Bhagwat; Claw, Katrina G; Stapleton, Patricia; Chaudhry, Amarjit; Schuetz, Erin G; Thummel, Kenneth E; Tyndale, Rachel F

    2017-01-01

    Cytochrome P450 2A6 CYP2A6: metabolizes several clinically relevant substrates, including nicotine, the primary psychoactive component in cigarette smoke. Smokers vary widely in their rate of inactivation and clearance of nicotine, altering numerous smoking phenotypes. We aimed to characterize independent and shared impact of genetic and nongenetic sources of variation in CYP2A6 mRNA, protein, and enzyme activity in a human liver bank (n = 360). For the assessment of genetic factors, we quantified levels of CYP2A6, cytochrome P450 oxidoreductase (POR), and aldo-keto reductase 1D1 (AKR1D1) mRNA, and CYP2A6 and POR proteins. CYP2A6 enzyme activity was determined through measurement of cotinine formation from nicotine and 7-hydroxycoumarin formation from coumarin. Donor DNA was genotyped for CYP2A6, POR, and AKR1D1 genetic variants. Nongenetic factors assessed included gender, age, and liver disease. CYP2A6 phenotype measures were positively correlated to each other (r values ranging from 0.47-0.88, P < 0.001). Female donors exhibited higher CYP2A6 mRNA expression relative to males (P < 0.05). Donor age was weakly positively correlated with CYP2A6 protein (r = 0.12, P < 0.05) and activity (r = 0.20, P < 0.001). CYP2A6 reduced-function genotypes, but not POR or AKR1D1 genotypes, were associated with lower CYP2A6 protein (P < 0.001) and activity (P < 0.01). AKR1D1 mRNA was correlated with CYP2A6 mRNA (r = 0.57, P < 0.001), protein (r = 0.30, P < 0.001), and activity (r = 0.34, P < 0.001). POR protein was correlated with CYP2A6 activity (r = 0.45, P < 0.001). Through regression analyses, we accounted for 17% (P < 0.001), 37% (P < 0.001), and 77% (P < 0.001) of the variation in CYP2A6 mRNA, protein, and activity, respectively. Overall, several independent and shared sources of variation in CYP2A6 activity in vitro have been identified, which could translate to variable hepatic clearance of nicotine.

  16. Community Engagement about Genetic Variation Research

    PubMed Central

    Christensen, Kurt D.; Metosky, Susan; Rudofsky, Gayle; Deignan, Kathleen P.; Martinez, Hulda; Johnson-Moore, Penelope; Citrin, Toby

    2012-01-01

    Abstract The aim of this article is to describe the methods and effectiveness of the Public Engagement in Genetic Variation and Haplotype Mapping Issues (PEGV) Project, which engaged a community in policy discussion about genetic variation research. The project implemented a 6-stage community engagement model in New Rochelle, New York. First, researchers recruited community partners. Second, the project team created community oversight. Third, focus groups discussed concerns generated by genetic variation research. Fourth, community dialogue sessions addressed focus group findings and developed policy recommendations. Fifth, a conference was held to present these policy recommendations and to provide a forum for HapMap (haplotype mapping) researchers to dialogue directly with residents. Finally, findings were disseminated via presentations and papers to the participants and to the wider community beyond. The project generated a list of proposed guidelines for genetic variation research that addressed the concerns of New Rochelle residents. Project team members expressed satisfaction with the engagement model overall but expressed concerns about how well community groups were utilized and what segment of the community actually engaged in the project. The PEGV Project represents a model for researchers to engage the general public in policy development about genetic research. There are benefits of such a process beyond the desired genetic research. (Population Health Management 2012;15:78–89) PMID:21815821

  17. Genetic Variations Involved in Vitamin E Status

    PubMed Central

    Borel, Patrick; Desmarchelier, Charles

    2016-01-01

    Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and α-tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE. PMID:27983595

  18. The population genetic theory of hidden variation and genetic robustness.

    PubMed

    Hermisson, Joachim; Wagner, Günter P

    2004-12-01

    One of the most solid generalizations of transmission genetics is that the phenotypic variance of populations carrying a major mutation is increased relative to the wild type. At least some part of this higher variance is genetic and due to release of previously hidden variation. Similarly, stressful environments also lead to the expression of hidden variation. These two observations have been considered as evidence that the wild type has evolved robustness against genetic variation, i.e., genetic canalization. In this article we present a general model for the interaction of a major mutation or a novel environment with the additive genetic basis of a quantitative character under stabilizing selection. We introduce an approximation to the genetic variance in mutation-selection-drift balance that includes the previously used stochastic Gaussian and house-of-cards approximations as limiting cases. We then show that the release of hidden genetic variation is a generic property of models with epistasis or genotype-environment interaction, regardless of whether the wild-type genotype is canalized or not. As a consequence, the additive genetic variance increases upon a change in the environment or the genetic background even if the mutant character state is as robust as the wild-type character. Estimates show that this predicted increase can be considerable, in particular in large populations and if there are conditionally neutral alleles at the loci underlying the trait. A brief review of the relevant literature suggests that the assumptions of this model are likely to be generic for polygenic traits. We conclude that the release of hidden genetic variance due to a major mutation or environmental stress does not demonstrate canalization of the wild-type genotype.

  19. Genetic architecture of natural variation in visual senescence in Drosophila

    PubMed Central

    Carbone, Mary Anna; Yamamoto, Akihiko; Huang, Wen; Lyman, Rachel A.; Meadors, Tess Brune; Yamamoto, Ryoan; Anholt, Robert R. H.; Mackay, Trudy F. C.

    2016-01-01

    Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span. PMID:27791033

  20. High Points of Human Genetics

    ERIC Educational Resources Information Center

    Stern, Curt

    1975-01-01

    Discusses such high points of human genetics as the study of chromosomes, somatic cell hybrids, the population formula: the Hardy-Weinberg Law, biochemical genetics, the single-active X Theory, behavioral genetics and finally how genetics can serve humanity. (BR)

  1. GEMINI: integrative exploration of genetic variation and genome annotations.

    PubMed

    Paila, Umadevi; Chapman, Brad A; Kirchner, Rory; Quinlan, Aaron R

    2013-01-01

    Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and adaptable set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploration. Whereas other methods provide an inflexible set of variant filters or prioritization methods, GEMINI allows researchers to compose complex queries based on sample genotypes, inheritance patterns, and both pre-installed and custom genome annotations. GEMINI also provides methods for ad hoc queries and data exploration, a simple programming interface for custom analyses that leverage the underlying database, and both command line and graphical tools for common analyses. We demonstrate GEMINI's utility for exploring variation in personal genomes and family based genetic studies, and illustrate its ability to scale to studies involving thousands of human samples. GEMINI is designed for reproducibility and flexibility and our goal is to provide researchers with a standard framework for medical genomics.

  2. GEMINI: Integrative Exploration of Genetic Variation and Genome Annotations

    PubMed Central

    Paila, Umadevi; Chapman, Brad A.; Kirchner, Rory; Quinlan, Aaron R.

    2013-01-01

    Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and adaptable set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploration. Whereas other methods provide an inflexible set of variant filters or prioritization methods, GEMINI allows researchers to compose complex queries based on sample genotypes, inheritance patterns, and both pre-installed and custom genome annotations. GEMINI also provides methods for ad hoc queries and data exploration, a simple programming interface for custom analyses that leverage the underlying database, and both command line and graphical tools for common analyses. We demonstrate GEMINI's utility for exploring variation in personal genomes and family based genetic studies, and illustrate its ability to scale to studies involving thousands of human samples. GEMINI is designed for reproducibility and flexibility and our goal is to provide researchers with a standard framework for medical genomics. PMID:23874191

  3. The effect of moderate acute psychological stress on working memory-related neural activity is modulated by a genetic variation in catecholaminergic function in humans.

    PubMed

    Qin, Shaozheng; Cousijn, Helena; Rijpkema, Mark; Luo, Jing; Franke, Barbara; Hermans, Erno J; Fernández, Guillén

    2012-01-01

    Acute stress has an important impact on higher-order cognitive functions supported by the prefrontal cortex (PFC) such as working memory (WM). In rodents, such effects are mediated by stress-induced alterations in catecholaminergic signaling, but human data in support of this notion is lacking. A common variation in the gene encoding Catechol-O-methyltransferase (COMT) is known to affect basal catecholaminergic availability and PFC functions. Here, we investigated whether this genetic variation (Val158Met) modulates effects of stress on WM-related neural activity in humans. In a counterbalanced crossover design, 41 healthy young men underwent functional magnetic resonance imaging (fMRI) while performing a numerical N-back WM task embedded in a stressful or neutral context. Moderate psychological stress was induced by a well-controlled procedure involving viewing strongly aversive (versus emotionally neutral) movie material in combination with a self-referencing instruction. Acute stress resulted in genotype-dependent effects on WM performance and WM-related activation in the dorsolateral PFC, with a relatively negative impact of stress in COMT Met-homozygotes as opposed to a relatively positive effect in Val-carriers. A parallel interaction was found for WM-related deactivation in the anterior medial temporal lobe (MTL). Our findings suggest that individuals with higher baseline catecholaminergic availability (COMT Met-homozygotes) appear to reach a supraoptimal state under moderate levels of stress. In contrast, individuals with lower baselines (Val-carriers) may reach an optimal state. Thus, our data show that effects of acute stress on higher-order cognitive functions vary depending on catecholaminergic availability at baseline, and thereby corroborate animal models of catecholaminergic signaling that propose a non-linear relationship between catecholaminergic activity and prefrontal functions.

  4. Cryptic genetic variation in natural populations: a predictive framework.

    PubMed

    Ledón-Rettig, Cris C; Pfennig, David W; Chunco, Amanda J; Dworkin, Ian

    2014-11-01

    Understanding how populations respond to rapid environmental change is critical both for preserving biodiversity and for human health. An increasing number of studies have shown that genetic variation that has no discernable effect under common ecological conditions can become amplified under stressful or novel conditions, suggesting that environmental change per se can provide the raw materials for adaptation. Indeed, the release of such hidden, or "cryptic," genetic variants has been increasingly viewed as playing a general and important role in allowing populations to respond to rapid environmental change. However, additional studies have suggested that there is a balance between cryptic genetic variants that are potentially adaptive in future environments and genetic variants that are deleterious. In this article, we begin by discussing how population and environmental parameters-such as effective population size and the historical frequency and strength of selection under inducing conditions-influence relative amounts of cryptic genetic variation among populations and the overall phenotypic effects of such variation. The amount and distribution of cryptic genetic variation will, in turn, determine the likelihood that cryptic variants, once expressed, will be adaptive or maladaptive during environmental transitions. We then present specific approaches for measuring these parameters in natural populations. Finally, we discuss one natural system that will be conducive to testing whether populations that vary in these parameters harbor different amounts, or types, of cryptic genetic variation. Generally, teasing apart how population and environmental parameters influence the accumulation of cryptic genetic variation will help us to understand how populations endure and adapt (or fail to adapt) to natural environmental change and anthropogenic disturbance.

  5. The probability of parallel genetic evolution from standing genetic variation.

    PubMed

    MacPherson, A; Nuismer, S L

    2017-02-01

    Parallel evolution is often assumed to result from repeated adaptation to novel, yet ecologically similar, environments. Here, we develop and analyse a mathematical model that predicts the probability of parallel genetic evolution from standing genetic variation as a function of the strength of phenotypic selection and constraints imposed by genetic architecture. Our results show that the probability of parallel genetic evolution increases with the strength of natural selection and effective population size and is particularly likely to occur for genes with large phenotypic effects. Building on these results, we develop a Bayesian framework for estimating the strength of parallel phenotypic selection from genetic data. Using extensive individual-based simulations, we show that our estimator is robust across a wide range of genetic and evolutionary scenarios and provides a useful tool for rigorously testing the hypothesis that parallel genetic evolution is the result of adaptive evolution. An important result that emerges from our analyses is that existing studies of parallel genetic evolution frequently rely on data that is insufficient for distinguishing between adaptive evolution and neutral evolution driven by random genetic drift. Overcoming this challenge will require sampling more populations and the inclusion of larger numbers of loci.

  6. Modeling genetic inheritance of copy number variations

    PubMed Central

    Wang, Kai; Chen, Zhen; Tadesse, Mahlet G.; Glessner, Joseph; Grant, Struan F. A.; Hakonarson, Hakon; Bucan, Maja

    2008-01-01

    Copy number variations (CNVs) are being used as genetic markers or functional candidates in gene-mapping studies. However, unlike single nucleotide polymorphism or microsatellite genotyping techniques, most CNV detection methods are limited to detecting total copy numbers, rather than copy number in each of the two homologous chromosomes. To address this issue, we developed a statistical framework for intensity-based CNV detection platforms using family data. Our algorithm identifies CNVs for a family simultaneously, thus avoiding the generation of calls with Mendelian inconsistency while maintaining the ability to detect de novo CNVs. Applications to simulated data and real data indicate that our method significantly improves both call rates and accuracy of boundary inference, compared to existing approaches. We further illustrate the use of Mendelian inheritance to infer SNP allele compositions in each of the two homologous chromosomes in CNV regions using real data. Finally, we applied our method to a set of families genotyped using both the Illumina HumanHap550 and Affymetrix genome-wide 5.0 arrays to demonstrate its performance on both inherited and de novo CNVs. In conclusion, our method produces accurate CNV calls, gives probabilistic estimates of CNV transmission and builds a solid foundation for the development of linkage and association tests utilizing CNVs. PMID:18832372

  7. Genetic variation of contact dermatitis in broilers.

    PubMed

    Ask, B

    2010-05-01

    This study aimed to investigate the presence of genetic variation in footpad dermatitis (FPD) and hock burns (HB) and the possibility to genetically select against these. A field trial including 10 commercial broiler lines (n = 102 to 265) was carried out at 2 Dutch farms. Footpad dermatitis and HB were subjectively scored at approximately 4, 5, and 7 wk on a scale from 0 through 5. Genetic parameters were estimated in 2 lines based on a larger data set. The overall agreement of repeated FPD and HB scores was high (0.66 to 0.86) and the scoring system was, therefore, considered reliable. Kendall's tau between left and right scores was lower than 1 (FPD: 0.73 and HB: 0.57), and both left and right FPD and HB must, therefore, be evaluated. High prevalences of FPD, but also HB, were achieved in the field trial, but lower prevalences may be sufficient for genetic evaluations and would be less detrimental to welfare. Genetic variation between and within lines was present for both FPD and HB as indicated by between-line differences and heritabilities, and selection against FPD and HB is, therefore, possible. It is important that selection is done against both FPD and HB, and such selection should not have a negative influence on the genetic improvement in BW. In contrast, continued selection for increased BW while ignoring FPD in the breeding goal is likely to lead to an increased propensity to develop FPD in broilers.

  8. Genetic architecture of natural variation in Drosophila melanogaster aggressive behavior.

    PubMed

    Shorter, John; Couch, Charlene; Huang, Wen; Carbone, Mary Anna; Peiffer, Jason; Anholt, Robert R H; Mackay, Trudy F C

    2015-07-07

    Aggression is an evolutionarily conserved complex behavior essential for survival and the organization of social hierarchies. With the exception of genetic variants associated with bioamine signaling, which have been implicated in aggression in many species, the genetic basis of natural variation in aggression is largely unknown. Drosophila melanogaster is a favorable model system for exploring the genetic basis of natural variation in aggression. Here, we performed genome-wide association analyses using the inbred, sequenced lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and replicate advanced intercross populations derived from the most and least aggressive DGRP lines. We identified genes that have been previously implicated in aggressive behavior as well as many novel loci, including gustatory receptor 63a (Gr63a), which encodes a subunit of the receptor for CO2, and genes associated with development and function of the nervous system. Although genes from the two association analyses were largely nonoverlapping, they mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We used mutations and RNAi knock-down alleles to functionally validate 79% of the candidate genes and 75% of the candidate epistatic interactions tested. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies in the outbred populations derived from extreme DGRP lines. This phenomenon may pertain to other fitness traits and species, with implications for evolution, applied breeding, and human genetics.

  9. Human Heredity: Genetic Mechanisms in Humans.

    ERIC Educational Resources Information Center

    Blank, C. E.

    1988-01-01

    Discussed are some of the uncertainties in human genetic mechanisms that are often presented as dogma in Biology textbooks. Presented is a brief historical background and illustrations involving chromosome abnormality in humans and linkage studies in humans. (CW)

  10. Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

    PubMed

    Shumay, E; Fowler, J S; Wang, G-J; Logan, J; Alia-Klein, N; Goldstein, R Z; Maloney, T; Wong, C; Volkow, N D

    2012-03-06

    Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [(11)C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.

  11. Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain

    PubMed Central

    Chen, Jingshan; Lipska, Barbara K.; Halim, Nader; Ma, Quang D.; Matsumoto, Mitsuyuki; Melhem, Samer; Kolachana, Bhaskar S.; Hyde, Thomas M.; Herman, Mary M.; Apud, Jose; Egan, Michael F.; Kleinman, Joel E.; Weinberger, Daniel R.

    2004-01-01

    Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3′ flanking region (rs165599)—both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val—had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3′ SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a

  12. Genetic variation in the natriuretic peptide system and heart failure.

    PubMed

    Lanfear, David E

    2010-05-01

    Heart failure (HF) is a modern epidemic and is one of the few cardiovascular diseases which is increasing in prevalence. The growing importance of the Natriuretic Peptide (NP) system in HF is well recognized. Laboratory tests for B-type Natriuretic Peptide (BNP) have proven value as diagnostic and prognostic tools in HF and are now part of routine clinical care. Furthermore, recombinant atrial natriuretic peptide (ANP) (carperitide) and BNP (nesiritide) and are approved HF therapies in Japan and the US, respectively and additional natriuretic peptides (e.g., CNP, urodilatin, and designer NPs) are under investigation for use in HF. Common genetic sequence variants are increasingly being recognized as determinants of disease risk or drug response and may help explain a portion of the inter-individual variation in the human NP system. This review describes current knowledge of NP system genetic variation as it pertains to HF as well as ongoing studies and where the field is expected to progress in the near future. To briefly summarize, NP system genetic variants have been associated with alterations in gene expression, NP levels, and cardiovascular disease. The next step forward will include specific investigations into how this genetic variation can advance 'Personalized Medicine', such as whether they impact the utility of diagnostic BNP testing or effectiveness of therapeutic NP infusion. This is already in progress, with pharmacogenetic studies of nesiritide currently underway. We expect that within 5 years there should be a reasonable idea of whether NP system genetic variation will have important clinical implications.

  13. Differential Regulation of Cryptic Genetic Variation Shapes the Genetic Interactome Underlying Complex Traits

    PubMed Central

    Yadav, Anupama; Dhole, Kaustubh

    2016-01-01

    Cryptic genetic variation (CGV) refers to genetic variants whose effects are buffered in most conditions but manifest phenotypically upon specific genetic and environmental perturbations. Despite having a central role in adaptation, contribution of CGV to regulation of quantitative traits is unclear. Instead, a relatively simplistic architecture of additive genetic loci is known to regulate phenotypic variation in most traits. In this paper, we investigate the regulation of CGV and its implication on the genetic architecture of quantitative traits at a genome-wide level. We use a previously published dataset of biparental recombinant population of Saccharomyces cerevisiae phenotyped in 34 diverse environments to perform single locus, two-locus, and covariance mapping. We identify loci that have independent additive effects as well as those which regulate the phenotypic manifestation of other genetic variants (variance QTL). We find that whereas additive genetic variance is predominant, a higher order genetic interaction network regulates variation in certain environments. Despite containing pleiotropic loci, with effects across environments, these genetic networks are highly environment specific. CGV is buffered under most allelic combinations of these networks and perturbed only in rare combinations resulting in high phenotypic variance. The presence of such environment specific genetic networks is the underlying cause of abundant gene–environment interactions. We demonstrate that overlaying identified molecular networks on such genetic networks can identify potential candidate genes and underlying mechanisms regulating phenotypic variation. Such an integrated approach applied to human disease datasets has the potential to improve the ability to predict disease predisposition and identify specific therapeutic targets. PMID:28172852

  14. Assessment of Human Tribbles Homolog 3 Genetic Variation (rs2295490) Effects on Type 2 Diabetes Patients with Glucose Control and Blood Pressure Lowering Treatment.

    PubMed

    He, Fazhong; Liu, Mouze; Chen, Zhangren; Liu, Guojing; Wang, Zhenmin; Liu, Rong; Luo, Jianquan; Tang, Jie; Wang, Xingyu; Liu, Xin; Zhou, Honghao; Chen, Xiaoping; Liu, Zhaoqian; Zhang, Wei

    2016-11-01

    Effects of human tribbles homolog 3 (TRIB3) genetic variation (c.251 A>G, Gln84Arg, rs2295490) on the clinical outcomes of vascular events has not been evaluated in patients with type 2 diabetes after blood pressure lowering and glucose controlling treatment. We did an analysis of a 2×2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled clinical trial at 61 centers in China, with a follow-up period of 5years. The major vascular endpoints were the composites of death from cardio-cerebral vascular diseases, non-fatal stroke and myocardial infraction, new or worsening renal and diabetic eye disease. A total of 1884 participants were included in our research with a 4.8years median follow-up. For glucose lowering axis, patients with TRIB3 (rs2295490) AA (n=609) genotype exhibited significantly reduced risk of major vascular events compared with AG+GG (n=335) genotype carriers (Hazard ratio 0.72, 95% CI 0.55-0.94, p=0.016), Paradoxically, the risk of vascular events were significantly increased in patients with AA (n=621) compared to AG+GG (n=319) genotype for intensive glucose control (Hazard ratio 1.46, 95% CI, 1.06-2.17, 35 p=0.018). For blood pressure lowering axis, marginally significant difference was found between TRIB3 variant and coronary events. Our findings suggest that good glucose and blood pressure control exhibited greater benefits on vascular outcomes in patients with TRIB3 (rs2295490) G allele.

  15. Genetic variation in attachment glycoprotein genes of human respiratory syncytial virus subgroups a and B in children in recent five consecutive years.

    PubMed

    Cui, Guanglin; Zhu, Runan; Qian, Yuan; Deng, Jie; Zhao, Linqing; Sun, Yu; Wang, Fang

    2013-01-01

    Human respiratory syncytial virus (HRSV) outranks other viral agents as the cause of respiratory tract diseases in children worldwide. Molecular epidemiological study of the virus provides useful information for the development of globally effective vaccine. We investigated the circulating pattern and genetic variation in the attachment glycoprotein genes of HRSV in Beijing during 5 consecutive seasons from 2007 to 2012. Out of 19,942 tested specimens, 3,160 (15.8%) were HRSV antigen-positive. The incidence of HRSV infection in males was significantly higher than in females. Of the total 723 (23.1%) randomly selected HRSV antigen-positive samples, 462 (63.9%) and 239 (33.1%) samples were identified as subgroup A and B, respectively. Subgroups A and B co-circulated in the 5 consecutive HRSV seasons, which showed a shifting mixed pattern of subgroup dominance. Complete G gene sequences were obtained from 190 HRSV-A and 72 HRSV-B by PCR for phylogenetic analysis. Although 4 new genotypes, NA3 and NA4 for HRSV-A and BA-C and CB1 for HRSV-B, were identified here, they were not predominant; NA1 and BA9 were the prevailing HRSV-A and -B genotypes, respectively. We provide the first report of a 9 consecutive nucleotide insertion in 3 CB1 genotype strains. One Beijing strain of ON1 genotype with a 72 nucleotide insertion was found among samples collected in February 2012. The reversion of codon states in glycosylation sites to previous ones were found from HRSV strains in this study, suggesting an immune-escape strategy of this important virus.

  16. Identifying environmental correlates of intraspecific genetic variation.

    PubMed

    Harrisson, K A; Yen, J D L; Pavlova, A; Rourke, M L; Gilligan, D; Ingram, B A; Lyon, J; Tonkin, Z; Sunnucks, P

    2016-09-01

    Genetic variation is critical to the persistence of populations and their capacity to adapt to environmental change. The distribution of genetic variation across a species' range can reveal critical information that is not necessarily represented in species occurrence or abundance patterns. We identified environmental factors associated with the amount of intraspecific, individual-based genetic variation across the range of a widespread freshwater fish species, the Murray cod Maccullochella peelii. We used two different approaches to statistically quantify the relative importance of predictor variables, allowing for nonlinear relationships: a random forest model and a Bayesian approach. The latter also accounted for population history. Both approaches identified associations between homozygosity by locus and both disturbance to the natural flow regime and mean annual flow. Homozygosity by locus was negatively associated with disturbance to the natural flow regime, suggesting that river reaches with more disturbed flow regimes may support larger, more genetically diverse populations. Our findings are consistent with the hypothesis that artificially induced perennial flows in regulated channels may provide greater and more consistent habitat and reduce the frequency of population bottlenecks that can occur frequently under the highly variable and unpredictable natural flow regime of the system. Although extensive river regulation across eastern Australia has not had an overall positive effect on Murray cod numbers over the past century, regulation may not represent the primary threat to Murray cod survival. Instead, pressures other than flow regulation may be more critical to the persistence of Murray cod (for example, reduced frequency of large floods, overfishing and chemical pollution).

  17. Basic principles and laboratory analysis of genetic variation.

    PubMed

    Gonzalez-Bosquet, Jesus; Chanock, Stephen J

    2011-01-01

    With the draft of the human genome and advances in technology, the approach toward mapping complex diseases and traits has changed. Human genetics has evolved into the study of the genome as a complex structure harbouring clues for multifaceted disease risk with the majority still unknown. The discovery of new candidate regions by genome-wide association studies (GWAS) has changed strategies for the study of genetic predisposition. More genome-wide, "agnostic" approaches, with increasing numbers of participants from high-quality epidemiological studies are for the first time replicating results in different settings. However, new-found regions (which become the new candidate "genes") require extensive follow-up and investigation of their functional significance. Understanding the true effect of genetic variability on the risk of complex diseases is paramount. The importance of designing high-quality studies to assess environmental contributions, as well as the interactions between genes and exposures, cannot be stressed enough. This chapter will address the basic issues of genetic variation, including population genetics, as well as analytical platforms and tools needed to investigate the contribution of genetics to human diseases and traits.

  18. Genetics and recent human evolution.

    PubMed

    Templeton, Alan R

    2007-07-01

    Starting with "mitochondrial Eve" in 1987, genetics has played an increasingly important role in studies of the last two million years of human evolution. It initially appeared that genetic data resolved the basic models of recent human evolution in favor of the "out-of-Africa replacement" hypothesis in which anatomically modern humans evolved in Africa about 150,000 years ago, started to spread throughout the world about 100,000 years ago, and subsequently drove to complete genetic extinction (replacement) all other human populations in Eurasia. Unfortunately, many of the genetic studies on recent human evolution have suffered from scientific flaws, including misrepresenting the models of recent human evolution, focusing upon hypothesis compatibility rather than hypothesis testing, committing the ecological fallacy, and failing to consider a broader array of alternative hypotheses. Once these flaws are corrected, there is actually little genetic support for the out-of-Africa replacement hypothesis. Indeed, when genetic data are used in a hypothesis-testing framework, the out-of-Africa replacement hypothesis is strongly rejected. The model of recent human evolution that emerges from a statistical hypothesis-testing framework does not correspond to any of the traditional models of human evolution, but it is compatible with fossil and archaeological data. These studies also reveal that any one gene or DNA region captures only a small part of human evolutionary history, so multilocus studies are essential. As more and more loci became available, genetics will undoubtedly offer additional insights and resolutions of human evolution.

  19. Genetic Variation in Healthy Oldest-Old

    PubMed Central

    Halaschek-Wiener, Julius; Amirabbasi-Beik, Mahsa; Monfared, Nasim; Pieczyk, Markus; Sailer, Christian; Kollar, Anita; Thomas, Ruth; Agalaridis, Georgios; Yamada, So; Oliveira, Lisa; Collins, Jennifer A.; Meneilly, Graydon; Marra, Marco A.; Madden, Kenneth M.; Le, Nhu D.; Connors, Joseph M.; Brooks-Wilson, Angela R.

    2009-01-01

    Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the ‘oldest-old’), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs. PMID:19680556

  20. Genetic variation in healthy oldest-old.

    PubMed

    Halaschek-Wiener, Julius; Amirabbasi-Beik, Mahsa; Monfared, Nasim; Pieczyk, Markus; Sailer, Christian; Kollar, Anita; Thomas, Ruth; Agalaridis, Georgios; Yamada, So; Oliveira, Lisa; Collins, Jennifer A; Meneilly, Graydon; Marra, Marco A; Madden, Kenneth M; Le, Nhu D; Connors, Joseph M; Brooks-Wilson, Angela R

    2009-08-14

    Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.

  1. Explaining additional genetic variation in complex traits

    PubMed Central

    Robinson, Matthew R.; Wray, Naomi R.; Visscher, Peter M.

    2015-01-01

    Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits, discovering >6000 variants associated with >500 quantitative traits and common complex diseases in humans. The associations identified so far represent only a fraction of those which influence phenotype, as there are likely to be very many variants across the entire frequency spectrum, each of which influences multiple traits, with only a small average contribution to the phenotypic variance. This presents a considerable challenge to further dissection of the remaining unexplained genetic variance within populations, which limits our ability to predict disease risk, identify new drug targets, improve and maintain food sources, and understand natural diversity. This challenge will be met within the current framework through larger sample size, better phenotyping including recording of non-genetic risk factors, focused study designs, and an integration of multiple sources of phenotypic and genetic information. The current evidence supports the application of quantitative genetic approaches, and we argue that one should retain simpler theories until simplicity can be traded for greater explanatory power. PMID:24629526

  2. Metric dental variation of major human populations.

    PubMed

    Hanihara, Tsunehiko; Ishida, Hajime

    2005-10-01

    Mesiodistal and buccolingual crown diameters of all teeth recorded in 72 major human population groups and seven geographic groups were analyzed. The results obtained are fivefold. First, the largest teeth are found among Australians, followed by Melanesians, Micronesians, sub-Saharan Africans, and Native Americans. Philippine Negritos, Jomon/Ainu, and Western Eurasians have small teeth, while East/Southeast Asians and Polynesians are intermediate in overall tooth size. Second, in terms of odontometric shape factors, world extremes are Europeans, aboriginal New World populations, and to a lesser extent, Australians. Third, East/Southeast Asians share similar dental features with sub-Saharan Africans, and fall in the center of the phenetic space occupied by a wide array of samples. Fourth, the patterning of dental variation among major geographic populations is more or less consistent with those obtained from genetic and craniometric data. Fifth, once differences in population size between sub-Saharan Africa, Europe, South/West Asia, Australia, and Far East, and genetic drift are taken into consideration, the pattern of sub-Saharan African distinctiveness becomes more or less comparable to that based on genetic and craniometric data. As such, worldwide patterning of odontometric variation provides an additional avenue in the ongoing investigation of the origin(s) of anatomically modern humans.

  3. The majority of genetic variation in orangutan personality and subjective well-being is nonadditive.

    PubMed

    Adams, Mark James; King, James E; Weiss, Alexander

    2012-07-01

    The heritability of human personality is well-established. Recent research indicates that nonadditive genetic effects, such as dominance and epistasis, play a large role in personality variation. One possible explanation for the latter finding is that there has been recent selection on human personality. To test this possibility, we estimated additive and nonadditive genetic variance in personality and subjective well-being of zoo-housed orangutans. More than half of the genetic variance in these traits could be attributed to nonadditive genetic effects, modeled as dominance. Subjective well-being had genetic overlap with personality, though less so than has been found in humans or chimpanzees. Since a large portion of nonadditive genetic variance in personality is not unique to humans, the nonadditivity of human personality is not sufficient evidence for recent selection of personality in humans. Nonadditive genetic variance may be a general feature of the genetic structure of personality in primates and other animals.

  4. 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

  5. Genetic basis of metabolome variation in yeast.

    PubMed

    Breunig, Jeffrey S; Hackett, Sean R; Rabinowitz, Joshua D; Kruglyak, Leonid

    2014-03-01

    Metabolism, the conversion of nutrients into usable energy and biochemical building blocks, is an essential feature of all cells. The genetic factors responsible for inter-individual metabolic variability remain poorly understood. To investigate genetic causes of metabolome variation, we measured the concentrations of 74 metabolites across ~ 100 segregants from a Saccharomyces cerevisiae cross by liquid chromatography-tandem mass spectrometry. We found 52 quantitative trait loci for 34 metabolites. These included linkages due to overt changes in metabolic genes, e.g., linking pyrimidine intermediates to the deletion of ura3. They also included linkages not directly related to metabolic enzymes, such as those for five central carbon metabolites to ira2, a Ras/PKA pathway regulator, and for the metabolites, S-adenosyl-methionine and S-adenosyl-homocysteine to slt2, a MAP kinase involved in cell wall integrity. The variant of ira2 that elevates metabolite levels also increases glucose uptake and ethanol secretion. These results highlight specific examples of genetic variability, including in genes without prior known metabolic regulatory function, that impact yeast metabolism.

  6. Genetic Basis of Metabolome Variation in Yeast

    PubMed Central

    Breunig, Jeffrey S.; Hackett, Sean R.; Rabinowitz, Joshua D.; Kruglyak, Leonid

    2014-01-01

    Metabolism, the conversion of nutrients into usable energy and biochemical building blocks, is an essential feature of all cells. The genetic factors responsible for inter-individual metabolic variability remain poorly understood. To investigate genetic causes of metabolome variation, we measured the concentrations of 74 metabolites across 100 segregants from a Saccharomyces cerevisiae cross by liquid chromatography-tandem mass spectrometry. We found 52 quantitative trait loci for 34 metabolites. These included linkages due to overt changes in metabolic genes, e.g., linking pyrimidine intermediates to the deletion of ura3. They also included linkages not directly related to metabolic enzymes, such as those for five central carbon metabolites to ira2, a Ras/PKA pathway regulator, and for the metabolites, S-adenosyl-methionine and S-adenosyl-homocysteine to slt2, a MAP kinase involved in cell wall integrity. The variant of ira2 that elevates metabolite levels also increases glucose uptake and ethanol secretion. These results highlight specific examples of genetic variability, including in genes without prior known metabolic regulatory function, that impact yeast metabolism. PMID:24603560

  7. A simple genetic architecture underlies morphological variation in dogs.

    PubMed

    Boyko, Adam R; Quignon, Pascale; Li, Lin; Schoenebeck, Jeffrey J; Degenhardt, Jeremiah D; Lohmueller, Kirk E; Zhao, Keyan; Brisbin, Abra; Parker, Heidi G; vonHoldt, Bridgett M; Cargill, Michele; Auton, Adam; Reynolds, Andy; Elkahloun, Abdel G; Castelhano, Marta; Mosher, Dana S; Sutter, Nathan B; Johnson, Gary S; Novembre, John; Hubisz, Melissa J; Siepel, Adam; Wayne, Robert K; Bustamante, Carlos D; Ostrander, Elaine A

    2010-08-10

    Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (< or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.

  8. Basic Genetics: A Human Approach.

    ERIC Educational Resources Information Center

    Biological Sciences Curriculum Study, Colorado Springs, CO. Center for Education in Human and Medical Genetics.

    This document (which has the form of a magazine) provides a variety of articles, stories, editorials, letters, interviews, and other types of magazine features (such as book reviews) which focus on human genetics. In addition to providing information about the principles of genetics, nearly all of the sections in the "magazine" address moral,…

  9. Human genetics of diabetic vascular complications.

    PubMed

    Tang, Zi-Hui; Fang, Zhou; Zhou, Linuo

    2013-12-01

    Diabetic vascular complications (DVC) affecting several important organ systems of human body such as the cardiovascular system constitute a major public health problem. There is evidence demonstrating that genetic factors contribute to the risk of DVC genetic variants, structural variants, and epigenetic changes play important roles in the development of DVC. Genetic linkage studies have uncovered a number of genetic loci that may shape the risk of DVC. Genetic association studies have identified many common genetic variants for susceptibility to DVC. Structural variants such as copy number variation and interactions of gene x environment have also been detected by association analysis. Apart from the nuclear genome, mitochondrial DNA plays a critical role in regulation of development of DVC. Epigenetic studies have indicated epigenetic changes in chromatin affecting gene transcription in response to environmental stimuli, which provided a large body of evidence of regulating development of diabetes mellitus. Recently, a new window has opened on identifying rare and common genetic loci through next generation sequencing technologies. This review focusses on the current knowledge of the genetic and epigenetic basis of DVC. Ultimately, identification of genes or genetic loci, structural variants and epigenetic changes contributing to risk of or protection from DVC will help uncover the complex mechanism(s) underlying DVC, with crucial implications for the development of personalized medicine for diabetes mellitus and its complications.

  10. Genetic variation in pea seed globulin composition.

    PubMed

    Tzitzikas, Emmanouil N; Vincken, Jean-Paul; de Groot, Jolan; Gruppen, Harry; Visser, Richard G F

    2006-01-25

    A quantitative characterization of seeds from 59 pea (Pisum sativum L.) lines and relative taxa with various external characteristics and wide geographical origin was performed to explore the genetic variation of pea concerning its starch and protein contents and globulin composition. Pea lines, which produce round, wrinkled, flat, and round-dimpled seeds, have starch as the major reserve, with an average content of 46%. Protein content varied from 13.7 to 30.7% of the seed dry matter, with an overall average of 22.3%. Densitometric quantification of the individual globulins (legumin, vicilin, convicilin, and globulin-related proteins) based on SDS-PAGE gels showed no lines lacking any particular globulin. Among the lines tested, variation was shown in both their total globulins content and their globulin composition. The total globulin content ranged from 49.2 to 81.8% of the total pea protein extract (TPPE). Legumin content varied between 5.9 and 24.5% of the TPPE. Vicilin was the most abundant protein of pea, and its content varied between 26.3 and 52.0% of the TPPE. Both processed and nonprocessed vicilins occurred. The processed vicilin was the predominant one, with values between 17.8 and 40.8%, whereas the nonprocessed ones constituted between 3.1 and 13.5% of the TPPE. Convicilin was the least abundant globulin, and its content ranged from 3.9 to 8.3%. Finally, the globulin-related proteins were present in amounts ranging from 2.8 to 17.3%. They were less abundant in comparison with legumin and vicilin, but they showed the largest relative variation of the four globulin classes. Correlations between the different external characteristics and globulin composition were determined. Comparison with soybean showed that pea lines show more variety in the abundance of globulin proteins, enabling a wider range of food application.

  11. Human pain and genetics: some basics

    PubMed Central

    2013-01-01

    Human pain causes untold misery and suffering, with major impact on functioning and resources. Recent advances in genetics have revealed that subtle changes in DNA could partly explain the variation in individual differences in pain. Various genes encoding for receptors are now known to play a major role in the sensitivity, perception and expression of pain. The fields of epigenetics and proteomics hold promises in the way pain could be treated and managed in future. PMID:26516521

  12. A Multi-scale Computational Platform to Mechanistically Assess the Effect of Genetic Variation on Drug Responses in Human Erythrocyte Metabolism

    PubMed Central

    Bordbar, Aarash; Palsson, Bernhard O.

    2016-01-01

    Progress in systems medicine brings promise to addressing patient heterogeneity and individualized therapies. Recently, genome-scale models of metabolism have been shown to provide insight into the mechanistic link between drug therapies and systems-level off-target effects while being expanded to explicitly include the three-dimensional structure of proteins. The integration of these molecular-level details, such as the physical, structural, and dynamical properties of proteins, notably expands the computational description of biochemical network-level properties and the possibility of understanding and predicting whole cell phenotypes. In this study, we present a multi-scale modeling framework that describes biological processes which range in scale from atomistic details to an entire metabolic network. Using this approach, we can understand how genetic variation, which impacts the structure and reactivity of a protein, influences both native and drug-induced metabolic states. As a proof-of-concept, we study three enzymes (catechol-O-methyltransferase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) and their respective genetic variants which have clinically relevant associations. Using all-atom molecular dynamic simulations enables the sampling of long timescale conformational dynamics of the proteins (and their mutant variants) in complex with their respective native metabolites or drug molecules. We find that changes in a protein’s structure due to a mutation influences protein binding affinity to metabolites and/or drug molecules, and inflicts large-scale changes in metabolism. PMID:27467583

  13. Involvement of endocannabinoids in alcohol “binge” drinking: studies of mice with human fatty acid amide hydrolase genetic variation and after CB1 receptor antagonists

    PubMed Central

    Zhou, Yan; Huang, Ted; Lee, Francis; Kreek, Mary Jeanne

    2016-01-01

    Background The endocannabinoid system has been found to play an important role in modulating alcohol intake. Inhibition or genetic deletion of fatty acid amide hydrolase (FAAH, a key catabolic enzyme for endocannabinoids) leads to increased alcohol consumption and preference in rodent models. A common human single-nucleotide polymorphism (SNP; C385A, rs324420) in the FAAH gene is associated with decreased enzymatic activity of FAAH, resulting in increased anandamide levels in both humans and FAAH C385A knock-in mice. Methods As this FAAH SNP has been reported to be associated with altered alcohol abuse, the present study used these genetic knock-in mice containing the human SNP C385A to determine the impact of variant FAAH gene on alcohol “binge” drinking in the drinking-in-the-dark (DID) model. Results We found that the FAAHA/A mice had greater alcohol intake and preference than the wild-type FAAHC/C mice, suggesting that increased endocannabinoid signaling in FAAHA/A mice led to increased alcohol “binge” consumption. The specificity on alcohol vulnerability was suggested by the lack of any FAAH genotype difference on sucrose or saccharin intake. Using the “binge” DID model, we confirmed that selective CB1 receptor antagonist AM251 reduced alcohol intake in the wild-type mice. Conclusions These data suggest that there is direct and selective involvement of the human FAAH C385A SNP and CB1 receptors in alcohol “binge” drinking. PMID:26857901

  14. Antigenic variation: Molecular and genetic mechanisms of relapsing disease

    SciTech Connect

    Cruse, J.M.; Lewis, R.E.

    1987-01-01

    This book contains 10 chapters. They are: Contemporary Concepts of Antigenic Variation; Antigenic Variation in the Influenza Viruses; Mechanisms of Escape of Visna Lentiviruses from Immunological Control; A Review of Antigenic Variation by the Equine Infectious Anemia Virus; Biologic and Molecular Variations in AIDS Retrovirus Isolates; Rabies Virus Infection: Genetic Mutations and the Impact on Viral Pathogenicity and Immunity; Immunobiology of Relapsing Fever; Antigenic Variation in African Trypanosomes; Antigenic Variation and Antigenic Diversity in Malaria; and Mechanisms of Immune Evasion in Schistosomiasis.

  15. Genetic variation in resistance to ionizing radiation

    SciTech Connect

    Ayala, F.J.

    1991-06-24

    We proposed an investigation of genetically-determined individual differences in sensitivity to ionizing radiation. The model organism is Drosophila melanogaster. The gene coding for Cu,Zn superoxide dismutase (SOD) is the target locus, but the effects of variation in other components of the genome that modulate SOD levels are also taken into account. SOD scavenges oxygen radicals generated during exposure to ionizing radiation. It has been shown to protect against ionizing radiation damage to DNA, viruses, bacteria, mammalian cells, whole mice, and Drosophila. Two alleles, S and F, are commonly found in natural populations of D. melanogaster; in addition we have isolated from a natural population null'' (CA1) mutant that yields only 3.5% of normal SOD activity. The S, F, and CA1 alleles provide an ideal model system to investigate SOD-dependent radioresistance, because each allele yields different levels of SOD, so that S > F >> CA1. The roles of SOD level in radioresistance are being investigated in a series of experiments that measure the somatic and germ-line effects of increasing doses of ionizing radiation. In addition, we have pursued an unexpected genetic event-namely the nearly simultaneous transformation of several lines homozygous for the SOD null'' allele into predominately S lines. Using specifically designed probes and DNA amplification by means of the Tag polymerase chain reaction (PCR) we have shown that (1) the null allele was still present in the transformed lines, but was being gradually replaced by the S allele as a consequence of natural selection; and (2) that the transformation was due to the spontaneous deletion of a 0.68 Kb truncated P-element, the insertion of which is characteristic of the CA1 null allele.

  16. Population genetics of malaria resistance in humans

    PubMed Central

    Hedrick, P W

    2011-01-01

    The high mortality and widespread impact of malaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best-known case studies of strong positive selection in modern humans. I begin by reviewing JBS Haldane's initial contribution to the potential of malaria genetic resistance in humans. Further, I discuss the population genetics aspects of many of the variants, including globin, G6PD deficiency, Duffy, ovalocytosis, ABO and human leukocyte antigen variants. Many of the variants conferring resistance to malaria are ‘loss-of-function' mutants and appear to be recent polymorphisms from the last 5000–10 000 years or less. I discuss estimation of selection coefficients from case–control data and make predictions about the change for S, C and G6PD-deficiency variants. In addition, I consider the predicted joint changes when the two β-globin alleles S and C are both variable in the same population and when there is a variation for α-thalassemia and S, two unlinked, but epistatic variants. As more becomes known about genes conferring genetic resistance to malaria in humans, population genetics approaches can contribute both to investigating past selection and predicting the consequences in future generations for these variants. PMID:21427751

  17. Human cooperation in groups: variation begets variation

    PubMed Central

    Berg, Pieter van den; Molleman, Lucas; Junikka, Jaakko; Puurtinen, Mikael; Weissing, Franz J.

    2015-01-01

    Many experiments on human cooperation have revealed that individuals differ systematically in their tendency to cooperate with others. It has also been shown that individuals condition their behaviour on the overall cooperation level of their peers. Yet, little is known about how individuals respond to heterogeneity in cooperativeness in their neighbourhood. Here, we present an experimental study investigating whether and how people respond to heterogeneous behaviour in a public goods game. We find that a large majority of subjects does respond to heterogeneity in their group, but they respond in quite different ways. Most subjects contribute less to the public good when the contributions of their peers are more heterogeneous, but a substantial fraction of individuals consistently contributes more in this case. In addition, we find that individuals that respond positively to heterogeneity have a higher general cooperation tendency. The finding that social responsiveness occurs in different forms and is correlated with cooperativeness may have important implications for the outcome of cooperative interactions. PMID:26531770

  18. Immunology taught by human genetics.

    PubMed

    Casanova, Jean-Laurent; Abel, Laurent; Quintana-Murci, Lluis

    2013-01-01

    Human genetic studies are rarely conducted for immunological purposes. Instead, they are typically driven by medical and evolutionary goals, such as understanding the predisposition or resistance to infectious or inflammatory diseases, the pathogenesis of such diseases, and human evolution in the context of the long-standing relationships between humans and their commensal and environmental microbes. However, the dissection of these experiments of Nature has also led to major immunological advances. In this review, we draw on some of the immunological lessons learned in the three branches of human molecular genetics most relevant to immunology: clinical genetics, epidemiological genetics, and evolutionary genetics. We argue that human genetics has become a new frontier not only for timely studies of specific features of human immunity, but also for defining general principles of immunity. These studies teach us about immunity as it occurs under "natural" conditions, through the transition from the almost complete wilderness that existed worldwide until about a century ago to the current unevenly distributed medically shaped environment. Hygiene, vaccines, antibiotics, and surgery have considerably decreased the burden of infection, but these interventions have been available only recently, so have yet to have a major impact on patterns of genomic diversity, making it possible to carry out unbiased evolutionary studies at the population level. Clinical genetic studies of childhood phenotypes have not been blurred by modern medicine either. Instead, medical advances have actually facilitated such studies, by making it possible for children with life-threatening infections to survive. In addition, the prevention and treatment of infectious diseases have increased life expectancy at birth from ∼20 yr to ∼80 yr, providing unique opportunities to study the genetic basis of immunological phenomena against which there is no natural counterselection, such as

  19. Comparative RNA sequencing reveals substantial genetic variation in endangered primates.

    PubMed

    Perry, George H; Melsted, Páll; Marioni, John C; Wang, Ying; Bainer, Russell; Pickrell, Joseph K; Michelini, Katelyn; Zehr, Sarah; Yoder, Anne D; Stephens, Matthew; Pritchard, Jonathan K; Gilad, Yoav

    2012-04-01

    Comparative genomic studies in primates have yielded important insights into the evolutionary forces that shape genetic diversity and revealed the likely genetic basis for certain species-specific adaptations. To date, however, these studies have focused on only a small number of species. For the majority of nonhuman primates, including some of the most critically endangered, genome-level data are not yet available. In this study, we have taken the first steps toward addressing this gap by sequencing RNA from the livers of multiple individuals from each of 16 mammalian species, including humans and 11 nonhuman primates. Of the nonhuman primate species, five are lemurs and two are lorisoids, for which little or no genomic data were previously available. To analyze these data, we developed a method for de novo assembly and alignment of orthologous gene sequences across species. We assembled an average of 5721 gene sequences per species and characterized diversity and divergence of both gene sequences and gene expression levels. We identified patterns of variation that are consistent with the action of positive or directional selection, including an 18-fold enrichment of peroxisomal genes among genes whose regulation likely evolved under directional selection in the ancestral primate lineage. Importantly, we found no relationship between genetic diversity and endangered status, with the two most endangered species in our study, the black and white ruffed lemur and the Coquerel's sifaka, having the highest genetic diversity among all primates. Our observations imply that many endangered lemur populations still harbor considerable genetic variation. Timely efforts to conserve these species alongside their habitats have, therefore, strong potential to achieve long-term success.

  20. Genetic & epigenetic approach to human obesity.

    PubMed

    Rao, K Rajender; Lal, Nirupama; Giridharan, N V

    2014-11-01

    Obesity is an important clinical and public health challenge, epitomized by excess adipose tissue accumulation resulting from an imbalance in energy intake and energy expenditure. It is a forerunner for a variety of other diseases such as type-2-diabetes (T2D), cardiovascular diseases, some types of cancer, stroke, hyperlipidaemia and can be fatal leading to premature death. Obesity is highly heritable and arises from the interplay of multiple genes and environmental factors. Recent advancements in Genome-wide association studies (GWAS) have shown important steps towards identifying genetic risks and identification of genetic markers for lifestyle diseases, especially for a metabolic disorder like obesity. According to the 12th Update of Human Obesity Gene Map there are 253 quantity trait loci (QTL) for obesity related phenotypes from 61 genome wide scan studies. Contribution of genetic propensity of individual ethnic and racial variations in obesity is an active area of research. Further, understanding its complexity as to how these variations could influence ones susceptibility to become or remain obese will lead us to a greater understanding of how obesity occurs and hopefully, how to prevent and treat this condition. In this review, various strategies adapted for such an analysis based on the recent advances in genome wide and functional variations in human obesity are discussed.

  1. The African Genome Variation Project shapes medical genetics in Africa.

    PubMed

    Gurdasani, Deepti; Carstensen, Tommy; Tekola-Ayele, Fasil; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin O; Choudhury, Ananyo; Ritchie, Graham R S; Xue, Yali; Asimit, Jennifer; Nsubuga, Rebecca N; Young, Elizabeth H; Pomilla, Cristina; Kivinen, Katja; Rockett, Kirk; Kamali, Anatoli; Doumatey, Ayo P; Asiki, Gershim; Seeley, Janet; Sisay-Joof, Fatoumatta; Jallow, Muminatou; Tollman, Stephen; Mekonnen, Ephrem; Ekong, Rosemary; Oljira, Tamiru; Bradman, Neil; Bojang, Kalifa; Ramsay, Michele; Adeyemo, Adebowale; Bekele, Endashaw; Motala, Ayesha; Norris, Shane A; Pirie, Fraser; Kaleebu, Pontiano; Kwiatkowski, Dominic; Tyler-Smith, Chris; Rotimi, Charles; Zeggini, Eleftheria; Sandhu, Manjinder S

    2015-01-15

    Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

  2. The African Genome Variation Project shapes medical genetics in Africa

    NASA Astrophysics Data System (ADS)

    Gurdasani, Deepti; Carstensen, Tommy; Tekola-Ayele, Fasil; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin O.; Choudhury, Ananyo; Ritchie, Graham R. S.; Xue, Yali; Asimit, Jennifer; Nsubuga, Rebecca N.; Young, Elizabeth H.; Pomilla, Cristina; Kivinen, Katja; Rockett, Kirk; Kamali, Anatoli; Doumatey, Ayo P.; Asiki, Gershim; Seeley, Janet; Sisay-Joof, Fatoumatta; Jallow, Muminatou; Tollman, Stephen; Mekonnen, Ephrem; Ekong, Rosemary; Oljira, Tamiru; Bradman, Neil; Bojang, Kalifa; Ramsay, Michele; Adeyemo, Adebowale; Bekele, Endashaw; Motala, Ayesha; Norris, Shane A.; Pirie, Fraser; Kaleebu, Pontiano; Kwiatkowski, Dominic; Tyler-Smith, Chris; Rotimi, Charles; Zeggini, Eleftheria; Sandhu, Manjinder S.

    2015-01-01

    Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

  3. Mapping human genetic diversity in Asia.

    PubMed

    Abdulla, Mahmood Ameen; Ahmed, Ikhlak; Assawamakin, Anunchai; Bhak, Jong; Brahmachari, Samir K; Calacal, Gayvelline C; Chaurasia, Amit; Chen, Chien-Hsiun; Chen, Jieming; Chen, Yuan-Tsong; Chu, Jiayou; Cutiongco-de la Paz, Eva Maria C; De Ungria, Maria Corazon A; Delfin, Frederick C; Edo, Juli; Fuchareon, Suthat; Ghang, Ho; Gojobori, Takashi; Han, Junsong; Ho, Sheng-Feng; Hoh, Boon Peng; Huang, Wei; Inoko, Hidetoshi; Jha, Pankaj; Jinam, Timothy A; Jin, Li; Jung, Jongsun; Kangwanpong, Daoroong; Kampuansai, Jatupol; Kennedy, Giulia C; Khurana, Preeti; Kim, Hyung-Lae; Kim, Kwangjoong; Kim, Sangsoo; Kim, Woo-Yeon; Kimm, Kuchan; Kimura, Ryosuke; Koike, Tomohiro; Kulawonganunchai, Supasak; Kumar, Vikrant; Lai, Poh San; Lee, Jong-Young; Lee, Sunghoon; Liu, Edison T; Majumder, Partha P; Mandapati, Kiran Kumar; Marzuki, Sangkot; Mitchell, Wayne; Mukerji, Mitali; Naritomi, Kenji; Ngamphiw, Chumpol; Niikawa, Norio; Nishida, Nao; Oh, Bermseok; Oh, Sangho; Ohashi, Jun; Oka, Akira; Ong, Rick; Padilla, Carmencita D; Palittapongarnpim, Prasit; Perdigon, Henry B; Phipps, Maude Elvira; Png, Eileen; Sakaki, Yoshiyuki; Salvador, Jazelyn M; Sandraling, Yuliana; Scaria, Vinod; Seielstad, Mark; Sidek, Mohd Ros; Sinha, Amit; Srikummool, Metawee; Sudoyo, Herawati; Sugano, Sumio; Suryadi, Helena; Suzuki, Yoshiyuki; Tabbada, Kristina A; Tan, Adrian; Tokunaga, Katsushi; Tongsima, Sissades; Villamor, Lilian P; Wang, Eric; Wang, Ying; Wang, Haifeng; Wu, Jer-Yuarn; Xiao, Huasheng; Xu, Shuhua; Yang, Jin Ok; Shugart, Yin Yao; Yoo, Hyang-Sook; Yuan, Wentao; Zhao, Guoping; Zilfalil, Bin Alwi

    2009-12-11

    Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.

  4. Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic–pituitary–adrenal axis: first evidence from two independent subsamples

    PubMed Central

    Ridder, S.; Treutlein, J.; Nees, F.; Lang, S.; Diener, S.; Wessa, M.; Kroll, A.; Pohlack, S.; Cacciaglia, R.; Gass, P.; Schütz, G.; Schumann, G.; Flor, H.

    2012-01-01

    Background Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis. Method In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. Results Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity. Conclusions This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning. PMID:22410078

  5. Dissecting the genetic architecture of human personality.

    PubMed

    Munafò, Marcus R; Flint, Jonathan

    2011-09-01

    The first candidate gene studies of human personality promised much but, in the fifteen years since their publication, have delivered little in the way of clear evidence for the contribution of specific genetic variants to observed variation in personality traits. This is most likely due to the very small effects conferred by individual loci. The advent of genome-wide association studies has brought growing awareness that high levels of statistical stringency, very large sample sizes, and independent replication will be minimum requirements for future genetic studies of personality. At the same time, evidence from other fields indicates that the genetic architecture of personality is likely to consist of the combined effect of many hundreds, if not thousands, of small effect loci.

  6. American Society of Human Genetics

    MedlinePlus

    ... Deficiency October 20, 2016 Parents of Children with Cancer Value Sequencing Results, Even if Non-actionable October 20, 2016 The American Society of Human Genetics, Incorporated 9650 Rockville Pike • Bethesda, Maryland 20814 society@ashg.org • 1-866-HUM-GENE • (301) 634-7300 Privacy Policy

  7. Size variation in Middle Pleistocene humans.

    PubMed

    Arsuaga, J L; Carretero, J M; Lorenzo, C; Gracia, A; Martínez, I; Bermúdez de Castro, J M; Carbonell, E

    1997-08-22

    It has been suggested that European Middle Pleistocene humans, Neandertals, and prehistoric modern humans had a greater sexual dimorphism than modern humans. Analysis of body size variation and cranial capacity variation in the large sample from the Sima de los Huesos site in Spain showed instead that the sexual dimorphism is comparable in Middle Pleistocene and modern populations.

  8. Anatomy, Medical Education, and Human Ancestral Variation

    ERIC Educational Resources Information Center

    Strkalj, Goran; Spocter, Muhammad A.; Wilkinson, A. Tracey

    2011-01-01

    It is argued in this article that the human body both in health and disease cannot be fully understood without adequately accounting for the different levels of human variation. The article focuses on variation due to ancestry, arguing that the inclusion of information pertaining to ancestry in human anatomy teaching materials and courses should…

  9. Human heart rate: Heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a micro-RNA motif in the 3’-UTR of cytochrome b561 (CYB561)

    PubMed Central

    Zhang, Kuixing; Deacon, Dekker C.; Rao, Fangwen; Schork, Andrew J.; Fung, Maple M.; Waalen, Jill; Schork, Nicholas J.; Nievergelt, Caroline M.; Chi, Neil C.; O'Connor, Daniel T.

    2013-01-01

    Objective To understand the role of genetic variation in the catecholamine biosynthetic pathway for control of human heart rate (HR). Background Human HR is an integrated cardiovascular trait predictive of morbidity and survival. Since the autonomic pathway exerts rapid control over the heart, we probed the role of heredity in control of HR, focusing on a component of the autonomic sympathetic pathway already predictive of outflow responses: Cytochrome b561 (CYB561), the electron shuttle in catecholamine vesicle membranes for transmitter biosynthesis. Methods We studied hereditary control of HR with the twin pair design, at rest and during environmental (cold) stress. SNP disruption of a micro-RNA recognition motif in the human CYB561 3’-UTR was identified computationally, and its differential effect on gene expression was demonstrated in a transfected luciferase reporter / 3’-UTR variant. We exposed of stem-cell-derived human embryoid bodies to the micro-RNA mimic or antagomir oligonucleotides, and observed effects on contraction rate in proto-hearts. Results Substantial heritability (h2) was demonstrated, by twin pair variance components, for both basal/resting HR (h2=50.9±6.4% of trait variation, p=2.47E-10) and stress-augmented HR (h2=55.1±5.9%, p=8.79E-13), and the two HR traits shared genetic determination (genetic covariance ρG=0.747±0.058, p=2.85E-09). CYB561 displayed one common genetic variant in the transcript region: A+1485G (rs3087776), in the 3’-UTR, 1485 bp downstream of the termination codon, in a conserved region, with the A-allele ancestral in primates. In a twin/sibling sample (n=576), A+1485G influenced HR, both at rest (p=0.010) and after environmental stress (p=0.002), with the minor (A) allele displaying a recessive effect with lower HR. The effect of A+1485G on HR was extended by meta-analysis into two additional population samples (total n=2579), and the influence remained directionally consistent and significant (p=0.007). A+1485

  10. FINDbase: a worldwide database for genetic variation allele frequencies updated

    PubMed Central

    Georgitsi, Marianthi; Viennas, Emmanouil; Antoniou, Dimitris I.; Gkantouna, Vassiliki; van Baal, Sjozef; Petricoin, Emanuel F.; Poulas, Konstantinos; Tzimas, Giannis; Patrinos, George P.

    2011-01-01

    Frequency of INherited Disorders database (FIND base; http://www.findbase.org) records frequencies of causative genetic variations worldwide. Database records include the population and ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related external resources and the genetic variation together with its frequency in that population. In addition to the regular data content updates, we report the following significant advances: (i) the systematic collection and thorough documentation of population/ethnic group-specific pharmacogenomic markers allele frequencies for 144 markers in 14 genes of pharmacogenomic interest from different classes of drug-metabolizing enzymes and transporters, representing 150 populations and ethnic groups worldwide; (ii) the development of new data querying and visualization tools in the expanded FINDbase data collection, built around Microsoft’s PivotViewer software (http://www.getpivot.com), based on Microsoft Silverlight technology (http://www.silverlight.net) that facilitates querying of large data sets and visualizing the results; and (iii) the establishment of the first database journal, by affiliating FINDbase with Human Genomics and Proteomics, a new open-access scientific journal, which would serve as a prime example of a non-profit model for sustainable database funding. PMID:21113021

  11. Folk beliefs about genetic variation predict avoidance of biracial individuals

    PubMed Central

    Kang, Sonia K.; Plaks, Jason E.; Remedios, Jessica D.

    2015-01-01

    People give widely varying estimates for the amount of genetic overlap that exists between humans. While some laypeople believe that humans are highly genetically similar to one another, others believe that humans share very little genetic overlap. These studies examine how beliefs about genetic overlap affect neural and evaluative reactions to racially-ambiguous and biracial targets. In Study 1, we found that lower genetic overlap estimates predicted a stronger neural avoidance response to biracial compared to monoracial targets. In Study 2, we found that lower genetic overlap estimates predicted longer response times to classify biracial (vs. monoracial) faces into racial categories. In Study 3, we manipulated genetic overlap beliefs and found that participants in the low overlap condition explicitly rated biracial targets more negatively than those in the high overlap condition. Taken together, these data suggest that genetic overlap beliefs influence perceivers’ processing fluency and evaluation of biracial and racially-ambiguous individuals. PMID:25904875

  12. Genetic variation among white croaker populations

    NASA Astrophysics Data System (ADS)

    Han, Zhiqiang; Gao, Tianxiang; Zhuang, Zhimeng; Tang, Qisheng

    2008-02-01

    To investigate the genetic structures and differentiation of different wild populations of white croaker ( Pennahia argentata), horizontal starch gel electrophoresis was performed on 133 individuals collected from five different locations in China and Japan. The eleven enzyme systems revealed 15 loci, of which eleven were polymorphic. The percentage of polymorphic loci of white croaker populations varied from 6.67% to 53.33%; the mean observed and expected heterozygosity ranged from 0.0033 to 0.0133 and 0.0032 to 0.0191, respectively. The expected heterozygosity revealed a low genetic variability for white croaker in comparison with other marine fishes. The genetic distances between populations ranged from 0.00005 to 0.00026. A weak differentiation was observed within each clade and between clades; and no significant differences in gene frequencies among populations were observed in white croaker. Among the five populations, three Chinese populations showed more genetic diversity than that in Japanese populations.

  13. Chromosome Variations And Human Behavior

    ERIC Educational Resources Information Center

    Soudek, D.

    1974-01-01

    Article focused on the science of cytogenetics, which studied the transmission of the units of heredity called chromosomes, and considered the advantage of proper diagnosis of genetic diseases, treated on the chromosomal level. (Author/RK)

  14. Genetics of human metabolism: an update

    PubMed Central

    Kastenmüller, Gabi; Raffler, Johannes; Gieger, Christian; Suhre, Karsten

    2015-01-01

    Genome-wide association studies with metabolomics (mGWAS) identify genetically influenced metabotypes (GIMs), their ensemble defining the heritable part of every human's metabolic individuality. Knowledge of genetic variation in metabolism has many applications of biomedical and pharmaceutical interests, including the functional understanding of genetic associations with clinical end points, design of strategies to correct dysregulations in metabolic disorders and the identification of genetic effect modifiers of metabolic disease biomarkers. Furthermore, it has been shown that GIMs provide testable hypotheses for functional genomics and metabolomics and for the identification of novel gene functions and metabolite identities. mGWAS with growing sample sizes and increasingly complex metabolic trait panels are being conducted, allowing for more comprehensive and systems-based downstream analyses. The generated large datasets of genetic associations can now be mined by the biomedical research community and provide valuable resources for hypothesis-driven studies. In this review, we provide a brief summary of the key aspects of mGWAS, followed by an update of recently published mGWAS. We then discuss new approaches of integrating and exploring mGWAS results and finish by presenting selected applications of GIMs in recent studies. PMID:26160913

  15. Molecular Darwinism: the contingency of spontaneous genetic variation.

    PubMed

    Arber, Werner

    2011-01-01

    The availability of spontaneously occurring genetic variants is an important driving force of biological evolution. Largely thanks to experimental investigations by microbial geneticists, we know today that several different molecular mechanisms contribute to the overall genetic variations. These mechanisms can be assigned to three natural strategies to generate genetic variants: 1) local sequence changes, 2) intragenomic reshuffling of DNA segments, and 3) acquisition of a segment of foreign DNA. In these processes, specific gene products are involved in cooperation with different nongenetic elements. Some genetic variations occur fully at random along the DNA filaments, others rather with a statistical reproducibility, although at many possible sites. We have to be aware that evolution in natural ecosystems is of higher complexity than under most laboratory conditions, not at least in view of symbiotic associations and the occurrence of horizontal gene transfer. The encountered contingency of genetic variation can possibly best ensure a long-term persistence of life under steadily changing living conditions.

  16. Exploiting genomics and natural genetic variation to decode macrophage enhancers

    PubMed Central

    Romanoski, Casey E.; Link, Verena M.; Heinz, Sven; Glass, Christopher K.

    2015-01-01

    The mammalian genome contains on the order of a million enhancer-like regions that are required to establish the identities and functions of specific cell types. Here, we review recent studies in immune cells that have provided insight into the mechanisms that selectively activate certain enhancers in response to cell lineage and environmental signals. We describe a working model wherein distinct classes of transcription factors define the repertoire of active enhancers in macrophages through collaborative and hierarchical interactions, and discuss important challenges to this model, specifically providing examples from T cells. We conclude by discussing the use of natural genetic variation as a powerful approach for decoding transcription factor combinations that play dominant roles in establishing the enhancer landscapes, and the potential that these insights have for advancing our understanding of the molecular causes of human disease. PMID:26298065

  17. Genetic variation in alkaloid accumulation in leaves of Nicotiana.

    PubMed

    Sun, Bo; Zhang, Fen; Zhou, Guo-jun; Chu, Guo-hai; Huang, Fang-fang; Wang, Qiao-mei; Jin, Li-feng; Lin, Fu-cheng; Yang, Jun

    2013-12-01

    Alkaloids are plant secondary metabolites that are widely distributed in Nicotiana species and contribute greatly to the quality of tobacco leaves. Some alkaloids, such as nornicotine and myosmine, have adverse effects on human health. To reduce the content of harmful alkaloids in tobacco leaves through conventional breeding, a genetic study of the alkaloid variation among different genotypes is required. In this study, alkaloid profiles in leaves of five Nicotiana tabacum cultivars and Nicotiana tomentosiformis were investigated. Six alkaloids were identified from all six genotypes via gas chromatograph-mass spectrometry (GC-MS). Significant differences in alkaloid content were observed both among different leaf positions and among cultivars. The contents of nornicotine and myosmine were positively and significantly correlated (R(2)=0.881), and were also separated from those of other alkaloids by clustering. Thus, the genotype plays a major role in alkaloid accumulation, indicating a high potential for manipulation of alkaloid content through traditional breeding.

  18. Independent natural genetic variation of punishment- versus relief-memory

    PubMed Central

    Appel, Mirjam; Kocabey, Samet; Savage, Sinead; König, Christian

    2016-01-01

    A painful event establishes two opponent memories: cues that are associated with pain onset are remembered negatively, whereas cues that coincide with the relief at pain offset acquire positive valence. Such punishment- versus relief-memories are conserved across species, including humans, and the balance between them is critical for adaptive behaviour with respect to pain and trauma. In the fruit fly, Drosophila melanogaster as a study case, we found that both punishment- and relief-memories display natural variation across wild-derived inbred strains, but they do not covary, suggesting a considerable level of dissociation in their genetic effectors. This provokes the question whether there may be heritable inter-individual differences in the balance between these opponent memories in man, with potential psycho-clinical implications. PMID:28003518

  19. Statistical genetics of an annual plant, Impatiens capensis. I. Genetic basis of quantitative variation.

    PubMed

    Mitchell-Olds, T; Bergelson, J

    1990-02-01

    Analysis of quantitative genetics in natural populations has been hindered by computational and methodological problems in statistical analysis. We developed and validated a jackknife procedure to test for existence of broad sense heritabilities and dominance or maternal effects influencing quantitative characters in Impatiens capensis. Early life cycle characters showed evidence of dominance and/or maternal effects, while later characters exhibited predominantly environmental variation. Monte Carlo simulations demonstrate that these jackknife tests of variance components are extremely robust to heterogeneous error variances. Statistical methods from human genetics provide evidence for either a major locus influencing germination date, or genes that affect phenotypic variability per se. We urge explicit consideration of statistical behavior of estimation and testing procedures for proper biological interpretation of statistical results.

  20. Heredity vs. Environment: The Effects of Genetic Variation with Age

    ERIC Educational Resources Information Center

    Gourlay, N.

    1978-01-01

    Major problems in the field are presented through a brief review of Burt's work and a critical account of the Hawaiian and British schools of biometrical genetics. The merits and demerits of Christopher Jencks' study are also discussed. There follows an account of the principle of genetic variation with age, a new concept to the…

  1. The contribution of additive genetic variation to personality variation: heritability of personality.

    PubMed

    Dochtermann, Ned A; Schwab, Tori; Sih, Andrew

    2015-01-07

    Individual animals frequently exhibit repeatable differences from other members of their population, differences now commonly referred to as 'animal personality'. Personality differences can arise, for example, from differences in permanent environmental effects--including parental and epigenetic contributors--and the effect of additive genetic variation. Although several studies have evaluated the heritability of behaviour, less is known about general patterns of heritability and additive genetic variation in animal personality. As overall variation in behaviour includes both the among-individual differences that reflect different personalities and temporary environmental effects, it is possible for personality to be largely genetically influenced even when heritability of behaviour per se is quite low. The relative contribution of additive genetic variation to personality variation can be estimated whenever both repeatability and heritability are estimated for the same data. Using published estimates to address this issue, we found that approximately 52% of animal personality variation was attributable to additive genetic variation. Thus, while the heritability of behaviour is often moderate or low, the heritability of personality is much higher. Our results therefore (i) demonstrate that genetic differences are likely to be a major contributor to variation in animal personality and (ii) support the phenotypic gambit: that evolutionary inferences drawn from repeatability estimates may often be justified.

  2. Genetic aspects of human obesity.

    PubMed

    Larder, Rachel; Lim, Chung Thong; Coll, Anthony P

    2014-01-01

    Obesity and its related metabolic consequences represent a major public health problem. Huge changes within the environment have undoubtedly contributed to the increased prevalence of obesity but genetic factors are also critical in determining an individual's predisposition to gain weight. The last two decades have seen a huge increase in the understanding of the mechanisms controlling appetitive behavior, body composition, and energy expenditure. Many regions throughout the central nervous system play critical roles in these processes but the hypothalamus, in particular, receives and orchestrates a variety of signals to bring about coordinated changes in energy balance. Reviewing data from human genetic and model organism studies, we consider how disruptions of hypothalamic pathways evolved to maintain energy homeostasis and go on to cause obesity. We highlight ongoing technological developments which continue to lead to novel insights and discuss how this increased knowledge may lead to effective therapeutic interventions in the future.

  3. A model for monitoring of Hsp90-buffered genetic variations

    NASA Astrophysics Data System (ADS)

    Kozeko, Liudmyla

    Genetic material of terrestrial organisms can be considerably injured by cosmic rays and UV-radiation in the space environment. Organisms onboard are also exposed to the entire complex of negative physical factors which can generate genetic variations and affect morphogenesis. However, species phenotypes must be robust to genetic variation, requiring "buffering" systems to ensure normal development. The molecular chaperone Hsp90 can serve as such "a buffer". It is important in the maturation and conformational regulation of a diverse set of signal transducers. The requirement of many principal regulatory proteins for Hsp90 renders entire metabolic pathways sensitive to impairment of its function. So inhibition of Hsp90 function can open cryptic genetic variations and produce morphological changes. In this paper, we present a model for monitoring of cryptic Hsp90-buffered genetic variations arising during exposure to space and spaceflight factors. This model has been developed with Arabidopsis thaliana seeds gathered in natural habitats with high anthropogenic pressure and wild type (Col-0) seeds subjected to negative influences (UV, heavy metals) experimentally. The phenotypic traits of early seedlings grown under reduction of Hsp90 activity were characterized to estimate Hsp90-buffered genetic variations. Geldanamycin was used as an inhibitor of Hsp90 function.

  4. Multiple capacitors for natural genetic variation in Drosophila melanogaster.

    PubMed

    Takahashi, Kazuo H

    2013-03-01

    Cryptic genetic variation (CGV) or a standing genetic variation that is not ordinarily expressed as a phenotype is released when the robustness of organisms is impaired under environmental or genetic perturbations. Evolutionary capacitors modulate the amount of genetic variation exposed to natural selection and hidden cryptically; they have a fundamental effect on the evolvability of traits on evolutionary timescales. In this study, I have demonstrated the effects of multiple genomic regions of Drosophila melanogaster on CGV in wing shape. I examined the effects of 61 genomic deficiencies on quantitative and qualitative natural genetic variation in the wing shape of D. melanogaster. I have identified 10 genomic deficiencies that do not encompass a known candidate evolutionary capacitor, Hsp90, exposing natural CGV differently depending on the location of the deficiencies in the genome. Furthermore, five genomic deficiencies uncovered qualitative CGV in wing morphology. These findings suggest that CGV in wing shape of wild-type D. melanogaster is regulated by multiple capacitors with divergent functions. Future analysis of genes encompassed by these genomic regions would help elucidate novel capacitor genes and better understand the general features of capacitors regarding natural genetic variation.

  5. A joint history of the nature of genetic variation and the nature of schizophrenia.

    PubMed

    Kendler, K S

    2015-02-01

    This essay traces the history of concepts of genetic variation and schizophrenia from Darwin and Mendel to the present. For Darwin, the important form of genetic variation for evolution is continuous in nature and small in effect. Biometricians led by Pearson agreed and developed statistical genetic approaches utilizing trait correlations in relatives. Mendel studied discontinuous traits and subsequent Mendelians, led by Bateson, assumed that important genetic variation was large in effect producing discontinuous phenotypes. Although biometricians studied 'insanity', schizophrenia genetics under Kraepelin and Rüdin utilized Mendelian approaches congruent with their anatomical-clinical disease model of dementia praecox. Fisher showed, assuming many genes of small effect, Mendelian and Biometrical models were consilient. Echoing prior conflicts, psychiatric genetics since then has utilized both biometrical models, largely in twins, and Mendelian models, based on advancing molecular techniques. In 1968, Gottesman proposed a polygenic model for schizophrenia based on a threshold version of Fisher's theory. Since then, rigorous studies of the schizophrenia spectrum suggest that genetic risk for schizophrenia is more likely continuous than categorical. The last 5 years has seen increasingly convincing evidence from genome-wide association study (GWAS) and sequencing that genetic risk for schizophrenia is largely polygenic, and congruent with Fisher's and Gottesman's models. The gap between biometrical and molecular Mendelian models for schizophrenia has largely closed. The efforts to ground a categorical biomedical model of schizophrenia in Mendelian genetics have failed. The genetic risk for schizophrenia is widely distributed in human populations so that we all carry some degree of risk.

  6. Ecologically relevant genetic variation from a non-Arabidopsis perspective.

    PubMed

    Karrenberg, Sophie; Widmer, Alex

    2008-04-01

    Ecologically relevant genetic variation occurs in genes harbouring alleles that are adaptive in some environments but not in others. Analysis of this type of genetic variation in model organisms has made substantial progress, and is now being expanded to other species in order to better cover the diversity of plant life. Recent advances in connecting ecological and molecular studies in non-model species have been made with regard to edaphic and climatic adaptation, plant reproduction, life-history parameters and biotic interactions. New research avenues that increase biological complexity and ecological relevance by integrating ecological experiments with population genetic and functional genomic approaches provide new insights into the genetic basis of ecologically relevant variation.

  7. Genetic Variations Leading to Familial Dilated Cardiomyopathy.

    PubMed

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-10-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions.

  8. Genetic variation within the Lidia bovine breed.

    PubMed

    Cañón, J; Tupac-Yupanqui, I; García-Atance, M A; Cortés, O; García, D; Fernández, J; Dunner, S

    2008-08-01

    The results of an exhaustive data collection from a bovine population with a low level of exchangeability, the Lidia breed, are presented. A total of 1683 individuals from 79 herds were sampled and genetic diversity within and among lineages was assessed using 24 microsatellite loci on 22 different chromosomes. Expected heterozygosity ranged between 0.46 and 0.68 per lineage and there was significant inbreeding in the lineages, which included several farms [mean F(IS) = 0.11, bootstrap 95% confidence interval (0.09, 0.14)], mainly because of the high genetic divergence between herds within those lineages. High genetic differentiation between lineages was also found with a mean F(ST) of 0.18 [bootstrap 95% confidence interval (0.17, 0.19)], and all pairwise values, which ranged from 0.07 to 0.35, were highly significant. The relationships among lineages showed weak statistical support. Nonetheless, lineages were highly discrete when analysed using correspondence analysis and a great proportion of the individuals were correctly assigned to their own lineage when performing standard assignment procedures.

  9. Genetic Variations Leading to Familial Dilated Cardiomyopathy

    PubMed Central

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-01-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions. PMID:27802374

  10. Genetics of human body size and shape: pleiotropic and independent genetic determinants of adiposity.

    PubMed

    Livshits, G; Yakovenko, K; Ginsburg, E; Kobyliansky, E

    1998-01-01

    The present study utilized pedigree data from three ethnically different populations of Kirghizstan, Turkmenia and Chuvasha. Principal component analysis was performed on a matrix of genetic correlations between 22 measures of adiposity, including skinfolds, circumferences and indices. Findings are summarized as follows: (1) All three genetic matrices were not positive definite and the first four factors retained even after exclusion RG > or = 1.0, explained from 88% to 97% of the total additive genetic variation in the 22 trials studied. This clearly emphasizes the massive involvement of pleiotropic gene effects in the variability of adiposity traits. (2) Despite the quite natural differences in pairwise correlations between the adiposity traits in the three ethnically different samples under study, factor analysis revealed a common basic pattern of covariability for the adiposity traits. In each of the three samples, four genetic factors were retained, namely, the amount of subcutaneous fat, the total body obesity, the pattern of distribution of subcutaneous fat and the central adiposity distribution. (3) Genetic correlations between the retained four factors were virtually non-existent, suggesting that several independent genetic sources may be governing the variation of adiposity traits. (4) Variance decomposition analysis on the obtained genetic factors leaves no doubt regarding the substantial familial and (most probably genetic) effects on variation of each factor in each studied population. The similarity of results in the three different samples indicates that the findings may be deemed valid and reliable descriptions of the genetic variation and covariation pattern of adiposity traits in the human species.

  11. Patterns of genetic variation within and between Gibbon species.

    PubMed

    Kim, Sung K; Carbone, Lucia; Becquet, Celine; Mootnick, Alan R; Li, David Jiang; de Jong, Pieter J; Wall, Jeffrey D

    2011-08-01

    Gibbons are small, arboreal, highly endangered apes that are understudied compared with other hominoids. At present, there are four recognized genera and approximately 17 species, all likely to have diverged from each other within the last 5-6 My. Although the gibbon phylogeny has been investigated using various approaches (i.e., vocalization, morphology, mitochondrial DNA, karyotype, etc.), the precise taxonomic relationships are still highly debated. Here, we present the first survey of nuclear sequence variation within and between gibbon species with the goal of estimating basic population genetic parameters. We gathered ~60 kb of sequence data from a panel of 19 gibbons representing nine species and all four genera. We observe high levels of nucleotide diversity within species, indicative of large historical population sizes. In addition, we find low levels of genetic differentiation between species within a genus comparable to what has been estimated for human populations. This is likely due to ongoing or episodic gene flow between species, and we estimate a migration rate between Nomascus leucogenys and N. gabriellae of roughly one migrant every two generations. Together, our findings suggest that gibbons have had a complex demographic history involving hybridization or mixing between diverged populations.

  12. Human Genetics: Educational Resources for the Classroom.

    ERIC Educational Resources Information Center

    Greendale, Karen; And Others

    1982-01-01

    Potential sources of information and assistance on human genetics are identified, including a brief description of the National Clearinghouse for Human Genetic Diseases, genetic service centers, voluntary groups, state programs, commercial procedures, workshops, speakers, curriculum development aids, and general references. (DC)

  13. 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.

  14. 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

  15. A joint history of the nature of genetic variation and the nature of schizophrenia

    PubMed Central

    Kendler, KS

    2014-01-01

    This essay traces the history of concepts of genetic variation and schizophrenia from Darwin and Mendel to the present. For Darwin, the important form of genetic variation for evolution is continuous in nature and small in effect. Biometricians led by Pearson agreed and developed statistical genetic approaches utilizing trait correlations in relatives. Mendel studied discontinuous traits and subsequent Mendelians, led by Bateson, assumed that important genetic variation was large in effect producing discontinuous phenotypes. Although biometricians studied ‘insanity’, schizophrenia genetics under Kraepelin and Rüdin utilized Mendelian approaches congruent with their anatomical-clinical disease model of dementia praecox. Fisher showed, assuming many genes of small effect, Mendelian and Biometrical models were consilient. Echoing prior conflicts, psychiatric genetics since then has utilized both biometrical models, largely in twins, and Mendelian models, based on advancing molecular techniques. In 1968, Gottesman proposed a polygenic model for schizophrenia based on a threshold version of Fisher’s theory. Since then, rigorous studies of the schizophrenia spectrum suggest that genetic risk for schizophrenia is more likely continuous than categorical. The last 5 years has seen increasingly convincing evidence from genome-wide association study (GWAS) and sequencing that genetic risk for schizophrenia is largely polygenic, and congruent with Fisher’s and Gottesman’s models. The gap between biometrical and molecular Mendelian models for schizophrenia has largely closed. The efforts to ground a categorical biomedical model of schizophrenia in Mendelian genetics have failed. The genetic risk for schizophrenia is widely distributed in human populations so that we all carry some degree of risk. …Variations, as Darwin and most breeders recognized, were of two types. There were sports, large discontinuous variations, relatively rare … [and] there were the less

  16. Intraspecific genetic variation and species coexistence in plant communities

    PubMed Central

    Ehlers, Bodil K.; Damgaard, Christian F.; Laroche, Fabien

    2016-01-01

    Many studies report that intraspecific genetic variation in plants can affect community composition and coexistence. However, less is known about which traits are responsible and the mechanisms by which variation in these traits affect the associated community. Focusing on plant–plant interactions, we review empirical studies exemplifying how intraspecific genetic variation in functional traits impacts plant coexistence. Intraspecific variation in chemical and architectural traits promotes species coexistence, by both increasing habitat heterogeneity and altering competitive hierarchies. Decomposing species interactions into interactions between genotypes shows that genotype × genotype interactions are often intransitive. The outcome of plant–plant interactions varies with local adaptation to the environment and with dominant neighbour genotypes, and some plants can recognize the genetic identity of neighbour plants if they have a common history of coexistence. Taken together, this reveals a very dynamic nature of coexistence. We outline how more traits mediating plant–plant interactions may be identified, and how future studies could use population genetic surveys of genotype distribution in nature and methods from trait-based ecology to better quantify the impact of intraspecific genetic variation on plant coexistence. PMID:26790707

  17. Evolutionary response when selection and genetic variation covary across environments.

    PubMed

    Wood, Corlett W; Brodie, Edmund D

    2016-10-01

    Although models of evolution usually assume that the strength of selection on a trait and the expression of genetic variation in that trait are independent, whenever the same ecological factor impacts both parameters, a correlation between the two may arise that accelerates trait evolution in some environments and slows it in others. Here, we address the evolutionary consequences and ecological causes of a correlation between selection and expressed genetic variation. Using a simple analytical model, we show that the correlation has a modest effect on the mean evolutionary response and a large effect on its variance, increasing among-population or among-generation variation in the response when positive, and diminishing variation when negative. We performed a literature review to identify the ecological factors that influence selection and expressed genetic variation across traits. We found that some factors - temperature and competition - are unlikely to generate the correlation because they affected one parameter more than the other, and identified others - most notably, environmental novelty - that merit further investigation because little is known about their impact on one of the two parameters. We argue that the correlation between selection and genetic variation deserves attention alongside other factors that promote or constrain evolution in heterogeneous landscapes.

  18. TEMPLE: analysing population genetic variation at transcription factor binding sites.

    PubMed

    Litovchenko, Maria; Laurent, Stefan

    2016-11-01

    Genetic variation occurring at the level of regulatory sequences can affect phenotypes and fitness in natural populations. This variation can be analysed in a population genetic framework to study how genetic drift and selection affect the evolution of these functional elements. However, doing this requires a good understanding of the location and nature of regulatory regions and has long been a major hurdle. The current proliferation of genomewide profiling experiments of transcription factor occupancies greatly improves our ability to identify genomic regions involved in specific DNA-protein interactions. Although software exists for predicting transcription factor binding sites (TFBS), and the effects of genetic variants on TFBS specificity, there are no tools currently available for inferring this information jointly with the genetic variation at TFBS in natural populations. We developed the software Transcription Elements Mapping at the Population LEvel (TEMPLE), which predicts TFBS, evaluates the effects of genetic variants on TFBS specificity and summarizes the genetic variation occurring at TFBS in intraspecific sequence alignments. We demonstrate that TEMPLE's TFBS prediction algorithms gives identical results to PATSER, a software distribution commonly used in the field. We also illustrate the unique features of TEMPLE by analysing TFBS diversity for the TF Senseless (SENS) in one ancestral and one cosmopolitan population of the fruit fly Drosophila melanogaster. TEMPLE can be used to localize TFBS that are characterized by strong genetic differentiation across natural populations. This will be particularly useful for studies aiming to identify adaptive mutations. TEMPLE is a java-based cross-platform software that easily maps the genetic diversity at predicted TFBSs using a graphical interface, or from the Unix command line.

  19. Adaptive genetic variation and population differences

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Humans are physiologically and morphologically diverse. Such diversities have been shaped by demographic history and adaptation to local environments, including regional climate, landscape, food source, culture, and pathogens since their expansion within and out of Africa between 50,000 and 100,000 ...

  20. The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

    PubMed Central

    Zhou, Shanshan; Morozova, Tatiana V.; Hussain, Yasmeen N.; Luoma, Sarah E.; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F.C.; Anholt, Robert R.H.

    2016-01-01

    Background: Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Objectives: Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. Methods: To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. Results: We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Conclusions: Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Citation: Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in

  1. Assortative mating by fitness and sexually antagonistic genetic variation.

    PubMed

    Arnqvist, Göran

    2011-07-01

    Recent documentations of sexually antagonistic genetic variation in fitness have spurred an interest in the mechanisms that may act to maintain such variation in natural populations. Using individual-based simulations, I show that positive assortative mating by fitness increases the amount of sexually antagonistic genetic variance in fitness, primarily by elevating the equilibrium frequency of heterozygotes, over most of the range of sex-specific selection and dominance. Further, although the effects of assortative mating by fitness on the protection conditions of polymorphism in sexually antagonistic loci were relatively minor, it widens the protection conditions under most reasonable scenarios (e.g., under heterozygote superiority when fitness is averaged across the sexes) but can also somewhat narrow the protection conditions under other circumstances. The near-ubiquity of assortative mating in nature suggests that it may contribute to upholding standing sexually antagonistic genetic variation in fitness.

  2. Cordova: Web-based management of genetic variation data

    PubMed Central

    Ephraim, Sean S.; Anand, Nikhil; DeLuca, Adam P.; Taylor, Kyle R.; Kolbe, Diana L.; Simpson, Allen C.; Azaiez, Hela; Sloan, Christina M.; Shearer, A. Eliot; Hallier, Andrea R.; Casavant, Thomas L.; Scheetz, Todd E.; Smith, Richard J. H.; Braun, Terry A.

    2014-01-01

    Summary: Cordova is an out-of-the-box solution for building and maintaining an online database of genetic variations integrated with pathogenicity prediction results from popular algorithms. Our primary motivation for developing this system is to aid researchers and clinician–scientists in determining the clinical significance of genetic variations. To achieve this goal, Cordova provides an interface to review and manually or computationally curate genetic variation data as well as share it for clinical diagnostics and the advancement of research. Availability and implementation: Cordova is open source under the MIT license and is freely available for download at https://github.com/clcg/cordova. Contact: sean.ephraim@gmail.com or terry-braun@uiowa.edu PMID:25123904

  3. Genetic variation and linkage disequilibrium in Bacillus anthracis.

    PubMed

    Zwick, Michael E; Thomason, Maureen Kiley; Chen, Peter E; Johnson, Henry R; Sozhamannan, Shanmuga; Mateczun, Alfred; Read, Timothy D

    2011-01-01

    We performed whole-genome amplification followed by hybridization of custom-designed resequencing arrays to resequence 303 kb of genomic sequence from a worldwide panel of 39 Bacillus anthracis strains. We used an efficient algorithm contained within a custom software program, UniqueMER, to identify and mask repetitive sequences on the resequencing array to reduce false-positive identification of genetic variation, which can arise from cross-hybridization. We discovered a total of 240 single nucleotide variants (SNVs) and showed that B. anthracis strains have an average of 2.25 differences per 10,000 bases in the region we resequenced. Common SNVs in this region are found to be in complete linkage disequilibrium. These patterns of variation suggest there has been little if any historical recombination among B. anthracis strains since the origin of the pathogen. This pattern of common genetic variation suggests a framework for recognizing new or genetically engineered strains.

  4. Genetic variation of St. Louis encephalitis virus.

    PubMed

    May, Fiona J; Li, Li; Zhang, Shuliu; Guzman, Hilda; Beasley, David W C; Tesh, Robert B; Higgs, Stephen; Raj, Pushker; Bueno, Rudy; Randle, Yvonne; Chandler, Laura; Barrett, Alan D T

    2008-08-01

    St. Louis encephalitis virus (SLEV) has been regularly isolated throughout the Americas since 1933. Previous phylogenetic studies involving 62 isolates have defined seven major lineages (I-VII), further divided into 14 clades. In this study, 28 strains isolated in Texas in 1991 and 2001-2003, and three older, previously unsequenced strains from Jamaica and California were sequenced over the envelope protein gene. The inclusion of these new sequences, and others published since 2001, has allowed better delineation of the previously published SLEV lineages, in particular the clades of lineage II. Phylogenetic analysis of 106 isolates identified 13 clades. All 1991 and 2001-2003 isolates from Nueces, Jefferson and Harris Counties (Texas Gulf Coast) group in clade IIB with other isolates from these counties isolated during the 1980s and 1990s. This lack of evidence for introduction of novel strains into the Texas Gulf Coast over a long period of time is consistent with overwintering of SLEV in this region. Two El Paso isolates, both from 2002, group in clade VA with recent Californian isolates from 1998-2001 and some South American strains with a broad temporal range. Overall, these data are consistent with multiple introductions of SLEV from South America into North America, and provide support for the hypothesis that in most situations, SLEV circulates within a locality, with occasional incursions from other areas. Finally, SLEV has much lower nucleotide (10.1 %) and amino acid variation (2.8 %) than other members of the Japanese encephalitis virus complex (maximum variation 24.6 % nucleotide and 11.8 % amino acid).

  5. Differential genetic variation of chickens and MD vaccine protective efficacy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vaccine protective efficacy is determined by multiple factors including host genetics, the type of vaccine, vaccine dosage, the virulence and dose of challenging viruses, and the interval between vaccination and viral challenge. Studies on human immune responses to vaccinations suggest host genetic...

  6. Genetic variation in resistance to ionizing radiation

    SciTech Connect

    Ayala, F.J.

    1992-01-01

    Results of an investigation of the gene coding for Cu, Zn superoxide dismutase (Sod) in Drosophila melanogaster seeking to understand the enzyme's role in cell protection against ionizing radiation are reported. Components of the investigation include molecular characterization of the gene; measuring the response of different genotypes to increasing levels of radiation; and investigation of the processes that maintain the Sod polymorphism in populations. While two alleles, S and F, are commonly found at the Sod locus in natural populations of D. melanogaster we have isolated from a natural population a null (CA1) mutant that yields only 3.5% of normal SOD activity. The S, F, and CA1 alleles provide a model system to investigate SOD-dependent radioresistance, because each allele yields different levels of SOD, so that S > F >> CAl. The radioprotective effects of SOD can be established by showing protective effects for the various genotypes that correspond to those inequalities. Because the allele variants studied are derived from natural populations, the proposed investigation avoids problems that arise when mutants obtained my mutagenesis are used. Moreover, each allele is studied in multiple genetic backgrounds, so that we correct for effects attributable to other loci by randomizing these effects.

  7. MutS Homologues hMSH4 and hMSH5: Genetic Variations, Functions, and Implications in Human Diseases.

    PubMed

    Clark, Nicole; Wu, Xiling; Her, Chengtao

    2013-04-01

    The prominence of the human mismatch repair (MMR) pathway is clearly reflected by the causal link between MMR gene mutations and the occurrence of Lynch syndrome (or HNPCC). The MMR family of proteins also carries out a plethora of diverse cellular functions beyond its primary role in MMR and homologous recombination. In fact, members of the MMR family of proteins are being increasingly recognized as critical mediators between DNA damage repair and cell survival. Thus, a better functional understanding of MMR proteins will undoubtedly aid the development of strategies to effectively enhance apoptotic signaling in response to DNA damage induced by anti-cancer therapeutics. Among the five known human MutS homologs, hMSH4 and hMSH5 form a unique heterocomplex. However, the expression profiles of the two genes are not correlated in a number of cell types, suggesting that they may function independently as well. Consistent with this, these two proteins are promiscuous and thought to play distinct roles through interacting with different binding partners. Here, we describe the gene and protein structures of eukaryotic MSH4 and MSH5 with a particular emphasis on their human homologues, and we discuss recent findings of the roles of these two genes in DNA damage response and repair. Finally, we delineate the potential links of single nucleotide polymorphism (SNP) loci of these two genes with several human diseases.

  8. Genetic Variations of Tyrosine Hydroxylase in the Pathogenesis of Hypertension

    PubMed Central

    Lee, Yu Ho; Kim, Yang Gyun; Moon, Ju-Young; Kim, Jin Sug; Jeong, Kyung-Hwan; Lee, Tae Won; Ihm, Chun-Gyoo

    2016-01-01

    One of the major pathophysiological features of primary hypertension is an inappropriate activation of the sympathetic nervous system, which is mediated by excessive synthesis and secretion of catecholamine into the blood. Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine, has been highlighted because genetic variations of TH could alter the activity of the sympathetic nervous system activity and subsequently contribute to the pathogenesis of hypertension. Here, we discuss the role of TH as a regulator of sympathetic activity and review several studies that investigated the relationship between genetic variations of TH and hypertension. PMID:28275384

  9. Fine-scaled human genetic structure revealed by SNP microarrays.

    PubMed

    Xing, Jinchuan; Watkins, W Scott; Witherspoon, David J; Zhang, Yuhua; Guthery, Stephen L; Thara, Rangaswamy; Mowry, Bryan J; Bulayeva, Kazima; Weiss, Robert B; Jorde, Lynn B

    2009-05-01

    We report an analysis of more than 240,000 loci genotyped using the Affymetrix SNP microarray in 554 individuals from 27 worldwide populations in Africa, Asia, and Europe. To provide a more extensive and complete sampling of human genetic variation, we have included caste and tribal samples from two states in South India, Daghestanis from eastern Europe, and the Iban from Malaysia. Consistent with observations made by Charles Darwin, our results highlight shared variation among human populations and demonstrate that much genetic variation is geographically continuous. At the same time, principal components analyses reveal discernible genetic differentiation among almost all identified populations in our sample, and in most cases, individuals can be clearly assigned to defined populations on the basis of SNP genotypes. All individuals are accurately classified into continental groups using a model-based clustering algorithm, but between closely related populations, genetic and self-classifications conflict for some individuals. The 250K data permitted high-level resolution of genetic variation among Indian caste and tribal populations and between highland and lowland Daghestani populations. In particular, upper-caste individuals from Tamil Nadu and Andhra Pradesh form one defined group, lower-caste individuals from these two states form another, and the tribal Irula samples form a third. Our results emphasize the correlation of genetic and geographic distances and highlight other elements, including social factors that have contributed to population structure.

  10. Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma

    PubMed Central

    Zhang, Yu-Jing

    2010-01-01

    In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B1 (AFB1) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB1 exposure and mutations in the K-ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N-acetyltransferases and glutathione S-transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk. PMID:21160980

  11. Genetic variation in steelhead of Oregon and northern California

    USGS Publications Warehouse

    Reisenbichler, R.R.; McIntyre, J.D.; Solazzi, M.F.; Landino, S.W

    1992-01-01

    Steelhead Oncorhynchus mykiss from various sites between the Columbia River and the Mad River, California, were genetically characterized at 10 protein-coding loci or pairs of loci by starch gel electrophoresis. Fish from coastal streams differed from fish east of the Cascade Mountains and from fish of the Willamette River (a tributary of the Columbia River, west of the Cascade Mountains). Coastal steelhead from the northern part of the study area differed from those in the southern part. Genetic differentiation within and among drainages was not statistically significant; however, gene diversity analysis and the life history of steelhead suggested that fish from different drainages should be considered as separate populations. Genetic variation among fish in separate drainages was similar to that reported in northwestern Washington and less than that reported in British Columbia. Allele frequencies varied significantly among year-classes. Genetic variation within samples accounted for 98.3% of the total genetic variation observed in this study. Most hatchery populations differed from wild populations, suggesting that conservation of genetic diversity among and within wild populations could be facilitated by altering hatchery programs.

  12. Intracolonial genetic variation in the scleractinian coral Seriatopora hystrix

    NASA Astrophysics Data System (ADS)

    Maier, E.; Buckenmaier, A.; Tollrian, R.; Nürnberger, B.

    2012-06-01

    In recent years, increasing numbers of studies revealed intraorganismal genetic variation, primarily in modular organisms like plants or colonial marine invertebrates. Two underlying mechanisms are distinguished: Mosaicism is caused by somatic mutation, whereas chimerism originates from allogeneic fusion. We investigated the occurrence of intracolonial genetic variation at microsatellite loci in five natural populations of the scleractinian coral Seriatopora hystrix on the Great Barrier Reef. This coral is a widely distributed, brooding species that is at present a target of intensive population genetic research on reproduction and dispersal patterns. From each of 155 S. hystrix colonies, either two or three samples were genotyped at five or six loci. Twenty-seven (~17%) genetically heterogeneous colonies were found. Statistical analyses indicated the occurrence of both mosaicism and chimerism. In most cases, intracolonial variation was found only at a single allele. Our analyses suggest that somatic mutations present a major source of genetic heterogeneity within a single colony. Moreover, we observed large, apparently stable chimeric colonies that harbored clearly distinct genotypes and contrast these findings with the patterns typically observed in laboratory-based experiments. We discuss the error that mosaicism and chimerism introduce into population genetic analyses.

  13. Genetic variation in the 3’ untranslated region of dengue virus serotype 3 strains isolated from mosquitoes and humans in Brazil

    PubMed Central

    2013-01-01

    Summary Background Dengue, a mosquito-borne viral infection caused by one of the four dengue virus (DENV) serotypes (DENV-1 to 4), replicate alternately on the mosquito vector and human host and are responsible for infections throughout tropical and subtropical regions of the world. In Brazil, the disease has become a major public health problem and the introduction of DENV-3 in 2000 in Rio de Janeiro (RJ) was associated with severe dengue epidemics. The potential emergence of strains associated with severe disease highlights the need for the surveillance of DENV in human host and vectors. Methods Aiming to contribute for DENV phylogenetic and vector-virus-human host studies, we sequenced the entire genome of one DENV-3 isolated from naturally infected Aedes aegypti from RJ in 2001 and characterized the 3’ UTR from strains isolated from mosquitoes and humans. Mosquitoes were pooled and submitted to virus isolation in Ae. albopictus C6/36 cells and the infecting serotype was identified by immunofluorescence using type-specific monoclonal antibody. Sequence analysis was performed using BioEdit software, the multiple alignments were performed using CLUSTAL W and the phylogenetic analysis by MEGA 5, using the Neighbor-joining method. Secondary structure prediction was performed by using the MFOLD program. Results Exclusive substitutions and a substitution leading to a stop codon on the NS5 gene were observed in the DENV-3 isolated from a naturally infected Ae. aegypti and fully sequenced. As an 8- nucleotides deletion was observed within the 11- nucleotides (nts) insertion on the variable region (VR) from the 3′UTR in this isolate, we further sequenced other DENV-3 from both mosquitoes and humans. The majority of DENV-3 from RJ analyzed were characterized by the 11-nts insertion in the VR of the 3′UTR, despite the observation of strains carrying the 8-nts deletion. The latter presented similar secondary structures, however not all strains presenting the 11-nts

  14. Genetic Variation in the Social Environment Contributes to Health and Disease

    PubMed Central

    Ingels, Jesse F.; Bohl, Casey J.; Callebert, Jacques; Launay, Jean-Marie; Krohn, Jon; Legarra, Andres; Williams, Robert W.; Stegle, Oliver

    2017-01-01

    Assessing the impact of the social environment on health and disease is challenging. As social effects are in part determined by the genetic makeup of social partners, they can be studied from associations between genotypes of one individual and phenotype of another (social genetic effects, SGE, also called indirect genetic effects). For the first time we quantified the contribution of SGE to more than 100 organismal phenotypes and genome-wide gene expression measured in laboratory mice. We find that genetic variation in cage mates (i.e. SGE) contributes to variation in organismal and molecular measures related to anxiety, wound healing, immune function, and body weight. Social genetic effects explained up to 29% of phenotypic variance, and for several traits their contribution exceeded that of direct genetic effects (effects of an individual’s genotypes on its own phenotype). Importantly, we show that ignoring SGE can severely bias estimates of direct genetic effects (heritability). Thus SGE may be an important source of “missing heritability” in studies of complex traits in human populations. In summary, our study uncovers an important contribution of the social environment to phenotypic variation, sets the basis for using SGE to dissect social effects, and identifies an opportunity to improve studies of direct genetic effects. PMID:28121987

  15. Genetic Variation of Bordetella pertussis in Austria.

    PubMed

    Wagner, Birgit; Melzer, Helen; Freymüller, Georg; Stumvoll, Sabine; Rendi-Wagner, Pamela; Paulke-Korinek, Maria; Repa, Andreas; Mooi, Frits R; Kollaritsch, Herwig; Mittermayer, Helmut; Kessler, Harald H; Stanek, Gerold; Steinborn, Ralf; Duchêne, Michael; Wiedermann, Ursula

    2015-01-01

    In Austria, vaccination coverage against Bordetella pertussis infections during infancy is estimated at around 90%. Within the last years, however, the number of pertussis cases has increased steadily, not only in children but also in adolescents and adults, indicating both insufficient herd immunity and vaccine coverage. Waning immunity in the host and/or adaptation of the bacterium to the immunised hosts could contribute to the observed re-emergence of pertussis. In this study we therefore addressed the genetic variability in B. pertussis strains from several Austrian cities. Between the years 2002 and 2008, 110 samples were collected from Vienna (n = 32), Linz (n = 63) and Graz (n = 15) by nasopharyngeal swabs. DNA was extracted from the swabs, and bacterial sequence polymorphisms were examined by MLVA (multiple-locus variable number of tandem repeat analysis) (n = 77), by PCR amplification and conventional Sanger sequencing of the polymorphic regions of the prn (pertactin) gene (n = 110), and by amplification refractory mutation system quantitative PCR (ARMS-qPCR) (n = 110) to directly address polymorphisms in the genes encoding two pertussis toxin subunits (ptxA and ptxB), a fimbrial adhesin (fimD), tracheal colonisation factor (tcfA), and the virulence sensor protein (bvgS). Finally, the ptxP promoter region was screened by ARMS-qPCR for the presence of the ptxP3 allele, which has been associated with elevated production of pertussis toxin. The MLVA analysis revealed the highest level of polymorphisms with an absence of MLVA Type 29, which is found outside Austria. Only Prn subtypes Prn1/7, Prn2 and Prn3 were found with a predominance of the non-vaccine type Prn2. The analysis of the ptxA, ptxB, fimD, tcfA and bvgS polymorphisms showed a genotype mixed between the vaccine strain Tohama I and a clinical isolate from 2006 (L517). The major part of the samples (93%) displayed the ptxP3 allele. The consequences for the vaccination strategy are discussed.

  16. Genetic Variation of Bordetella pertussis in Austria

    PubMed Central

    Wagner, Birgit; Melzer, Helen; Freymüller, Georg; Stumvoll, Sabine; Rendi-Wagner, Pamela; Paulke-Korinek, Maria; Repa, Andreas; Mooi, Frits R.; Kollaritsch, Herwig; Kessler, Harald H.; Stanek, Gerold; Steinborn, Ralf; Duchêne, Michael; Wiedermann, Ursula

    2015-01-01

    In Austria, vaccination coverage against Bordetella pertussis infections during infancy is estimated at around 90%. Within the last years, however, the number of pertussis cases has increased steadily, not only in children but also in adolescents and adults, indicating both insufficient herd immunity and vaccine coverage. Waning immunity in the host and/or adaptation of the bacterium to the immunised hosts could contribute to the observed re-emergence of pertussis. In this study we therefore addressed the genetic variability in B. pertussis strains from several Austrian cities. Between the years 2002 and 2008, 110 samples were collected from Vienna (n = 32), Linz (n = 63) and Graz (n = 15) by nasopharyngeal swabs. DNA was extracted from the swabs, and bacterial sequence polymorphisms were examined by MLVA (multiple-locus variable number of tandem repeat analysis) (n = 77), by PCR amplification and conventional Sanger sequencing of the polymorphic regions of the prn (pertactin) gene (n = 110), and by amplification refractory mutation system quantitative PCR (ARMS-qPCR) (n = 110) to directly address polymorphisms in the genes encoding two pertussis toxin subunits (ptxA and ptxB), a fimbrial adhesin (fimD), tracheal colonisation factor (tcfA), and the virulence sensor protein (bvgS). Finally, the ptxP promoter region was screened by ARMS-qPCR for the presence of the ptxP3 allele, which has been associated with elevated production of pertussis toxin. The MLVA analysis revealed the highest level of polymorphisms with an absence of MLVA Type 29, which is found outside Austria. Only Prn subtypes Prn1/7, Prn2 and Prn3 were found with a predominance of the non-vaccine type Prn2. The analysis of the ptxA, ptxB, fimD, tcfA and bvgS polymorphisms showed a genotype mixed between the vaccine strain Tohama I and a clinical isolate from 2006 (L517). The major part of the samples (93%) displayed the ptxP3 allele. The consequences for the vaccination strategy are discussed. PMID

  17. The genetic basis for variation in resistance to infection in the Drosophila melanogaster genetic reference panel

    PubMed Central

    Wang, Jonathan B.

    2017-01-01

    Individuals vary extensively in the way they respond to disease but the genetic basis of this variation is not fully understood. We found substantial individual variation in resistance and tolerance to the fungal pathogen Metarhizium anisopliae Ma549 using the Drosophila melanogaster Genetic Reference Panel (DGRP). In addition, we found that host defense to Ma549 was correlated with defense to the bacterium Pseudomonas aeruginosa Pa14, and several previously published DGRP phenotypes including oxidative stress sensitivity, starvation stress resistance, hemolymph glucose levels, and sleep indices. We identified polymorphisms associated with differences between lines in both their mean survival times and microenvironmental plasticity, suggesting that lines differ in their ability to adapt to variable pathogen exposures. The majority of polymorphisms increasing resistance to Ma549 were sex biased, located in non-coding regions, had moderately large effect and were rare, suggesting that there is a general cost to defense. Nevertheless, host defense was not negatively correlated with overall longevity and fecundity. In contrast to Ma549, minor alleles were concentrated in the most Pa14-susceptible as well as the most Pa14-resistant lines. A pathway based analysis revealed a network of Pa14 and Ma549-resistance genes that are functionally connected through processes that encompass phagocytosis and engulfment, cell mobility, intermediary metabolism, protein phosphorylation, axon guidance, response to DNA damage, and drug metabolism. Functional testing with insertional mutagenesis lines indicates that 12/13 candidate genes tested influence susceptibility to Ma549. Many candidate genes have homologs identified in studies of human disease, suggesting that genes affecting variation in susceptibility are conserved across species. PMID:28257468

  18. The evolution of personality variation in humans and other animals.

    PubMed

    Nettle, Daniel

    2006-09-01

    A comprehensive evolutionary framework for understanding the maintenance of heritable behavioral variation in humans is yet to be developed. Some evolutionary psychologists have argued that heritable variation will not be found in important, fitness-relevant characteristics because of the winnowing effect of natural selection. This article propounds the opposite view. Heritable variation is ubiquitous in all species, and there are a number of frameworks for understanding its persistence. The author argues that each of the Big Five dimensions of human personality can be seen as the result of a trade-off between different fitness costs and benefits. As there is no unconditionally optimal value of these trade-offs, it is to be expected that genetic diversity will be retained in the population.

  19. MetaRanker 2.0: a web server for prioritization of genetic variation data.

    PubMed

    Pers, Tune H; Dworzyński, Piotr; Thomas, Cecilia Engel; Lage, Kasper; Brunak, Søren

    2013-07-01

    MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein-protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0.

  20. ENGINES: exploring single nucleotide variation in entire human genomes

    PubMed Central

    2011-01-01

    Background Next generation ultra-sequencing technologies are starting to produce extensive quantities of data from entire human genome or exome sequences, and therefore new software is needed to present and analyse this vast amount of information. The 1000 Genomes project has recently released raw data for 629 complete genomes representing several human populations through their Phase I interim analysis and, although there are certain public tools available that allow exploration of these genomes, to date there is no tool that permits comprehensive population analysis of the variation catalogued by such data. Description We have developed a genetic variant site explorer able to retrieve data for Single Nucleotide Variation (SNVs), population by population, from entire genomes without compromising future scalability and agility. ENGINES (ENtire Genome INterface for Exploring SNVs) uses data from the 1000 Genomes Phase I to demonstrate its capacity to handle large amounts of genetic variation (>7.3 billion genotypes and 28 million SNVs), as well as deriving summary statistics of interest for medical and population genetics applications. The whole dataset is pre-processed and summarized into a data mart accessible through a web interface. The query system allows the combination and comparison of each available population sample, while searching by rs-number list, chromosome region, or genes of interest. Frequency and FST filters are available to further refine queries, while results can be visually compared with other large-scale Single Nucleotide Polymorphism (SNP) repositories such as HapMap or Perlegen. Conclusions ENGINES is capable of accessing large-scale variation data repositories in a fast and comprehensive manner. It allows quick browsing of whole genome variation, while providing statistical information for each variant site such as allele frequency, heterozygosity or FST values for genetic differentiation. Access to the data mart generating scripts and to

  1. Angiogenesis-related genes and thalidomide teratogenesis in humans: an approach on genetic variation and review of past in vitro studies.

    PubMed

    Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

    2017-02-01

    Thalidomide embryopathy (TE) has affected more than 10,000 babies worldwide. The hypothesis of antiangiogenesis as the teratogenic mechanism of thalidomide has been investigated in several experimental models; but, in humans, it has only been accessed by in vitro studies. Here, we hypothesized the effect of thalidomide upon angiogenesis-related molecules or proteins, previously identified in human embryonic cells, through the in silico STRING-tool. We also investigated ten polymorphisms in angiogenesis-related genes in 38 Brazilian TE individuals and 136 non-affected Brazilians. NOS2, PTGS2, and VEGFA polymorphisms were chosen for genotyping. The STRING-tool suggested nitric oxide and β-catenin as the central angiogenesis-related molecules affected by thalidomide's antiangiogenic property. We did not identify a significant difference of allelic, genotypic or haplotypic frequencies between the groups. We could not predict a risk allele or a protective one for TE in NOS2, PTGS2, or VEGFA, although other genes should be analyzed in larger samples. The role of nitric oxide and β-catenin must be further evaluated, regarding thalidomide teratogenesis complex etiology.

  2. Androgens and doping tests: genetic variation and pit-falls

    PubMed Central

    Rane, Anders; Ekström, Lena

    2012-01-01

    The large variation in disposition known for most drugs is also true for anabolic androgenic steroids. Genetic factors are probably the single most important cause of this variation. Further, there are reasons to believe that there is a corresponding variation in efficacy of doping agents. Doped individuals employ a large variety of doping strategies in respect of choice of substance, dose, dose interval, duration of treatment and use of other drugs for enforcement of effects or correction of side effects. Metabolic steps up-stream and down-stream of testosterone are genetically variable and contribute substantially to the variation in disposition of testosterone, the most common doping agent in sports and in society. Large inter- and intra-ethnic variation in testosterone glucuronidation and excretion is described as well as the pit-falls in evaluation of testosterone doping test results. The hydrolysis and bioactivation of testosterone enanthate is also genetically variable yielding a 2–3 fold variation in excretion rate and serum concentration, thereby implicating a substantial variation in ‘efficacy’ of testosterone. Given this situation it is logical to adopt the new findings in the doping control programme. The population based cut-off level for the testosterone : epitestosterone ratio should be replaced by a Bayesian interpretation of consecutive tests in the same individual. When combined with the above genetic information the sensitivity of the test is considerably improved. The combination of the three approaches should reduce the rate of falsely negative or positive results and the number of expensive follow-up tests, stipulated by the World Anti-Doping Agency. PMID:22506612

  3. Genetically modified pig models for human diseases.

    PubMed

    Fan, Nana; Lai, Liangxue

    2013-02-20

    Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies. Although genetically modified mice have been widely used to model human diseases, some of these mouse models do not replicate important disease symptoms or pathology. Pigs are more similar to humans than mice in anatomy, physiology, and genome. Thus, pigs are considered to be better animal models to mimic some human diseases. This review describes genetically modified pigs that have been used to model various diseases including neurological, cardiovascular, and diabetic disorders. We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.

  4. [Bioethical principles concerning human genetic data].

    PubMed

    Cruz-Coke, Ricardo

    2003-01-01

    UNESCO'S Universal declaration on the human genome and human rights (1997) has been accepted by the international scientific community. To apply these laws, it is necessary to get more specific rules about data regulation, human genetic samples and its derived information in biomedic research. Indeed, genetic material recollection, processing, use and storing, has potential risks over human rights' protection and exercise. The author, member of UNESCO'S intergovernmental Bioethics Committee which approved the final draft in June 2003, has taken part in the writing of the final text of an international declaration about human genetic data, whose abbreviate text is described and commented in this communication.

  5. Obesity, hypertension and genetic variation in the TIGER Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity and hypertension are multifactoral conditions in which the onset and severity of the conditions are influenced by the interplay of genetic and environmental factors. We hypothesize that multiple genes and environmental factors account for a significant amount of variation in BMI and blood pr...

  6. Permanence or change? The meaning of genetic variation

    PubMed Central

    Salzano, Francisco M.

    2000-01-01

    Selected aspects of the evolutionary process and more specifically of the genetic variation are considered, with an emphasis in studies performed by my group. One key aspect of evolution seems to be the concomitant occurrence of dichotomic, contradictory (dialect) processes. Genetic variation is structured, and the dynamics of change at one level is not necessarily paralleled by that in another. The pathogenesis-related protein superfamily can be cited as an example in which permanence (the maintenance of certain key genetic features) coexists with change (modifications that led to different functions in different classes of organisms). Relationships between structure and function are exemplified by studies with hemoglobin Porto Alegre. The genetic structure of tribal populations may differ in important aspects from that of industrialized societies. Evolutionary histories also may differ when considered through the investigation of patrilineal or matrilineal lineages. Global evaluations taking into consideration all of these aspects are needed if we really want to understand the meaning of genetic variation. PMID:10805790

  7. Genetic variation in the widespread lichenicolous fungus Marchandiomyces corallinus.

    PubMed

    Molina, M Carmen; DePriest, Paula T; Lawrey, James D

    2005-01-01

    The lichenicolous basidiomycete Marchandiomyces corallinus is widely distributed in North America and Europe, where it commonly is found on a variety of lichens. Theoretically either of these characteristics, a wide geographic range or generalized host ecology, could provide opportunities for genetic differentiation within this species. To determine how genetic variation is partitioned in M. corallinus, 12 fungal isolates were obtained from locations in North America and Europe; at two locations, in Washington County, Maine, and on the Isle of Mull in Scotland, fungi also were isolated from different lichen hosts. Vegetative mycelial compatibility tests were used to determine compatibility groupings from among the isolates; in addition, several PCR amplification products (RAPD, nuITS rDNA) were obtained for each isolate. A number of distinct compatibility groups were recognizable based on geography, not host ecology. In addition compatible isolates always were restricted to either North America or Europe. However RAPD markers indicated that compatible isolates are not always genetically identical. The presence of sequence heterozygosity at specific positions indicated that the isolates are heterokaryotic and a number of distinct haplotypes could be identified based on ITS variation at three separate locations. This type of genetic variation in these fungi suggests that sexual recombination is possible and that genetic differentiation has taken place recently as a result of geographic isolation, not host switching.

  8. Human longevity: Genetics or Lifestyle? It takes two to tango.

    PubMed

    Passarino, Giuseppe; De Rango, Francesco; Montesanto, Alberto

    2016-01-01

    Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25 % of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging. On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

  9. The Expression of Additive and Nonadditive Genetic Variation under Stress

    PubMed Central

    Blows, M. W.; Sokolowski, M. B.

    1995-01-01

    Experimental lines of Drosophila melanogaster derived from a natural population, which had been isolated in the laboratory for ~70 generations, were crossed to determine if the expression of additive, dominance and epistatic genetic variation in development time and viability was associated with the environment. No association was found between the level of additive genetic effects and environmental value for either trait, but nonadditive genetic effects increased at both extremes of the environmental range for development time. The expression of high levels of dominance and epistatic genetic variation at environmental extremes may be a general expectation for some traits. The disruption of the epistatic gene complexes in the parental lines resulted in hybrid breakdown toward faster development and there was some indication of hybrid breakdown toward higher viability. A combination of genetic drift and natural selection had therefore resulted in different epistatic gene complexes being selected after ~70 generations from a common genetic base. After crossing, the hybrid populations were observed for 10 generations. Epistasis contributed on average 12 hr in development time. Fluctuating asymmetry in sternopleural bristle number also evolved in the hybrid populations, decreasing by >18% in the first seven generations after hybridization. PMID:7672585

  10. Genetic variation of human respiratory syncytial virus among children with fever and respiratory symptoms in Shanghai, China, from 2009 to 2012.

    PubMed

    Liu, Jia; Mu, Yonglin; Dong, Wei; Yao, Fujia; Wang, Lili; Yan, Huajie; Lan, Ke; Zhang, Chiyu

    2014-10-01

    Human respiratory syncytial virus (HRSV) of genus Pneumovirus is one of the most common pathogens causing severe acute lower respiratory tract infection in infants and children. No information on the genotype distribution of HRSV is available in East China (e.g. Shanghai). From August 2009 to December 2012, 2407 nasopharyngeal swabs were collected from outpatient children with fever and respiratory symptoms in Shanghai. HRSV infection was determined using a multiplex RT-PCR assay. The second hypervariable region (HVR2) of G protein gene of HRSV was amplified and sequenced from HRSV positive samples. Genotypes were characterized by phylogenetic analyses. Of 2407 nasopharyngeal samples, 184 (7.6%) were tested as HRSV positive. From 160 positive subjects with sufficient nasopharyngeal samples, 69 HVR2 sequences were obtained by RT-PCR and sequencing. Three HRSV epidemic seasons were observed from August 2009 to December 2012, and an extreme outbreak of HRSV occurred in the 2009-2010 epidemic season. A genotype shift of predominant HRSV strains from B group in the 2009-2010 epidemic season to group A in the subsequent epidemic seasons was observed. Ten HRSV genotypes, including four group A genotypes NA1, NA3, NA4, and ON1, and six group B genotypes BA9, BA10, SAB4, CB1, BAc, and BA?, were detected in Shanghai. Seven genotypes (NA1, BA9-10, SAB4, CB1, BAc and BA?) were found in the 2009-2010 epidemic season. The co-circulation of multiple genotypes was associated with the extreme outbreak of HRSV among children with fever and respiratory symptoms in the 2009-2010 epidemic season.

  11. Age-specific variation in immune response in Drosophila melanogaster has a genetic basis.

    PubMed

    Felix, Tashauna M; Hughes, Kimberly A; Stone, Eric A; Drnevich, Jenny M; Leips, Jeff

    2012-07-01

    Immunosenescence, the age-related decline in immune system function, is a general hallmark of aging. While much is known about the cellular and physiological changes that accompany immunosenescence, we know little about the genetic influences on this phenomenon. In this study we combined age-specific measurements of bacterial clearance ability following infection with whole-genome measurements of the transcriptional response to infection and wounding to identify genes that contribute to the natural variation in immunosenescence, using Drosophila melanogaster as a model system. Twenty inbred lines derived from nature were measured for their ability to clear an Escherichia coli infection at 1 and 4 weeks of age. We used microarrays to simultaneously determine genome-wide expression profiles in infected and wounded flies at each age for 12 of these lines. Lines exhibited significant genetically based variation in bacterial clearance at both ages; however, the genetic basis of this variation changed dramatically with age. Variation in gene expression was significantly correlated with bacterial clearance ability only in the older age group. At 4 weeks of age variation in the expression of 247 genes following infection was associated with genetic variation in bacterial clearance. Functional annotation analyses implicate genes involved in energy metabolism including those in the insulin signaling/TOR pathway as having significant associations with bacterial clearance in older individuals. Given the evolutionary conservation of the genes involved in energy metabolism, our results could have important implications for understanding immunosenescence in other organisms, including humans.

  12. 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

  13. Evolutionary developmental genetics of fruit morphological variation within the Solanaceae.

    PubMed

    Wang, Li; Li, Jing; Zhao, Jing; He, Chaoying

    2015-01-01

    Morphological variations of fruits such as shape and size, and color are a result of adaptive evolution. The evolution of morphological novelties is particularly intriguing. An understanding of these evolutionary processes calls for the elucidation of the developmental and genetic mechanisms that result in particular fruit morphological characteristics, which determine seed dispersal. The genetic and developmental basis for fruit morphological variation was established at a microevolutionary time scale. Here, we summarize the progress on the evolutionary developmental genetics of fruit size, shape and color in the Solanaceae. Studies suggest that the recruitment of a pre-existing gene and subsequent modification of its interaction and regulatory networks are frequently involved in the evolution of morphological diversity. The basic mechanisms underlying changes in plant morphology are alterations in gene expression and/or gene function. We also deliberate on the future direction in evolutionary developmental genetics of fruit morphological variation such as fruit type. These studies will provide insights into plant developmental processes and will help to improve the productivity and fruit quality of crops.

  14. Evolutionary developmental genetics of fruit morphological variation within the Solanaceae

    PubMed Central

    Wang, Li; Li, Jing; Zhao, Jing; He, Chaoying

    2015-01-01

    Morphological variations of fruits such as shape and size, and color are a result of adaptive evolution. The evolution of morphological novelties is particularly intriguing. An understanding of these evolutionary processes calls for the elucidation of the developmental and genetic mechanisms that result in particular fruit morphological characteristics, which determine seed dispersal. The genetic and developmental basis for fruit morphological variation was established at a microevolutionary time scale. Here, we summarize the progress on the evolutionary developmental genetics of fruit size, shape and color in the Solanaceae. Studies suggest that the recruitment of a pre-existing gene and subsequent modification of its interaction and regulatory networks are frequently involved in the evolution of morphological diversity. The basic mechanisms underlying changes in plant morphology are alterations in gene expression and/or gene function. We also deliberate on the future direction in evolutionary developmental genetics of fruit morphological variation such as fruit type. These studies will provide insights into plant developmental processes and will help to improve the productivity and fruit quality of crops. PMID:25918515

  15. Developmental and Genetic Origins of Murine Long Bone Length Variation

    PubMed Central

    Sanger, Thomas J.; Norgard, Elizabeth A.; Pletscher, L. Susan; Bevilacqua, Michael; Brooks, Victoria R.; Sandell, Linda M.; Cheverud, James M.

    2011-01-01

    If we wish to understand whether development influences the rate or direction of morphological evolution, we must first understand the developmental bases of morphological variation within species. However, quantitative variation in adult morphology is the product of molecular and cellular processes unfolding from embryonic development through juvenile growth to maturity. The Atchley-Hall model provides a useful framework for dissecting complex morphologies into their component parts as a way of determining which developmental processes contribute to variation in adult form. We have examined differences in postnatal allometry and the patterns of genetic correlation between age-specific traits for 10 recombinant inbred strains of mice generated from an intercross of LG/J and SM/J. Long bone length is closely tied to body size, but variation in adult morphology is more closely tied to differences in growth rate between 3 and 5 weeks of age. These analyses show that variation generated during early development is overridden by variation generated later in life. To more precisely determine the cellular processes generating this variation we then examined the cellular dynamics of long bone growth plates at the time of maximum elongation rate differences in the parent strains. Our analyses revealed that variation in long bone length is the result of faster elongation rates of the LG/J stain. The developmental bases for these differences in growth rate involve the rate of cell division and chondrocyte hypertrophy in the growth plate. PMID:21328530

  16. Genetic Regulation of Transcriptional Variation in Natural Arabidopsis thaliana Accessions

    PubMed Central

    Zan, Yanjun; Shen, Xia; Forsberg, Simon K. G.; Carlborg, Örjan

    2016-01-01

    An increased knowledge of the genetic regulation of expression in Arabidopsis thaliana is likely to provide important insights about the basis of the plant’s extensive phenotypic variation. Here, we reanalyzed two publicly available datasets with genome-wide data on genetic and transcript variation in large collections of natural A. thaliana accessions. Transcripts from more than half of all genes were detected in the leaves of all accessions, and from nearly all annotated genes in at least one accession. Thousands of genes had high transcript levels in some accessions, but no transcripts at all in others, and this pattern was correlated with the genome-wide genotype. In total, 2669 eQTL were mapped in the largest population, and 717 of them were replicated in the other population. A total of 646 cis-eQTL-regulated genes that lacked detectable transcripts in some accessions was found, and for 159 of these we identified one, or several, common structural variants in the populations that were shown to be likely contributors to the lack of detectable RNA transcripts for these genes. This study thus provides new insights into the overall genetic regulation of global gene expression diversity in the leaf of natural A. thaliana accessions. Further, it also shows that strong cis-acting polymorphisms, many of which are likely to be structural variations, make important contributions to the transcriptional variation in the worldwide A. thaliana population. PMID:27226169

  17. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

    PubMed Central

    Scott, Eric M.; Halees, Anason; Itan, Yuval; Spencer, Emily G.; He, Yupeng; Azab, Mostafa Abdellateef; Gabriel, Stacey B.; Belkadi, Aziz; Boisson, Bertrand; Abel, Laurent; Clark, Andrew G.; Alkuraya, Fowzan S.; Casanova, Jean-Laurent; Gleeson, Joseph G.

    2016-01-01

    The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Gulf region, North Africa, and Central Asia 1–3, has resulted in an elevated burden of recessive disease4. Here we generated a whole exome GME variome from 1,111 unrelated subjects. We detected substantial diversity from sub-geographies, continental and subregional admixture, several ancient founder populations with little evidence of bottlenecks. Measured consanguinity was an order-of-magnitude above that of other sampled populations, and included an increased burden of runs of homozygosity (ROH), but no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved GME recessive conditions reduced the number of potential disease-causing variants by 4–7-fold. These results reveal the variegated GME genetic architecture and support future human genetic discoveries in Mendelian and population genetics. PMID:27428751

  18. Additive and nonadditive genetic variation in avian personality traits.

    PubMed

    van Oers, K; Drent, P J; de Jong, G; van Noordwijk, A J

    2004-11-01

    Individuals of all vertebrate species differ consistently in their reactions to mildly stressful challenges. These typical reactions, described as personalities or coping strategies, have a clear genetic basis, but the structure of their inheritance in natural populations is almost unknown. We carried out a quantitative genetic analysis of two personality traits (exploration and boldness) and the combination of these two traits (early exploratory behaviour). This study was carried out on the lines resulting from a two-directional artificial selection experiment on early exploratory behaviour (EEB) of great tits (Parus major) originating from a wild population. In analyses using the original lines, reciprocal F(1) and reciprocal first backcross generations, additive, dominance, maternal effects ands sex-dependent expression of exploration, boldness and EEB were estimated. Both additive and dominant genetic effects were important determinants of phenotypic variation in exploratory behaviour and boldness. However, no sex-dependent expression was observed in either of these personality traits. These results are discussed with respect to the maintenance of genetic variation in personality traits, and the expected genetic structure of other behavioural and life history traits in general.

  19. The study of human Y chromosome variation through ancient DNA.

    PubMed

    Kivisild, Toomas

    2017-03-04

    High throughput sequencing methods have completely transformed the study of human Y chromosome variation by offering a genome-scale view on genetic variation retrieved from ancient human remains in context of a growing number of high coverage whole Y chromosome sequence data from living populations from across the world. The ancient Y chromosome sequences are providing us the first exciting glimpses into the past variation of male-specific compartment of the genome and the opportunity to evaluate models based on previously made inferences from patterns of genetic variation in living populations. Analyses of the ancient Y chromosome sequences are challenging not only because of issues generally related to ancient DNA work, such as DNA damage-induced mutations and low content of endogenous DNA in most human remains, but also because of specific properties of the Y chromosome, such as its highly repetitive nature and high homology with the X chromosome. Shotgun sequencing of uniquely mapping regions of the Y chromosomes to sufficiently high coverage is still challenging and costly in poorly preserved samples. To increase the coverage of specific target SNPs capture-based methods have been developed and used in recent years to generate Y chromosome sequence data from hundreds of prehistoric skeletal remains. Besides the prospects of testing directly as how much genetic change in a given time period has accompanied changes in material culture the sequencing of ancient Y chromosomes allows us also to better understand the rate at which mutations accumulate and get fixed over time. This review considers genome-scale evidence on ancient Y chromosome diversity that has recently started to accumulate in geographic areas favourable to DNA preservation. More specifically the review focuses on examples of regional continuity and change of the Y chromosome haplogroups in North Eurasia and in the New World.

  20. Genetic enhancement, human nature, and rights.

    PubMed

    McConnell, Terrance

    2010-08-01

    Authors such as Francis Fukuyama, the President's Council on Bioethics, and George Annas have argued that biotechnological interventions that aim to promote genetic enhancement pose a threat to human nature. This paper clarifies what conclusions these critics seek to establish, and then shows that there is no plausible account of human nature that will meet the conditions necessary to support this position. Appeals to human nature cannot establish a prohibition against the pursuit of genetic enhancement.

  1. Influence of barriers to movement on within-watershed genetic variation of coastal cutthroat trout

    USGS Publications Warehouse

    Wofford, John E.B.; Gresswell, Robert E.; Banks, Michael A.

    2005-01-01

    Because human land use activities often result in increased fragmentation of aquatic and terrestrial habitats, a better understanding of the effects of fragmentation on the genetic heterogeneity of animal populations may be useful for effective management. We used eight microsatellites to examine the genetic structure of coastal cutthroat trout (Oncorhynchus clarki clarki) in Camp Creek, an isolated headwater stream in western Oregon. Our objectives were to determine if coastal cutthroat trout were genetically structured within streams and to assess the effects of natural and anthropogenic barriers on coastal cutthroat trout genetic variation. Fish sampling occurred at 10 locations, and allele frequencies differed significantly among all sampling sections. Dispersal barriers strongly influenced coastal cutthroat trout genetic structure and were associated with reduced genetic diversity and increased genetic differentiation. Results indicate that Camp Creek coastal cutthroat trout exist as many small, partially independent populations that are strongly affected by genetic drift. In headwater streams, barriers to movement can result in genetic and demographic isolation leading to reduced coastal cutthroat trout genetic diversity, and potentially compromising long-term population persistence. When habitat fragmentation eliminates gene flow among small populations, similar results may occur in other species.

  2. Immunity Traits in Pigs: Substantial Genetic Variation and Limited Covariation

    PubMed Central

    Flori, Laurence; Gao, Yu; Laloë, Denis; Lemonnier, Gaëtan; Leplat, Jean-Jacques; Teillaud, Angélique; Cossalter, Anne-Marie; Laffitte, Joëlle; Pinton, Philippe; de Vaureix, Christiane; Bouffaud, Marcel; Mercat, Marie-José; Lefèvre, François; Oswald, Isabelle P.; Bidanel, Jean-Pierre; Rogel-Gaillard, Claire

    2011-01-01

    Background Increasing robustness via improvement of resistance to pathogens is a major selection objective in livestock breeding. As resistance traits are difficult or impossible to measure directly, potential indirect criteria are measures of immune traits (ITs). Our underlying hypothesis is that levels of ITs with no focus on specific pathogens define an individual's immunocompetence and thus predict response to pathogens in general. Since variation in ITs depends on genetic, environmental and probably epigenetic factors, our aim was to estimate the relative importance of genetics. In this report, we present a large genetic survey of innate and adaptive ITs in pig families bred in the same environment. Methodology/Principal Findings Fifty four ITs were studied on 443 Large White pigs vaccinated against Mycoplasma hyopneumoniae and analyzed by combining a principal component analysis (PCA) and genetic parameter estimation. ITs include specific and non specific antibodies, seric inflammatory proteins, cell subsets by hemogram and flow cytometry, ex vivo production of cytokines (IFNα, TNFα, IL6, IL8, IL12, IFNγ, IL2, IL4, IL10), phagocytosis and lymphocyte proliferation. While six ITs had heritabilities that were weak or not significantly different from zero, 18 and 30 ITs had moderate (0.10.4) heritability values, respectively. Phenotypic and genetic correlations between ITs were weak except for a few traits that mostly include cell subsets. PCA revealed no cluster of innate or adaptive ITs. Conclusions/Significance Our results demonstrate that variation in many innate and adaptive ITs is genetically controlled in swine, as already reported for a smaller number of traits by other laboratories. A limited redundancy of the traits was also observed confirming the high degree of complementarity between innate and adaptive ITs. Our data provide a genetic framework for choosing ITs to be included as selection criteria in multitrait selection

  3. Recommendations for Genetic Variation Data Capture in Developing Countries to Ensure a Comprehensive Worldwide Data Collection

    PubMed Central

    Patrinos, George P; Al Aama, Jumana; Al Aqeel, Aida; Al-Mulla, Fahd; Borg, Joseph; Devereux, Andrew; Felice, Alex E; Macrae, Finlay; Marafie, Makia J; Petersen, Michael B; Qi, Ming; Ramesar, Rajkumar S; Zlotogora, Joel; Cotton, Richard GH

    2011-01-01

    Developing countries have significantly contributed to the elucidation of the genetic basis of both common and rare disorders, providing an invaluable resource of cases due to large family sizes, consanguinity, and potential founder effects. Moreover, the recognized depth of genomic variation in indigenous African populations, reflecting the ancient origins of humanity on the African continent, and the effect of selection pressures on the genome, will be valuable in understanding the range of both pathological and nonpathological variations. The involvement of these populations in accurately documenting the extant genetic heterogeneity is more than essential. Developing nations are regarded as key contributors to the Human Variome Project (HVP; http://www.humanvariomeproject.org), a major effort to systematically collect mutations that contribute to or cause human disease and create a cyber infrastructure to tie databases together. However, biomedical research has not been the primary focus in these countries even though such activities are likely to produce economic and health benefits for all. Here, we propose several recommendations and guidelines to facilitate participation of developing countries in genetic variation data documentation, ensuring an accurate and comprehensive worldwide data collection. We also summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc. PMID:21089065

  4. An atlas of genetic influences on human blood metabolites

    PubMed Central

    Santos, Rita; Huang, Jie; Arnold, Matthias; Erte, Idil; Forgetta, Vincenzo; Yang, Tsun-Po; Walter, Klaudia; Menni, Cristina; Chen, Lu; Vasquez, Louella; Valdes, Ana M.; Hyde, Craig L.; Wang, Vicky; Ziemek, Daniel; Xi, Li; Grundberg, Elin; Waldenberger, Melanie; Richards, J. Brent; Mohney, Robert P.; Milburn, Michael V.; John, Sally L.; Trimmer, Jeff; Theis, Fabian J.; Overington, John P.; Suhre, Karsten; Brosnan, M. Julia; Gieger, Christian; Kastenmüller, Gabi; Spector, Tim D; Soranzo, Nicole

    2014-01-01

    Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism to date, including 7,824 adult individuals from two European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity regarding more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information regarding gene expression, heritability, overlap with known drug targets, previous association with complex disorders and inborn errors of metabolism. We further developed a database and web-based resources for data mining and results visualization. Our findings contribute to a greater understanding of the role of inherited variation in blood metabolic diversity, and identify potential new opportunities for pharmacologic development and disease understanding. PMID:24816252

  5. Genetic mapping of variation in spatial learning in the mouse.

    PubMed

    Steinberger, Daniela; Reynolds, David S; Ferris, Pushpindar; Lincoln, Rachael; Datta, Susmita; Stanley, Joanna; Paterson, Andrea; Dawson, Gerard R; Flint, Jonathan

    2003-03-15

    Inbred strains of mice are known to differ in their performance in the Morris water maze task, a test of spatial discrimination and place navigation in rodents, but the genetic basis of individual variation in spatial learning is unknown. We have mapped genetic effects that contribute to the difference between two strains, DBA/2 and C57BL6/J, using an F2 intercross and methods to detect quantitative trait loci (QTL). We found two QTL, one on chromosome 4 and one on chromosome 12, that influence behavior in the probe trial of the water maze (genome-wide significance p = 0.017 and 0.015, respectively). By including tests of avoidance conditioning and behavior in a novel environment, we show that the QTL on chromosomes 4 and 12 specifically influence variation in spatial learning. QTL that influence differences in fearful behavior (on chromosomes 1, 3, 7, 15, and 19) operate while mice are trained in the water maze apparatus.

  6. Interpretation of patterns of genetic variation in endemic plant species of oceanic islands

    PubMed Central

    Stuessy, Tod F; Takayama, Koji; López-Sepúlveda, Patricio; Crawford, Daniel J

    2014-01-01

    Oceanic islands offer special opportunities for understanding the patterns and processes of evolution. The availability of molecular markers in recent decades has enhanced these opportunities, facilitating the use of population genetics to reveal divergence and speciation in island systems. A common pattern seen in taxa on oceanic islands is a decreased level of genetic variation within and among populations, and the founder effect has often been invoked to explain this observation. Founder effects have a major impact on immigrant populations, but, over millions of years, the original genetic signature will normally be erased as a result of mutation, recombination, drift and selection. Therefore, the types and degrees of genetic modifications that occur must often be caused by other factors, which should be considered when explaining the patterns of genetic variation. The age of the island is extremely important because oceanic islands subside on their submarine plates over time. Erosion caused by wind, rain and wave action combine to grind down soft volcanic substrates. These geomorphological events can have a dramatic impact on population number and size, and hence levels of genetic diversity. The mode of speciation is also of significance. With anagenesis, genetic variation accumulates through time, whereas, with cladogenenesis, the gene pool splits into populations of adaptively radiating species. Breeding systems, population sizes and generation times are also important, as is hybridization between closely related taxa. Human disturbance has affected plant population number and size through the harvesting of forests and the introduction of invasive plants and animals. Therefore, the explanation of the observed levels of genetic variation in species of oceanic islands requires the consideration of many interconnected physical, biological and anthropomorphic factors. PMID:26074627

  7. Rapid loss of genetic variation in an endangered possum.

    PubMed

    Mitrovski, P; Hoffmann, A A; Heinze, D A; Weeks, A R

    2008-02-23

    The endangered mountain pygmy possum is the only Australian marsupial that hibernates under snow cover. Most of its alpine habitat was burnt by a rare fire in 2003, and habitat loss and disturbance have also occurred owing to ski resort development. Here we show that there has been a rapid loss of genetic variation following habitat loss associated with resort development, but no detectable loss of alleles or decrease in heterozygosity following the fire.

  8. Genetic Variation of Echinococcus canadensis (G7) in Mexico

    PubMed Central

    Rodriguez-Prado, Ulises; Jimenez-Gonzalez, Diego Emiliano; Avila, Guillermina; Gonzalez, Armando E.; Martinez-Flores, Williams Arony; Mondragon de la Peña, Carmen; Hernandez-Castro, Rigoberto; Romero-Valdovinos, Mirza; Flisser, Ana; Martinez-Hernandez, Fernando; Maravilla, Pablo; Martinez-Maya, Jose Juan

    2014-01-01

    We evaluated the genetic variation of Echinococcus G7 strain in larval and adult stages using a fragment of the mitochondrial cox1 gen. Viscera of pigs, bovines, and sheep and fecal samples of dogs were inspected for cystic and canine echinococcosis, respectively; only pigs had hydatid cysts. Bayesian inferences grouped the sequences in an E. canadensis G7 cluster, suggesting that, in Mexico, this strain might be mainly present. Additionally, the population genetic and network analysis showed that E. canadensis in Mexico is very diverse and has probably been introduced several times from different sources. Finally, a scarce genetic differentiation between G6 (camel strain) and G7 (pig strain) populations was identified. PMID:25266350

  9. Genetic Architectures of Quantitative Variation in RNA Editing Pathways.

    PubMed

    Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj; Snyder, Elizabeth M; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L; Dotu, Ivan; Chuang, Jeffrey H; Keller, Mark P; Attie, Alan D; Braun, Robert E; Churchill, Gary A

    2016-02-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing.

  10. Genomic exploitation of genetic variation for crop improvement

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crop plants produce food, fiber, and fuel that are essential to human civilization and mainstays of economic prosperity. Our society continues to cultivate and improve the crop plants for better quality and productivity with sustainable environments. The process of crop genetic improvement has bee...

  11. Patterns of molecular genetic variation among cat breeds.

    PubMed

    Menotti-Raymond, Marilyn; David, Victor A; Pflueger, Solveig M; Lindblad-Toh, Kerstin; Wade, Claire M; O'Brien, Stephen J; Johnson, Warren E

    2008-01-01

    Genetic variation in cat breeds was assessed utilizing a panel of short tandem repeat (STR) loci genotyped in 38 cat breeds and 284 single-nucleotide polymorphisms (SNPs) genotyped in 24 breeds. Population structure in cat breeds generally reflects their recent ancestry and absence of strong breed barriers between some breeds. There is a wide range in the robustness of population definition, from breeds demonstrating high definition to breeds with as little as a third of their genetic variation partitioning into a single population. Utilizing the STRUCTURE algorithm, there was no clear demarcation of the number of population subdivisions; 16 breeds could not be resolved into independent populations, the consequence of outcrossing in established breeds to recently developed breeds with common ancestry. These 16 breeds were divided into 6 populations. Ninety-six percent of cats in a sample set of 1040 were correctly assigned to their classified breed or breed group/population. Average breed STR heterozygosities ranged from moderate (0.53; Havana, Korat) to high (0.85; Norwegian Forest Cat, Manx). Most of the variation in cat breeds was observed within a breed population (83.7%), versus 16.3% of the variation observed between populations. The hierarchical relationships of cat breeds is poorly defined as demonstrated by phylogenetic trees generated from both STR and SNP data, though phylogeographic grouping of breeds derived completely or in part from Southeast Asian ancestors was apparent.

  12. The genetics of innate immunity sensors and human disease.

    PubMed

    Pothlichet, Julien; Quintana-Murci, Lluis

    2013-04-01

    Since their discovery, innate immunity microbial sensors have been increasingly studied and shown to play a critical role in innate responses to microbes in several experimental in vitro, ex vivo, and animal models. However, their role in the human response to infection in natural conditions has just started to be deciphered, by means of clinical studies of primary immunodeficiencies and epidemiological genetic studies. Here, we summarize the major findings concerning the genetic diversity of the various families of microbial sensors in humans, and of other molecules involved in the signaling pathways they trigger. Specifically, we review the genetic associations, revealed by both clinical and epidemiological genetics studies, of microbial sensors from five different families: Toll-like receptors, C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. In particular, we consider the relationships between variation at the genes encoding these molecules and susceptibility to and the severity of infectious diseases and other clinical conditions associated with immune dysfunction, including autoimmunity, inflammation, allergy, and cancer. Despite the fact that the genetic links between innate immunity sensors and human disorders remain still limited, human genetics studies are increasingly improving our understanding of the genuine functions of microbial sensors and downstream signaling molecules in the natural setting.

  13. Genetic variation in insulin-induced kinase signaling

    PubMed Central

    Wang, Isabel Xiaorong; Ramrattan, Girish; Cheung, Vivian G

    2015-01-01

    Individual differences in sensitivity to insulin contribute to disease susceptibility including diabetes and metabolic syndrome. Cellular responses to insulin are well studied. However, which steps in these response pathways differ across individuals remains largely unknown. Such knowledge is needed to guide more precise therapeutic interventions. Here, we studied insulin response and found extensive individual variation in the activation of key signaling factors, including ERK whose induction differs by more than 20-fold among our subjects. This variation in kinase activity is propagated to differences in downstream gene expression response to insulin. By genetic analysis, we identified cis-acting DNA variants that influence signaling response, which in turn affects downstream changes in gene expression and cellular phenotypes, such as protein translation and cell proliferation. These findings show that polymorphic differences in signal transduction contribute to individual variation in insulin response, and suggest kinase modulators as promising therapeutics for diseases characterized by insulin resistance. PMID:26202599

  14. Intraspecific variation in social organization by genetic variation, developmental plasticity, social flexibility or entirely extrinsic factors

    PubMed Central

    Schradin, Carsten

    2013-01-01

    Previously, it was widely believed that each species has a specific social organization, but we know now that many species show intraspecific variation in their social organization. Four different processes can lead to intraspecific variation in social organization: (i) genetic variation between individuals owing to local adaptation (between populations) or evolutionarily stable strategies within populations; (ii) developmental plasticity evolved in long-term (more than one generation) unpredictable and short-term (one generation) predictable environments, which is mediated by organizational physiological effects during early ontogeny; (iii) social flexibility evolved in highly unpredictable environments, which is mediated by activational physiological effects in adults; (iv) entirely extrinsic factors such as the death of a dominant breeder. Variation in social behaviour occurs between individuals in the case of genetic variation and developmental plasticity, but within individuals in the case of social flexibility. It is important to study intraspecific variation in social organization to understand the social systems of species because it reveals the mechanisms by which species can adapt to changing environments, offers a useful tool to study the ultimate and proximate causes of sociality, and is an interesting phenomenon by itself that needs scientific explanation. PMID:23569294

  15. Population amalgamation and genetic variation: observations on artificially agglomerated tribal populations of Central and South America.

    PubMed Central

    Chakraborty, R; Smouse, P E; Neel, J V

    1988-01-01

    The interpretation of data on genetic variation with regard to the relative roles of different evolutionary factors that produce and maintain genetic variation depends critically on our assumptions concerning effective population size and the level of migration between neighboring populations. In humans, recent population growth and movements of specific ethnic groups across wide geographic areas mean that any theory based on assumptions of constant population size and absence of substructure is generally untenable. We examine the effects of population subdivision on the pattern of protein genetic variation in a total sample drawn from an artificial agglomerate of 12 tribal populations of Central and South America, analyzing the pooled sample as though it were a single population. Several striking findings emerge. (1) Mean heterozygosity is not sensitive to agglomeration, but the number of different alleles (allele count) is inflated, relative to neutral mutation/drift/equilibrium expectation. (2) The inflation is most serious for rare alleles, especially those which originally occurred as tribally restricted "private" polymorphisms. (3) The degree of inflation is an increasing function of both the number of populations encompassed by the sample and of the genetic divergence among them. (4) Treating an agglomerated population as though it were a panmictic unit of long standing can lead to serious biases in estimates of mutation rates, selection pressures, and effective population sizes. Current DNA studies indicate the presence of numerous genetic variants in human populations. The findings and conclusions of this paper are all fully applicable to the study of genetic variation at the DNA level as well. PMID:3189334

  16. Cosmic Rays Variations and Human Physiological State

    NASA Astrophysics Data System (ADS)

    Dimitrova, S.

    2009-12-01

    It was obtained in our previous investigations that geomagnetic activity as an indirect indicator of solar activity correlates with some human physiological and psycho-physiological parameters. A lot of studies indicate that other parameters of space weather like cosmic rays Forbush decreases affect myocardial infarction, brain stroke, car accidents, etc. The purpose of that work was to study the effect of cosmic rays variations on human physiological status. It was established that the decrease in cosmic rays intensity was related to an increase in systolic and diastolic blood pressure and reported subjective psycho-physiological complaints in healthy volunteers.

  17. Reproductive Flexibility: Genetic Variation, Genetic Costs and Long-Term Evolution in a Collembola

    PubMed Central

    Tully, Thomas; Ferrière, Régis

    2008-01-01

    In a variable yet predictable world, organisms may use environmental cues to make adaptive adjustments to their phenotype. Such phenotypic flexibility is expected commonly to evolve in life history traits, which are closely tied to Darwinian fitness. Yet adaptive life history flexibility remains poorly documented. Here we introduce the collembolan Folsomia candida, a soil-dweller, parthenogenetic (all-female) microarthropod, as a model organism to study the phenotypic expression, genetic variation, fitness consequences and long-term evolution of life history flexibility. We demonstrate that collembola have a remarkable adaptive ability for adjusting their reproductive phenotype: when transferred from harsh to good conditions (in terms of food ration and crowding), a mother can fine-tune the number and the size of her eggs from one clutch to the next. The comparative analysis of eleven clonal populations of worldwide origins reveals (i) genetic variation in mean egg size under both good and bad conditions; (ii) no genetic variation in egg size flexibility, consistent with convergent evolution to a common physiological limit; (iii) genetic variation of both mean reproductive investment and reproductive investment flexibility, associated with a reversal of the genetic correlation between egg size and clutch size between environmental conditions ; (iv) a negative genetic correlation between reproductive investment flexibility and adult lifespan. Phylogenetic reconstruction shows that two life history strategies, called HIFLEX and LOFLEX, evolved early in evolutionary history. HIFLEX includes six of our 11 clones, and is characterized by large mean egg size and reproductive investment, high reproductive investment flexibility, and low adult survival. LOFLEX (the other five clones) has small mean egg size and low reproductive investment, low reproductive investment flexibility, and high adult survival. The divergence of HIFLEX and LOFLEX could represent different

  18. Genetic variation in paternal investment in a seed beetle.

    PubMed

    Savalli; Fox

    1998-10-01

    Males of many species invest resources in their offspring. For paternal investment to evolve, it must exhibit heritable variation. Using a standard half-sibling quantitative genetic design, we investigated whether genetic variation in male ejaculate size, a trait that affects female fecundity and copulation duration, are present in the seed beetle Callosobruchus maculatus. Ejaculate size was estimated as the amount of weight lost by males during mating. Dams, but not sires, had significant effects on their sons' absolute ejaculate size (both replicates) and relative ejaculate size (proportion of body weight; one replicate only), explaining 21-25% of the variance in absolute ejaculate size and 8-16% of the variance in relative ejaculate size. These results suggest either a large maternal effect on ejaculate size or sex-linkage of loci that affect the variation in ejaculate size. The proportion of phenotypic variance explained by sex- linkage (assuming no maternal effects) was 42 and 49% (ejaculate size) and 17 and 31% (relative ejaculate size) in the two replicates. These results indicate that male paternal investment can respond to selection, and that it may be able to do so especially rapidly because sex-linked traits have the potential to evolve much more quickly than autosomal traits. There were only weak negative correlations between ejaculate size and mating duration, contrary to what we predicted. There was additive genetic variation in female copulation duration, but not in male copulation duration, suggesting that copulation duration is under female control. Copyright 1998 The Association for the Study of Animal Behaviour.

  19. The genetics of human obesity.

    PubMed

    Waalen, Jill

    2014-10-01

    The heritability of obesity has long been appreciated and the genetics of obesity has been the focus of intensive study for decades. Early studies elucidating genetic factors involved in rare monogenic and syndromic forms of extreme obesity focused attention on dysfunction of hypothalamic leptin-related pathways in the control of food intake as a major contributor. Subsequent genome-wide association studies of common genetic variants identified novel loci that are involved in more common forms of obesity across populations of diverse ethnicities and ages. The subsequent search for factors contributing to the heritability of obesity not explained by these 2 approaches ("missing heritability") has revealed additional rare variants, copy number variants, and epigenetic changes that contribute. Although clinical applications of these findings have been limited to date, the increasing understanding of the interplay of these genetic factors with environmental conditions, such as the increased availability of high calorie foods and decreased energy expenditure of sedentary lifestyles, promises to accelerate the translation of genetic findings into more successful preventive and therapeutic interventions.

  20. Caries: Review of Human Genetics Research

    PubMed Central

    Vieira, Alexandre R.; Modesto, Adriana; Marazita, Mary L.

    2014-01-01

    The NIH Consensus Development Program released a statement in 2001 (NIH Consensus Statement, 2001) and listed six major clinical caries research directions. One of these directions was the need for genetic studies to identify genes and genetic markers of diagnostic, prognostic, and therapeutic value. This last decade has seen a steep increase in studies investigating the presence of genetic factors influencing individual susceptibility to caries. This review revisits recent caries human genetic studies and provides a perspective for future studies in order to fulfill their promise of revolutionizing our understanding of and the standard of care for the most prevalent bacteria-mediated non-contagious disease in the world. PMID:24853115

  1. 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.

  2. Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits.

    PubMed

    Moreno-Estrada, Andrés; Gignoux, Christopher R; Fernández-López, Juan Carlos; Zakharia, Fouad; Sikora, Martin; Contreras, Alejandra V; Acuña-Alonzo, Victor; Sandoval, Karla; Eng, Celeste; Romero-Hidalgo, Sandra; Ortiz-Tello, Patricia; Robles, Victoria; Kenny, Eimear E; Nuño-Arana, Ismael; Barquera-Lozano, Rodrigo; Macín-Pérez, Gastón; Granados-Arriola, Julio; Huntsman, Scott; Galanter, Joshua M; Via, Marc; Ford, Jean G; Chapela, Rocío; Rodriguez-Cintron, William; Rodríguez-Santana, Jose R; Romieu, Isabelle; Sienra-Monge, Juan José; del Rio Navarro, Blanca; London, Stephanie J; Ruiz-Linares, Andrés; Garcia-Herrera, Rodrigo; Estrada, Karol; Hidalgo-Miranda, Alfredo; Jimenez-Sanchez, Gerardo; Carnevale, Alessandra; Soberón, Xavier; Canizales-Quinteros, Samuel; Rangel-Villalobos, Héctor; Silva-Zolezzi, Irma; Burchard, Esteban Gonzalez; Bustamante, Carlos D

    2014-06-13

    Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.

  3. The genetics of neuroticism and human values.

    PubMed

    Zacharopoulos, George; Lancaster, Thomas M; Maio, Gregory R; Linden, David E J

    2016-04-01

    Human values and personality have been shown to share genetic variance in twin studies. However, there is a lack of evidence about the genetic components of this association. This study examined the interplay between genes, values and personality in the case of neuroticism, because polygenic scores were available for this personality trait. First, we replicated prior evidence of a positive association between the polygenic neuroticism score (PNS) and neuroticism. Second, we found that the PNS was significantly associated with the whole human value space in a sinusoidal waveform that was consistent with Schwartz's circular model of human values. These results suggest that it is useful to consider human values in the analyses of genetic contributions to personality traits. They also pave the way for an investigation of the biological mechanisms contributing to human value orientations.

  4. The genetics of neuroticism and human values

    PubMed Central

    Lancaster, Thomas M.; Maio, Gregory R.; Linden, David E. J.

    2016-01-01

    Human values and personality have been shown to share genetic variance in twin studies. However, there is a lack of evidence about the genetic components of this association. This study examined the interplay between genes, values and personality in the case of neuroticism, because polygenic scores were available for this personality trait. First, we replicated prior evidence of a positive association between the polygenic neuroticism score (PNS) and neuroticism. Second, we found that the PNS was significantly associated with the whole human value space in a sinusoidal waveform that was consistent with Schwartz's circular model of human values. These results suggest that it is useful to consider human values in the analyses of genetic contributions to personality traits. They also pave the way for an investigation of the biological mechanisms contributing to human value orientations. PMID:26915771

  5. Standing genetic variation in host preference for mutualist microbial symbionts

    PubMed Central

    Simonsen, Anna K.; Stinchcombe, John R.

    2014-01-01

    Many models of mutualisms show that mutualisms are unstable if hosts lack mechanisms enabling preferential associations with mutualistic symbiotic partners over exploitative partners. Despite the theoretical importance of mutualism-stabilizing mechanisms, we have little empirical evidence to infer their evolutionary dynamics in response to exploitation by non-beneficial partners. Using a model mutualism—the interaction between legumes and nitrogen-fixing soil symbionts—we tested for quantitative genetic variation in plant responses to mutualistic and exploitative symbiotic rhizobia in controlled greenhouse conditions. We found significant broad-sense heritability in a legume host's preferential association with mutualistic over exploitative symbionts and selection to reduce frequency of associations with exploitative partners. We failed to detect evidence that selection will favour the loss of mutualism-stabilizing mechanisms in the absence of exploitation, as we found no evidence for a fitness cost to the host trait or indirect selection on genetically correlated traits. Our results show that genetic variation in the ability to preferentially reduce associations with an exploitative partner exists within mutualisms and is under selection, indicating that micro-evolutionary responses in mutualism-stabilizing traits in the face of rapidly evolving mutualistic and exploitative symbiotic bacteria can occur in natural host populations. PMID:25355477

  6. Genetic variation in domestic reindeer and wild caribou in Alaska

    USGS Publications Warehouse

    Cronin, M.; Renecker, L.; Pierson, Barbara J.; Patton, J.C.

    1995-01-01

    Reindeer were introduced into Alaska 100 years ago and have been maintained as semidomestic livestock. They have had contact with wild caribou herds, including deliberate cross-breeding and mixing in the wild. Reindeer have considerable potential as a domestic animal for meat or velvet antler production, and wild caribou are important to subsistence and sport hunters. Our objective was to quantify the genetic relationships of reindeer and caribou in Alaska. We identified allelic variation among five herds of wild caribou and three herds of reindeer with DNA sequencing and restriction enzymes for three loci: a DQA locus of the major histocompatibility complex (Rata-DQA1), k-casein and the D-loop of mitochondrial DNA. These loci are of interest because of their potential influence on domestic animal performance and the fitness of wild populations. There is considerable genetic variation in reindeer and caribou for all three loci, including five, three and six alleles for DQA, k-casein and D-loop respectively. Most alleles occur in both reindeer and caribou, which may be the result of recent common ancestry or genetic introgression in either direction. However, allele frequencies differ considerably between reindeer and caribou, which suggests that gene flow has been limited.

  7. Populus trichocarpa cell wall chemistry and ultrastructure trait variation, genetic control and genetic correlations.

    PubMed

    Porth, Ilga; Klápště, Jaroslav; Skyba, Oleksandr; Lai, Ben S K; Geraldes, Armando; Muchero, Wellington; Tuskan, Gerald A; Douglas, Carl J; El-Kassaby, Yousry A; Mansfield, Shawn D

    2013-02-01

    The increasing ecological and economical importance of Populus species and hybrids has stimulated research into the investigation of the natural variation of the species and the estimation of the extent of genetic control over its wood quality traits for traditional forestry activities as well as the emerging bioenergy sector. A realized kinship matrix based on informative, high-density, biallelic single nucleotide polymorphism (SNP) genetic markers was constructed to estimate trait variance components, heritabilities, and genetic and phenotypic correlations. Seventeen traits related to wood chemistry and ultrastructure were examined in 334 9-yr-old Populus trichocarpa grown in a common-garden plot representing populations spanning the latitudinal range 44° to 58.6°. In these individuals, 9342 SNPs that conformed to Hardy-Weinberg expectations were employed to assess the genomic pair-wise kinship to estimate narrow-sense heritabilities and genetic correlations among traits. The range-wide phenotypic variation in all traits was substantial and several trait heritabilities were > 0.6. In total, 61 significant genetic and phenotypic correlations and a network of highly interrelated traits were identified. The high trait variation, the evidence for moderate to high heritabilities and the identification of advantageous trait combinations of industrially important characteristics should aid in providing the foundation for the enhancement of poplar tree breeding strategies for modern industrial use.

  8. Genetically Engineered Pig Models for Human Diseases

    PubMed Central

    Prather, Randall S.; Lorson, Monique; Ross, Jason W.; Whyte, Jeffrey J.; Walters, Eric

    2015-01-01

    Although pigs are used widely as models of human disease, their utility as models has been enhanced by genetic engineering. Initially, transgenes were added randomly to the genome, but with the application of homologous recombination, zinc finger nucleases, and transcription activator-like effector nuclease (TALEN) technologies, now most any genetic change that can be envisioned can be completed. To date these genetic modifications have resulted in animals that have the potential to provide new insights into human diseases for which a good animal model did not exist previously. These new animal models should provide the preclinical data for treatments that are developed for diseases such as Alzheimer's disease, cystic fibrosis, retinitis pigmentosa, spinal muscular atrophy, diabetes, and organ failure. These new models will help to uncover aspects and treatments of these diseases that were otherwise unattainable. The focus of this review is to describe genetically engineered pigs that have resulted in models of human diseases. PMID:25387017

  9. Defining the Genetic Architecture of Human Developmental Language Impairment

    PubMed Central

    Li, Ning; Bartlett, Christopher W.

    2012-01-01

    Language is a uniquely human trait, which poses limitations on animal models for discovering biological substrates and pathways. Despite this challenge, rapidly developing biotechnology in the field of genomics has made human genetics studies a viable alternative route for defining the molecular neuroscience of human language. This is accomplished by studying families that transmit both normal and disordered language across generations. The language disorder reviewed here is specific language impairment (SLI), a developmental deficiency in language acquisition despite adequate opportunity, normal intelligence, and without any apparent neurological etiology. Here, we describe disease gene discovery paradigms as applied to SLI families and review the progress this field has made. After review the evidence that genetic factors influence SLI, we discuss methods and findings from scans of the human chromosomes, including the main replicated regions on chromosomes 13, 16 and 19 and two identified genes, ATP2C2 and CMIP that appear to account for the language variation on chromosome 16. Additional work has been done on candidate genes, i.e., genes chosen a priori and not through a genome scanning studies, including several studies of CNTNAP2 and some recent work implicating BDNF as a gene × gene interaction partner of genetic variation on chromosome 13 that influences language. These recent developments may allow for better use of post-mortem human brain samples functional studies and animal models for circumscribed language subcomponents. In the future, the identification of genetic variation associated with language phenotypes will provide the molecular pathways to understanding human language. PMID:22365959

  10. The dynamics of genetic and morphological variation on volcanic islands

    PubMed Central

    Gübitz, Thomas; Thorpe, Roger S; Malhotra, Anita

    2005-01-01

    Oceanic archipelagos of volcanic origin have been important in the study of evolution because they provide repeated natural experiments allowing rigorous tests of evolutionary hypotheses. Ongoing volcanism on these islands may, however, affect the evolutionary diversification of species. Analysis of population structure and phylogeographic patterns in island populations can provide insight into evolutionary dynamics on volcanic islands. We analysed genetic and morphological variation in the gecko Tarentola boettgeri on the island of Gran Canaria and compared it with Tarentola delalandii on Tenerife, a neighbouring volcanic island of similar age but distinctly different geological past. Intraspecific divergence of mitochondrial haplotypes indicates long-term persistence of Tarentola on each island, with a phylogeographic signal left by older volcanic events. More recent volcanic eruptions (approximately 0.2 million years ago on Tenerife, approximately 2.2 million years ago on Gran Canaria) have left a signature of population expansion in the population genetic structure, the strength of which depends on the time since the last major volcanic eruption on each island. While these stochastic events have left traces in morphological variation in Tenerife, in Gran Canaria geographical variation was solely associated with environmental variables. This suggests that historically caused patterns in morphology may be overwritten by natural selection within 2 million years. PMID:15870037

  11. Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography.

    PubMed

    Rebbeck, Timothy R

    2017-01-01

    Prostate cancer rates vary substantially by race, ethnicity, and geography. These disparities can be explained by variation in access to screening and treatment, variation in exposure to prostate cancer risk factors, and variation in the underlying biology of prostate carcinogenesis (including genomic propensity of some groups to develop biologically aggressive disease). It is clear that access to screening and access to treatment are critical influencing factors of prostate cancer rates; yet, even among geographically diverse populations with similar access to care (eg, low- and medium-income countries), African descent men have higher prostate cancer rates and poorer prognosis. To date, the proportion of prostate cancer that can be explained by environmental exposures is small, and the effect of these factors across different racial, ethnic, or geographical populations is poorly understood. In contrast, prostate cancer has one of the highest heritabilities of all major cancers. Numerous genetic susceptibility markers have been identified from family-based studies, candidate gene association studies, and genome-wide association studies. Some prostate cancer loci, including the risk loci found at chromosome 8q24, have consistent effects in all groups studied to date. However, replication of many susceptibility loci across race, ethnicity, and geography remains limited, and additional studies in certain populations (particularly in men of African descent) are needed to better understand the underlying genetic basis of prostate cancer.

  12. Ecogeography, genetics, and the evolution of human body form.

    PubMed

    Roseman, Charles C; Auerbach, Benjamin M

    2015-01-01

    Genetic resemblances among groups are non-randomly distributed in humans. This population structure may influence the correlations between traits and environmental drivers of natural selection thus complicating the interpretation of the fossil record when modern human variation is used as a referential model. In this paper, we examine the effects of population structure and natural selection on postcranial traits that reflect body size and shape with application to the more general issue of how climate - using latitude as a proxy - has influenced hominin morphological variation. We compare models that include terms reflecting population structure, ascertained from globally distributed microsatellite data, and latitude on postcranial phenotypes derived from skeletal dimensions taken from a large global sample of modern humans. We find that models with a population structure term fit better than a model of natural selection along a latitudinal cline in all cases. A model including both latitude and population structure terms is a good fit to distal limb element lengths and bi-iliac breadth, indicating that multiple evolutionary forces shaped these morphologies. In contrast, a model that included only a population structure term best explained femoral head diameter and the crural index. The results demonstrate that population structure is an important part of human postcranial variation, and that clinally distributed natural selection is not sufficient to explain among-group differentiation. The distribution of human body form is strongly influenced by the contingencies of modern human origins, which calls for new ways to approach problems in the evolution of human variation, past and present.

  13. Genetic Diversity and Human Equality.

    ERIC Educational Resources Information Center

    Dobzhansky, Theodosius

    The idea of equality often, if not frequently, bogs down in confusion and apparent contradictions; equality is confused with identity, and diversity with inequality. It would seem that the easiest way to discredit the idea of equality is to show that people are innately, genetically, and, therefore, irremediably diverse and unlike. The snare is,…

  14. Soft sweeps: molecular population genetics of adaptation from standing genetic variation.

    PubMed

    Hermisson, Joachim; Pennings, Pleuni S

    2005-04-01

    A population can adapt to a rapid environmental change or habitat expansion in two ways. It may adapt either through new beneficial mutations that subsequently sweep through the population or by using alleles from the standing genetic variation. We use diffusion theory to calculate the probabilities for selective adaptations and find a large increase in the fixation probability for weak substitutions, if alleles originate from the standing genetic variation. We then determine the parameter regions where each scenario-standing variation vs. new mutations-is more likely. Adaptations from the standing genetic variation are favored if either the selective advantage is weak or the selection coefficient and the mutation rate are both high. Finally, we analyze the probability of "soft sweeps," where multiple copies of the selected allele contribute to a substitution, and discuss the consequences for the footprint of selection on linked neutral variation. We find that soft sweeps with weaker selective footprints are likely under both scenarios if the mutation rate and/or the selection coefficient is high.

  15. Seasonal Variation in Human Gut Microbiome Composition

    PubMed Central

    Davenport, Emily R.; Mizrahi-Man, Orna; Michelini, Katelyn; Barreiro, Luis B.; Ober, Carole; Gilad, Yoav

    2014-01-01

    The composition of the human gut microbiome is influenced by many environmental factors. Diet is thought to be one of the most important determinants, though we have limited understanding of the extent to which dietary fluctuations alter variation in the gut microbiome between individuals. In this study, we examined variation in gut microbiome composition between winter and summer over the course of one year in 60 members of a founder population, the Hutterites. Because of their communal lifestyle, Hutterite diets are similar across individuals and remarkably stable throughout the year, with the exception that fresh produce is primarily served during the summer and autumn months. Our data indicate that despite overall gut microbiome stability within individuals over time, there are consistent and significant population-wide shifts in microbiome composition across seasons. We found seasonal differences in both (i) the abundance of particular taxa (false discovery rate <0.05), including highly abundant phyla Bacteroidetes and Firmicutes, and (ii) overall gut microbiome diversity (by Shannon diversity; P = 0.001). It is likely that the dietary fluctuations between seasons with respect to produce availability explain, at least in part, these differences in microbiome composition. For example, high levels of produce containing complex carbohydrates consumed during the summer months might explain increased abundance of Bacteroidetes, which contain complex carbohydrate digesters, and decreased levels of Actinobacteria, which have been negatively correlated to fiber content in food questionnaires. Our observations demonstrate the plastic nature of the human gut microbiome in response to variation in diet. PMID:24618913

  16. How plasticity, genetic assimilation and cryptic genetic variation may contribute to adaptive radiations.

    PubMed

    Schneider, Ralf F; Meyer, Axel

    2017-01-01

    There is increasing evidence that phenotypic plasticity can promote population divergence by facilitating phenotypic diversification and, eventually, genetic divergence. When a 'plastic' population colonizes a new habitat, it has the possibility to occupy multiple niches by expressing several distinct phenotypes. These initially reflect the population's plastic range but may later become genetically fixed by selection via the process of 'genetic assimilation' (GA). Through this process multiple specialized sister lineages can arise that share a common plastic ancestor - the 'flexible stem'. Here, we review possible molecular mechanisms through which natural selection could fix an initially plastic trait during GA. These mechanisms could also explain how GA may contribute to cryptic genetic variation that can subsequently be coopted into other phenotypes or traits, but also lead to nonadaptive responses. We outline the predicted patterns of genetic and transcriptional divergence accompanying flexible stem radiations. The analysis of such patterns of (retained) adaptive and nonadaptive plastic responses within and across radiating lineages can inform on the state of ongoing GA. We conclude that, depending on the stability of the environment, the molecular architecture underlying plastic traits can facilitate diversification, followed by fixation and consolidation of an adaptive phenotype and degeneration of nonadaptive ones. Additionally, the process of GA may increase the cryptic genetic variation of populations, which on one hand may serve as substrate for evolution, but on another may be responsible for nonadaptive responses that consolidate local allopatry and thus reproductive isolation.

  17. Genetic variation in Bactericera cockerelli (Hemiptera: Triozidae) from Mexico.

    PubMed

    Lopez, Beatriz; Favela, Susana; Ponce, Gustavo; Foroughbakhch, Rahim; Flores, Adriana E

    2013-04-01

    Bactericera cockerelli (Sulc) is a significant pest of several solanacious crops in Mexico and the United States since 1970. In 2001 significant outbreaks of outstanding importance were observed for the first time in areas where infestations of this insect were historically rare. Molecular studies revealed that this was because of the development of a new biotype of B. cockerelli that had become adapted to south-western United States, further demonstrating that this genetic differentiation was reflected in the survival, development cycle, fertility, and growth rate of both the native biotype as well as the one recently reported. To determine genetic variation in populations of B. cockerelli from Mexico, inter simple sequence repeat were used. Results showed that populations of B. cockerelli from central and northeastern Mexico (Guanajuato, Morelos, Estado de Mexico, and Nuevo Leon states) are genetically similar, meanwhile B. cockerelli from northwest, southwest, and southeast of the country (Sinaloa, Michoacan, and Oaxaca states) are genetically distinct from each other and from the rest of the populations included in the study.

  18. Ecology and genetic variation of Amblyomma tonelliae in Argentina.

    PubMed

    Tarragona, E L; Mangold, A J; Mastropaolo, M; Guglielmone, A A; Nava, S

    2015-09-01

    The ecology of Amblyomma tonelliae (Ixodida: Ixodidae), including its seasonal distribution and the development periods of each stage, was investigated during a study carried out over two consecutive years in northwestern Argentina. In addition, the genetic variation of this tick was studied through analyses of 16S rDNA sequences. Amblyomma tonelliae has a 1-year lifecycle characterized by a long pre-moult period in larvae with no development of morphogenetic diapause. Larvae peak in abundance during late autumn and early winter; nymphs peak in abundance in spring, and adults do so from late spring to early summer. Amblyomma tonelliae shows a marked ecological preference for the driest areas of the Chaco ecoregion. In analyses of 16S rDNA sequences in genes from different populations of A. tonelliae, values for nucleotide diversity and the average number of nucleotide differences showed genetic diversity within this species to be low. No significant differences were found in comparisons among populations.

  19. Finding and interpreting genetic variations that are important to ophthalmologists.

    PubMed Central

    Stone, Edwin M

    2003-01-01

    PURPOSE: To explore two approaches for making the human genome more accessible and useful to practicing ophthalmologists. METHODS: DNA samples were obtained from patients with inherited eye diseases, and these samples were screened for sequence variations in known disease genes with a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. Data from this screening were then used to evaluate strategies for productively narrowing the sample space as well as for estimating the pathogenic potential of variations that were discovered in individual patients. For the latter purpose, a universal nomenclature for pathogenic potential was proposed based upon the segregation of disease alleles and the evolutionary conservation of specific residues as reflected by a substitution matrix known as blosum 62. RESULTS: Sequence variations were found to be unevenly distributed among disease-associated genes, such that screening strategies could be refined to discover more than 50% of clinically important sequence variations with only 10% of the effort. The use of the blosum 62 matrix was more statistically powerful than our previous method of estimating pathogenic probability. CONCLUSIONS: The size of the human genome requires that clinical questions be very carefully focused if they are to be meaningfully answered in a reasonable amount of time and with a reasonable amount of resources. By examining the behavior of known disease genes, one can design strategies for significantly focusing the sample space and for more effectively interpreting the variations that are found. PMID:14971589

  20. Geographic variation and genetic structure in Spotted Owls

    USGS Publications Warehouse

    Haig, Susan M.; Wagner, R.S.; Forsman, E.D.; Mullins, Thomas D.

    2001-01-01

    We examined genetic variation, population structure, and definition of conservation units in Spotted Owls (Strix occidentalis). Spotted Owls are mostly non-migratory, long-lived, socially monogamous birds that have decreased population viability due to their occupation of highly-fragmented late successional forests in western North America. To investigate potential effects of habitat fragmentation on population structure, we used random amplified polymorphic DNA (RAPD) to examine genetic variation hierarchically among local breeding areas, subregional groups, regional groups, and subspecies via sampling of 21 breeding areas (276 individuals) among the three subspecies of Spotted Owls. Data from 11 variable bands suggest a significant relationship between geographic distance among local breeding groups and genetic distance (Mantel r = 0.53, P < 0.02) although multi-dimensional scaling of three significant axes did not identify significant grouping at any hierarchical level. Similarly, neighbor-joining clustering of Manhattan distances indicated geographic structure at all levels and identified Mexican Spotted Owls as a distinct clade. RAPD analyses did not clearly differentiate Northern Spotted Owls from California Spotted Owls. Among Northern Spotted Owls, estimates of population differentiation (FST) ranged from 0.27 among breeding areas to 0.11 among regions. Concordantly, within-group agreement values estimated via multi-response permutation procedures of Jaccarda??s distances ranged from 0.22 among local sites to 0.11 among regions. Pairwise comparisons of FST and geographic distance within regions suggested only the Klamath region was in equilibrium with respect to gene flow and genetic drift. Merging nuclear data with recent mitochondrial data provides support for designation of an Evolutionary Significant Unit for Mexican Spotted Owls and two overlapping Management Units for Northern and California Spotted Owls.

  1. Genetic variation in Asiatic lions and Indian tigers.

    PubMed

    Shankaranarayanan, P; Banerjee, M; Kacker, R K; Aggarwal, R K; Singh, L

    1997-08-01

    Previous reports have suggested that Asiatic lions and tigers are highly inbred and exhibit very low levels of genetic variation. Our analyses on these species have shown much higher degrees of polymorphism than reported. Randomly amplified polymorphic DNA (RAPD) analysis of 38 Asiatic lions, which exist as a single population in the Gir Forest Sanctuary in India, shows an average heterozygosity of 25.82% with four primers. Sperm motility studies by our colleagues corroborate this data. In Indian tigers, microsatellite analysis of five CA repeat loci and multilocus fingerprinting using Bkm 2(8) probe on a population of 22 individuals revealed a heterozygosity of 22.65%. Microsatellite analysis of loci Fca 77 and Fca 126 revealed polymorphism amongst the Asiatic x African lion hybrids, which has enabled us to use these as markers to discriminate the pure Asiatic lions from the hybrids. A similar analysis was used to identify hybrids of Indian and Siberian tigers through polymerase chain reaction (PCR) amplification of hair samples. To ascertain the variation which existed before the population bottleneck at the turn of the present century, microsatellite analysis was performed on 50- to 125-year-old skin samples from museum specimens. Our results show similar levels of genetic variability as in the present population (21.01%). This suggests that low genetic variability may be the characteristic feature of these species and not the result of intensive inbreeding. DNA fingerprinting studies of Asiatic lions and tigers have helped in identifying individuals with high genetic variability which can be used for conservation breeding programs.

  2. Mendelism in human genetics: 100 years on.

    PubMed

    Majumdar, Sisir K

    2003-01-01

    Genetics (Greek word--'genes' = born) is a science without an objective past. But the genre of genetics was always roaming in the corridors of human psyche since antiquity. The account of heritable deformities in human often appears in myths and legends. Ancient Hindu Caste system was based on the assumption that both desirable and undesirable traits are passed from generation to generation. In Babylonia 60 birth defects were listed on Clay tablets written around 5,000 year ago. The Jewish Talmud contains accurate description of the inheritance of haemophilia--a human genetic disorder. The Upanisads vedant--800--200 BC provides instructions for the choice of a wife emphasizing that no heritable illness should be present and that the family should show evidence of good character for several preceding generations. These examples indicate that heritable human traits played a significant role in social customs are presented in this article.

  3. Genetic Variation and Population Structure in Native Americans

    PubMed Central

    Ramachandran, Sohini; Ray, Nicolas; Bedoya, Gabriel; Rojas, Winston; Parra, Maria V; Molina, Julio A; Gallo, Carla; Mazzotti, Guido; Poletti, Giovanni; Hill, Kim; Hurtado, Ana M; Labuda, Damian; Klitz, William; Barrantes, Ramiro; Bortolini, Maria Cátira; Salzano, Francisco M; Petzl-Erler, Maria Luiza; Tsuneto, Luiza T; Llop, Elena; Rothhammer, Francisco; Excoffier, Laurent; Feldman, Marcus W; Rosenberg, Noah A; Ruiz-Linares, Andrés

    2007-01-01

    We examined genetic diversity and population structure in the American landmass using 678 autosomal microsatellite markers genotyped in 422 individuals representing 24 Native American populations sampled from North, Central, and South America. These data were analyzed jointly with similar data available in 54 other indigenous populations worldwide, including an additional five Native American groups. The Native American populations have lower genetic diversity and greater differentiation than populations from other continental regions. We observe gradients both of decreasing genetic diversity as a function of geographic distance from the Bering Strait and of decreasing genetic similarity to Siberians—signals of the southward dispersal of human populations from the northwestern tip of the Americas. We also observe evidence of: (1) a higher level of diversity and lower level of population structure in western South America compared to eastern South America, (2) a relative lack of differentiation between Mesoamerican and Andean populations, (3) a scenario in which coastal routes were easier for migrating peoples to traverse in comparison with inland routes, and (4) a partial agreement on a local scale between genetic similarity and the linguistic classification of populations. These findings offer new insights into the process of population dispersal and differentiation during the peopling of the Americas. PMID:18039031

  4. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length

    PubMed Central

    Cook, Daniel E.; Zdraljevic, Stefan; Tanny, Robyn E.; Seo, Beomseok; Riccardi, David D.; Noble, Luke M.; Rockman, Matthew V.; Alkema, Mark J.; Braendle, Christian; Kammenga, Jan E.; Wang, John; Kruglyak, Leonid; Félix, Marie-Anne; Lee, Junho; Andersen, Erik C.

    2016-01-01

    Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans. PMID:27449056

  5. Mapping genetic influences on the corticospinal motor system in humans.

    PubMed

    Cheeran, B J; Ritter, C; Rothwell, J C; Siebner, H R

    2009-11-24

    It is becoming increasingly clear that genetic variations account for a certain amount of variance in the acquisition and maintenance of different skills. Until now, several levels of genetic influences were examined, ranging from global heritability estimates down to the analysis of the contribution of single nucleotide polymorphisms (SNP) and variable number tandem repeats. In humans, the corticospinal motor system is essential to the acquisition of fine manual motor skills which require a finely tuned coordination of activity in distal forelimb muscles. Here we review recent brain mapping studies that have begun to explore the influence of functional genetic variation as well as mutations on function and structure of the human corticospinal motor system, and also the clinical implications of these studies. Transcranial magnetic stimulation of the primary motor hand area revealed a modulatory role of the common val66met polymorphism in the BDNF gene on corticospinal plasticity. Diffusion-sensitive magnetic resonance imaging has been employed to pinpoint subtle structural changes in corticospinal motor projections in individuals carrying a mutation in genes associated with motor neuron degeneration. These studies underscore the potential of non-invasive brain mapping techniques to characterize the genetic influence on the human corticospinal motor system.

  6. Multilocus patterns of genetic variation across Cryptosporidium species suggest balancing selection at the gp60 locus.

    PubMed

    Abal-Fabeiro, J L; Maside, X; Bello, X; Llovo, J; Bartolomé, C

    2013-09-01

    Cryptosporidium is an apicomplexan protozoan that lives in most vertebrates, including humans. Its gp60 gene is functionally involved in its attachment to host cells, and its high level of genetic variation has made it the reference marker for sample typing in epidemiological studies. To understand the origin of such high diversity and to determine the extent to which this classification applies to the rest of the genome, we analysed the patterns of variation at gp60 and nine other nuclear loci in isolates of three Cryptosporidium species. Most loci showed low genetic polymorphism (πS <1%) and similar levels of between-species divergence. Contrastingly, gp60 exhibited very different characteristics: (i) it was nearly ten times more variable than the other loci; (ii) it displayed a significant excess of polymorphisms relative to between-species differences in a maximum-likelihood Hudson-Kreitman-Aguadé test; (iii) gp60 subtypes turned out to be much older than the species they were found in; and (iv) showed a significant excess of polymorphic variants shared across species from random expectations. These observations suggest that this locus evolves under balancing selection and specifically under negative frequency-dependent selection (FDS). Interestingly, genetic variation at the other loci clusters very well within the groups of isolates defined by gp60 subtypes, which may provide new tools to understand the genome-wide patterns of genetic variation of the parasite in the wild. These results suggest that gp60 plays an active and essential role in the life cycle of the parasite and that genetic variation at this locus might be essential for the parasite's long-term success.

  7. Genetics of human aggressive behaviour.

    PubMed

    Craig, Ian W; Halton, Kelly E

    2009-07-01

    A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual differences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual differentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major effect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These findings will have major significance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants affecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.

  8. Genetic variations and head and neck cancer risks.

    PubMed

    Masood, Nosheen; Yasmin, Azra; Kayani, Mahmood Akhtar

    2014-01-01

    Variations in CYP1A1, GSTM1, GSTT1 and GSTP1 in head and neck cancer have been frequently found in literature. But these studies give an overview of these genetic variations in different populations. The current mini review focus on the analysis of these genetic variations at DNA, mRNA and protein levels in the same study group. Eight publications were reviewed on the same study samples yielding results at DNA, mRNA and protein levels. At DNA level, CYP1A1 showed significantly higher mutations in head and neck cancer patients compared to controls at g.2842A>C and g.2842_2843insT. GSTM1 and GSTT1 showed deletion polymorphisms and heterozygous deletion confers protection against cancer. Mutations were also found in GSTP1 at g.2848A>T, g.2849G>A, g.1074delC and g.1466delC. mRNA and protein expressional analysis revealed underexpression of CYP1A1, loss or underexpression of GSTM1 and GSTT1 and overexpression of GSTP1. In addition an unusual intronic variant of GSTP1 mRNA was also found, retaining the intronic portion between exons. The current review gives a complete study overview regarding CYP1A1, GSTM1, GSTT1 and GSTP1 variations at DNA, mRNA and protein levels in head and neck cancer. The review is helpful in designing a new experiment or gene therapy for head and neck cancer patients.

  9. Genetic variation facilitates seedling establishment but not population growth rate of a perennial invader

    PubMed Central

    Li, Shou-Li; Vasemägi, Anti; Ramula, Satu

    2016-01-01

    Background and Aims Assessing the demographic consequences of genetic variation is fundamental to invasion biology. However, genetic and demographic approaches are rarely combined to explore the effects of genetic variation on invasive populations in natural environments. This study combined population genetics, demographic data and a greenhouse experiment to investigate the consequences of genetic variation for the population fitness of the perennial, invasive herb Lupinus polyphyllus. Methods Genetic and demographic data were collected from 37 L. polyphyllus populations representing different latitudes in Finland, and genetic variation was characterized based on 13 microsatellite loci. Associations between genetic variation and population size, population density, latitude and habitat were investigated. Genetic variation was then explored in relation to four fitness components (establishment, survival, growth, fecundity) measured at the population level, and the long-term population growth rate (λ). For a subset of populations genetic variation was also examined in relation to the temporal variability of λ. A further assessment was made of the role of natural selection in the observed variation of certain fitness components among populations under greenhouse conditions. Key Results It was found that genetic variation correlated positively with population size, particularly at higher latitudes, and differed among habitat types. Average seedling establishment per population increased with genetic variation in the field, but not under greenhouse conditions. Quantitative genetic divergence (QST) based on seedling establishment in the greenhouse was smaller than allelic genetic divergence (F′ST), indicating that unifying selection has a prominent role in this fitness component. Genetic variation was not associated with average survival, growth or fecundity measured at the population level, λ or its variability. Conclusions The study suggests that although genetic

  10. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development.

    PubMed

    Pires, Nuno D; Bemer, Marian; Müller, Lena M; Baroux, Célia; Spillane, Charles; Grossniklaus, Ueli

    2016-01-01

    Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship) theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict.

  11. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development

    PubMed Central

    Pires, Nuno D.; Bemer, Marian; Müller, Lena M.; Baroux, Célia; Spillane, Charles; Grossniklaus, Ueli

    2016-01-01

    Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship) theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict. PMID:26811909

  12. Global genetic variations predict brain response to faces.

    PubMed

    Dickie, Erin W; Tahmasebi, Amir; French, Leon; Kovacevic, Natasa; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun; Büchel, Christian; Conrod, Patricia; Flor, Herta; Garavan, Hugh; Gallinat, Juergen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Lawrence, Claire; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Nichols, Thomas; Lathrop, Mark; Loth, Eva; Pausova, Zdenka; Rietschel, Marcela; Smolka, Michal N; Ströhle, Andreas; Toro, Roberto; Schumann, Gunter; Paus, Tomáš

    2014-08-01

    Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R(2) = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R(2) = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.

  13. Global Genetic Variations Predict Brain Response to Faces

    PubMed Central

    Dickie, Erin W.; Tahmasebi, Amir; French, Leon; Kovacevic, Natasa; Banaschewski, Tobias; Barker, Gareth J.; Bokde, Arun; Büchel, Christian; Conrod, Patricia; Flor, Herta; Garavan, Hugh; Gallinat, Juergen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Lawrence, Claire; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Nichols, Thomas; Lathrop, Mark; Loth, Eva; Pausova, Zdenka; Rietschel, Marcela; Smolka, Michal N.; Ströhle, Andreas; Toro, Roberto; Schumann, Gunter; Paus, Tomáš

    2014-01-01

    Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40–50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R2 = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R2 = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network. PMID:25122193

  14. Genetics of Brazil nut (Bertholletia excelsa Humb. & Bonpl.: Lecythidaceae) : 1. Genetic variation in natural populations.

    PubMed

    Buckley, D P; O'Malley, D M; Apsit, V; Prance, G T; Bawa, K S

    1988-12-01

    We provide an estimate of genetic variation within and between two populations of Bertholletia excelsa (Brazil nut), a large canopy tree found in the rain forests of South America. Average heterozygosity is 0.190, and 54.3% of the sampled loci are polymorphic. The population structure deviates significantly from Hardy-Weinberg expectations for Fest2 and Pgm2 (F =0.405 and 0.443, respectively) in one population, and highly significantly (F=-0.341) for Gdh in the other population. Although allele frequencies of the two populations differ significantly for Aat2, Est5, Mdh1, and Mdh2B, Nei's coefficient of gene differentiation (Gst) indicates that the between-population component (Dst) of genic diversity represents only 3.75% of the size of the within-population component (Hs). The implications of these findings in terms of conservation genetics are that much of the genetic diversity of this species may be preserved within one or a few populations. However, such populations must be very large because it appears that the large amount of genetic variation in Brazil nut populations is maintained by extensive gene flow and bonds of mating over a large area. The genetic architecture of Bertholletia excelsa is similar to that expected for an extensively diploidized paleopolyploid species.

  15. Ethical genetic research on human subjects.

    PubMed

    Harris, J

    1999-01-01

    Since the Nuremberg trials and the Nazi doctors trial following World War II, international ethics protocols have emerged designed to protect human subjects from the atrocities of medical experimentation that were literally routine under the Nazis. Some of the apparent "lessons" from the Nazi period have been encapsulated in the Declaration of Helsinki, perhaps the leading medical ethics protocol. This paper argues that these protocols have not been notably conducive to human welfare or to the protection of human rights in the field of human genetics research. The paper proposes new protocols and a new approach to the ethics of research on human subjects.

  16. Genetic polymorphisms in human drug-metabolizing enzymes: potential uses of reverse genetics to identify genes of toxicological relevance.

    PubMed

    Puga, A; Nebert, D W; McKinnon, R A; Menon, A G

    1997-03-01

    The human mind was engaged with fundamental questions on the nature of heredity long before the study of genetics became a scientific discipline. Many traits, such as height, eye color, blood pressure, or cancer susceptibility, have been known to run in families, although the genes or combination of genes that underlie these observable characteristics remain unknown in most cases. Differences in susceptibility to environmental agents in humans are likewise determined by variations in genetic background--genetic polymorphisms. In this article, we review the current status of studies on human polymorphisms in drug-metabolizing enzymes and discuss various approaches to the analysis of genetic polymorphisms. We expect that in the near future, novel methods in genetic analysis of human populations will be likely to play a key role in the identification of genes of toxicological relevance.

  17. Genetic variation in bank vole populations in natural and metal-contaminated areas.

    PubMed

    Mikowska, Magdalena; Gaura, Aneta; Sadowska, Edyta; Koteja, Paweł; Świergosz-Kowalewska, Renata

    2014-11-01

    The effects of isolation and heavy-metal pollution on genetic diversity in Myodes (=Clethrionomys) glareolus populations were studied. Isolation and pollution are considered to have important effects on biodiversity. Animals were collected from ten populations in isolated (island), mainland, and metal-polluted areas. Three populations were in areas near zinc and lead smelters; four were on islands in the relatively unpolluted Mazurian Lake District and in the Bieszczady Mountains; and three were in clean-mainland areas in the Mazurian Lake District, the Niepołomice Forest, and the Bieszczady Mountains. Cadmium and lead concentrations in liver and kidney were measured to assess the animals' exposure to metals. The metal concentrations were greater in animals from areas classed as polluted than in animals from the clean-mainland areas and islands. The genetic diversity of each population was analyzed using eight microsatellite markers. The results confirmed that isolation adversely affects genetic diversity in M. glareolus populations (giving low heterozygosity and poor allelic richness), but the effect of metal exposure on genetic diversity was not strong. Of the samples from polluted areas, only the Katowice population, which is exposed to high levels of metal pollution and is also isolated because of human activity, showed genetic variation parameters that were similar to those for the island populations. Nei's genetic distances indicated that the island populations were genetically distant from each other and from the other populations, and there were noticeable inbreeding effects that would have been caused by the isolation of these populations.

  18. Variation in the peacock's train shows a genetic component.

    PubMed

    Petrie, Marion; Cotgreave, Peter; Pike, Thomas W

    2009-01-01

    Female peafowl (Pavo cristatus) show a strong mating preference for males with elaborate trains. This, however, poses something of a paradox because intense directional selection should erode genetic variation in the males' trains, so that females will no longer benefit by discriminating among males on the basis of these traits. This situation is known as the 'lek paradox', and leads to the theoretical expectation of low heritability in the peacock's train. We used two independent breeding experiments, involving a total of 42 sires and 86 of their male offspring, to estimate the narrow sense heritabilities of male ornaments and other morphometric traits. Contrary to expectation, we found significant levels of heritability in a trait known to be used by females during mate choice (train length), while no significant heritabilities were evident for other, non-fitness related morphological traits (tarsus length, body weight or spur length). This study adds to the building body of evidence that high levels of additive genetic variance can exist in secondary sexual traits under directional selection, but further emphasizes the main problem of what maintains this variation.

  19. HPA Axis Genetic Variation, Cortisol, and Psychosis in Major Depression

    PubMed Central

    Schatzberg, Alan F.; Keller, Jennifer; Tennakoon, Lakshika; Lembke, Anna; Williams, Gordon; Kraemer, Fredric B.; Sarginson, Jane E.; Lazzeroni, Laura C.; Murphy, Greer M.

    2013-01-01

    Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis over-activity in healthy controls and patients with severe forms of major depression has not been well explored but could explain risk for cortisol dysregulation. 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with nonpsychotic major depression (NPMD); and 29 healthy controls (HC). Collection of genetic material was added one third of the way into a larger study on cortisol, cognition, and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 6pm to 9am and for the assessment of alleles for 6 genes involved in HPA Axis regulation. Two of the 6 genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression, and psychosis, and medication status, only allelic variation for the glucocorticoid receptor gene (GR) accounted for significant variance for mean cortisol levels from 6pm to 1am (r2=.317) and from 1am to 9am (r2=.194). Interestingly, neither depression severity nor psychosis predicted cortisol variance. In addition, GR and corticotropin-releasing hormone receptor 1 (CRH-R1) contributed significantly to psychosis measures and CRH-R1 contributed significantly to depression severity rating. PMID:24166410

  20. Genetic Variation in Virulence among Chalkbrood Strains Infecting Honeybees

    PubMed Central

    Vojvodic, Svjetlana; Jensen, Annette B.; Markussen, Bo; Eilenberg, Jørgen; Boomsma, Jacobus J.

    2011-01-01

    Ascosphaera apis causes chalkbrood in honeybees, a chronic disease that reduces the number of viable offspring in the nest. Although lethal for larvae, the disease normally has relatively low virulence at the colony level. A recent study showed that there is genetic variation for host susceptibility, but whether Ascosphaera apis strains differ in virulence is unknown. We exploited a recently modified in vitro rearing technique to infect honeybee larvae from three colonies with naturally mated queens under strictly controlled laboratory conditions, using four strains from two distinct A. apis clades. We found that both strain and colony of larval origin affected mortality rates. The strains from one clade caused 12–14% mortality while those from the other clade induced 71–92% mortality. Larvae from one colony showed significantly higher susceptibility to chalkbrood infection than larvae from the other two colonies, confirming the existence of genetic variation in susceptibility across colonies. Our results are consistent with antagonistic coevolution between a specialized fungal pathogen and its host, and suggest that beekeeping industries would benefit from more systematic monitoring of this chronic stress factor of their colonies. PMID:21966406

  1. A genetic atlas of human admixture history

    PubMed Central

    Hellenthal, Garrett; Busby, George B.J.; Band, Gavin; Wilson, James F.; Capelli, Cristian

    2014-01-01

    Modern genetic data combined with appropriate statistical methods have the potential to contribute substantially to our understanding of human history. We have developed an approach that exploits the genomic structure of admixed populations to date and characterize historical mixture events at fine scales. We used this to produce an atlas of worldwide human admixture history, constructed using genetic data alone and encompassing over 100 events occurring over the past 4,000 years. We identify events whose dates and participants suggest they describe genetic impacts of the Mongol Empire, Arab slave trade, Bantu expansion, first millennium CE migrations in eastern Europe, and European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations. PMID:24531965

  2. Human structural variation: mechanisms of chromosome rearrangements

    PubMed Central

    Weckselblatt, Brooke; Rudd, M. Katharine

    2015-01-01

    Chromosome structural variation (SV) is a normal part of variation in the human genome, but some classes of SV can cause neurodevelopmental disorders. Analysis of the DNA sequence at SV breakpoints can reveal mutational mechanisms and risk factors for chromosome rearrangement. Large-scale SV breakpoint studies have become possible recently owing to advances in next-generation sequencing (NGS) including whole-genome sequencing (WGS). These findings have shed light on complex forms of SV such as triplications, inverted duplications, insertional translocations, and chromothripsis. Sequence-level breakpoint data resolve SV structure and determine how genes are disrupted, fused, and/or misregulated by breakpoints. Recent improvements in breakpoint sequencing have also revealed non-allelic homologous recombination (NAHR) between paralogous long interspersed nuclear element (LINE) or human endogenous retrovirus (HERV) repeats as a cause of deletions, duplications, and translocations. This review covers the genomic organization of simple and complex constitutional SVs, as well as the molecular mechanisms of their formation. PMID:26209074

  3. Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.

    PubMed

    Qidwai, Tabish; Khan, M Y

    2016-10-01

    Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed.

  4. From homothally to heterothally: Mating preferences and genetic variation within clones of the dinoflagellate Gymnodinium catenatum

    NASA Astrophysics Data System (ADS)

    Figueroa, Rosa Isabel; Rengefors, Karin; Bravo, Isabel; Bensch, Staffan

    2010-02-01

    The chain-forming dinoflagellate Gymnodinium catenatum Graham is responsible for outbreaks of paralytic shellfish poisoning (PSP), a human health threat in coastal waters. Sexuality in this species is of great importance in its bloom dynamics, and has been shown to be very complex but lacks an explanation. For this reason, we tested if unreported homothallic behavior and rapid genetic changes may clarify the sexual system of this alga. To achieve this objective, 12 clonal strains collected from the Spanish coast were analyzed for the presence of sexual reproduction. Mating affinity results, self-compatibility studies, and genetic fingerprinting (amplified fragment length polymorphism, AFLP) analysis on clonal strains, showed three facts not previously described for this species: (i) That there is a continuous mating system within G. catenatum, with either self-compatible strains (homothallic), or strains that needed to be outcrossed (heterothallic), and with a range of differences in cyst production among the crosses. (ii) There was intraclonal genetic variation, i.e. genetic variation within an asexual lineage. Moreover, the variability among homothallic clones was smaller than among the heterothallic ones. (iii) Sibling strains (the two strains established by the germination of one cyst) increased their intra- and inter-sexual compatibility with time. To summarize, we have found that G. catenatum's sexual system is much more complex than previously described, including complex homothallic/heterothallic behaviors. Additionally, high rates of genetic variability may arise in clonal strains, although explanations for the mechanisms responsible are still lacking.

  5. Identification of common genetic variation that modulates alternative splicing.

    PubMed

    Hull, Jeremy; Campino, Susana; Rowlands, Kate; Chan, Man-Suen; Copley, Richard R; Taylor, Martin S; Rockett, Kirk; Elvidge, Gareth; Keating, Brendan; Knight, Julian; Kwiatkowski, Dominic

    2007-06-01

    Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function.

  6. Evaluation of genetic variation among wild rice populations in Cambodia

    PubMed Central

    Orn, Chhourn; Shishido, Rieko; Akimoto, Masahiro; Ishikawa, Ryo; Htun, Than Myint; Nonomura, Ken-Ichi; Koide, Yohei; Sarom, Men; Vang, Seng; Sophany, Sakhan; Makara, Ouk; Ishii, Takashige

    2015-01-01

    A total of 448 samples in five natural populations of wild rice (Oryza rufipogon) were collected in Cambodia. They were examined using 12 SSR and two chloroplast markers to evaluate the degree of variation among populations and the genetic structure within populations. In the two annual populations, the number of plants with homozygous alleles at all 12 SSR loci were high (66.3% and 79.5%), suggesting that these plants propagate mainly through self-pollination. In the three perennial populations, no individuals had all homozygous genotypes, but redundant genotypes resulted from clonal propagation were observed. Percentages of the redundant genotypes were highly varied (3.6%, 29.2% and 86.0%). This may be due to the different stable levels of environmental conditions. As for chloroplast genome, most of the wild plants showed the same chloroplast types as most Indica-type cultivars have. However, plants with different chloroplast types were maintained, even in the same population. In tropical Asian countries, many wild rice populations were observed under similar ecological conditions examined in this study. Therefore, the present results concerning population structure will be important to further elucidate genetic features of wild rice, and will also give strong clues to utilize and conserve wild natural genetic resources. PMID:26719746

  7. Functional significance of genetic variation underlying limb bone diaphyseal structure

    PubMed Central

    Wallace, Ian J.; Middleton, Kevin M.; Lublinsky, Svetlana; Kelly, Scott A.; Judex, Stefan; Garland, Theodore; Demes, Brigitte

    2010-01-01

    Limb bone diaphyseal structure is frequently used to infer hominin activity levels from skeletal remains, an approach based on the well-documented ability of bone to adjust to its loading environment during life. However, diaphyseal structure is also determined in part by genetic factors. This study investigates the possibility that genetic variation underlying diaphyseal structure is influenced by the activity levels of ancestral populations and might also have functional significance in an evolutionary context. We adopted an experimental evolution approach and tested for differences in femoral diaphyseal structure in one-week-old mice from a line that had been artificially selected (45 generations) for high voluntary wheel running and unselected controls. As adults, selected mice are significantly more active on wheels and in home cages, and have thicker diaphyses. Structural differences at one week can be assumed to primarily reflect the effects of selective breeding rather than direct mechanical stimuli, given that the onset of locomotion in mice is shortly after day seven. We hypothesized that if genetically determined diaphyseal structure reflects the activity patterns of members of a lineage, then selected animals will have relatively larger diaphyseal dimensions at one week compared to controls. The results provide strong support for this hypothesis and suggest that limb bone cross sections may not always only reflect the activity levels of particular fossil individuals, but also convey an evolutionary signal providing information about hominin activity in the past. PMID:20310061

  8. Natural variation and genetic covariance in adult hippocampal neurogenesis

    SciTech Connect

    Kempermann, Gerd; Chesler, Elissa J; Lu, Lu; Williams, Robert; Gage, Fred

    2006-01-01

    Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB?BXA, n ? 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1?CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis- cting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

  9. Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes

    PubMed Central

    Pinto, Navin; Dolan, M. Eileen

    2011-01-01

    In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed. PMID:21453273

  10. Climate variables explain neutral and adaptive variation within salmonid metapopulations: The importance of replication in landscape genetics

    USGS Publications Warehouse

    Hand, Brian K; Muhlfeld, Clint C.; Wade, Alisa A.; Kovach, Ryan; Whited, Diane C.; Narum, Shawn R.; Matala, Andrew P; Ackerman, Michael W.; Garner, B. A.; Kimball, John S; Stanford, Jack A.; Luikart, Gordon

    2016-01-01

    Understanding how environmental variation influences population genetic structure is important for conservation management because it can reveal how human stressors influence population connectivity, genetic diversity and persistence. We used riverscape genetics modelling to assess whether climatic and habitat variables were related to neutral and adaptive patterns of genetic differentiation (population-specific and pairwise FST) within five metapopulations (79 populations, 4583 individuals) of steelhead trout (Oncorhynchus mykiss) in the Columbia River Basin, USA. Using 151 putatively neutral and 29 candidate adaptive SNP loci, we found that climate-related variables (winter precipitation, summer maximum temperature, winter highest 5% flow events and summer mean flow) best explained neutral and adaptive patterns of genetic differentiation within metapopulations, suggesting that climatic variation likely influences both demography (neutral variation) and local adaptation (adaptive variation). However, we did not observe consistent relationships between climate variables and FST across all metapopulations, underscoring the need for replication when extrapolating results from one scale to another (e.g. basin-wide to the metapopulation scale). Sensitivity analysis (leave-one-population-out) revealed consistent relationships between climate variables and FST within three metapopulations; however, these patterns were not consistent in two metapopulations likely due to small sample sizes (N = 10). These results provide correlative evidence that climatic variation has shaped the genetic structure of steelhead populations and highlight the need for replication and sensitivity analyses in land and riverscape genetics.

  11. Climate variables explain neutral and adaptive variation within salmonid metapopulations: the importance of replication in landscape genetics.

    PubMed

    Hand, Brian K; Muhlfeld, Clint C; Wade, Alisa A; Kovach, Ryan P; Whited, Diane C; Narum, Shawn R; Matala, Andrew P; Ackerman, Michael W; Garner, Brittany A; Kimball, John S; Stanford, Jack A; Luikart, Gordon

    2016-02-01

    Understanding how environmental variation influences population genetic structure is important for conservation management because it can reveal how human stressors influence population connectivity, genetic diversity and persistence. We used riverscape genetics modelling to assess whether climatic and habitat variables were related to neutral and adaptive patterns of genetic differentiation (population-specific and pairwise FST ) within five metapopulations (79 populations, 4583 individuals) of steelhead trout (Oncorhynchus mykiss) in the Columbia River Basin, USA. Using 151 putatively neutral and 29 candidate adaptive SNP loci, we found that climate-related variables (winter precipitation, summer maximum temperature, winter highest 5% flow events and summer mean flow) best explained neutral and adaptive patterns of genetic differentiation within metapopulations, suggesting that climatic variation likely influences both demography (neutral variation) and local adaptation (adaptive variation). However, we did not observe consistent relationships between climate variables and FST across all metapopulations, underscoring the need for replication when extrapolating results from one scale to another (e.g. basin-wide to the metapopulation scale). Sensitivity analysis (leave-one-population-out) revealed consistent relationships between climate variables and FST within three metapopulations; however, these patterns were not consistent in two metapopulations likely due to small sample sizes (N = 10). These results provide correlative evidence that climatic variation has shaped the genetic structure of steelhead populations and highlight the need for replication and sensitivity analyses in land and riverscape genetics.

  12. Genetic aspects of human congenital diaphragmatic hernia

    PubMed Central

    Pober, BR

    2010-01-01

    Congenital diaphragmatic hernia (CDH) is a common major malformation affecting 1/3000–1/4000 births, which continues to be associated with significant perinatal mortality. Much current research is focused on elucidating the genetics and pathophysiology contributing to CDH to develop more effective therapies. The latest data suggest that many cases of CDH are genetically determined and also indicate that CDH is etiologically heterogeneous. The present review will provide a brief summary of diaphragm development and model organism work most relevant to human CDH and will primarily describe important human phenotypes associated with CDH and also provide recommendations for diagnostic evaluation of a fetus or infant with CDH. PMID:18510546

  13. Genetic control of the alternative pathway of complement in humans and age-related macular degeneration.

    PubMed

    Hecker, Laura A; Edwards, Albert O; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H; Brown, William L; Charbel Issa, Peter; Scholl, Hendrik P; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E; Bailey, Kent R; Oppermann, Martin

    2010-01-01

    Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.

  14. Genetic variation in natural populations of Populus tremuloide

    SciTech Connect

    Cheliak, W.M.

    1980-01-01

    Vegetative reproduction results in a mosaic of clones throughout the extensive natural range of this species. An electrophoretic survey of 26 loci in 222 trees from seven natural populations in Alberta demonstrated great variability. Average observed population heterozygosity was 0.52 with an average of 2.3 alleles per locus; 84% of the loci were polymorphic. A model (for a finite population with neutral alleles) was developed to investigate the effects of partial vegetative reproduction on the amount of variation in a population. Results of the survey conformed to those predicted by the model for a population with a rate of sexual establishment greater than 1/N, where N is the population size. The model states that under these conditions, vegetative reproduction has no effect on the population. Therefore, the high level of observed variation is not an artifact of the mode of natural reproduction. These results support conclusions about high population variability based on phenotypic measurements and also suggest a genetic basis for this variation, rather than simply phenotypic plasticity.

  15. Pervasive genetic integration directs the evolution of human skull shape.

    PubMed

    Martínez-Abadías, Neus; Esparza, Mireia; Sjøvold, Torstein; González-José, Rolando; Santos, Mauro; Hernández, Miquel; Klingenberg, Christian Peter

    2012-04-01

    It has long been unclear whether the different derived cranial traits of modern humans evolved independently in response to separate selection pressures or whether they resulted from the inherent morphological integration throughout the skull. In a novel approach to this issue, we combine evolutionary quantitative genetics and geometric morphometrics to analyze genetic and phenotypic integration in human skull shape. We measured human skulls in the ossuary of Hallstatt (Austria), which offer a unique opportunity because they are associated with genealogical data. Our results indicate pronounced covariation of traits throughout the skull. Separate simulations of selection for localized shape changes corresponding to some of the principal derived characters of modern human skulls produced outcomes that were similar to each other and involved a joint response in all of these traits. The data for both genetic and phenotypic shape variation were not consistent with the hypothesis that the face, cranial base, and cranial vault are completely independent modules but relatively strongly integrated structures. These results indicate pervasive integration in the human skull and suggest a reinterpretation of the selective scenario for human evolution where the origin of any one of the derived characters may have facilitated the evolution of the others.

  16. Validating therapeutic targets through human genetics.

    PubMed

    Plenge, Robert M; Scolnick, Edward M; Altshuler, David

    2013-08-01

    More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' - naturally occurring mutations in humans that affect the activity of a particular protein target or targets - can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose-response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug-gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics.

  17. Can genetic differences explain vocal dialect variation in sperm whales, Physeter macrocephalus?

    PubMed

    Rendell, Luke; Mesnick, Sarah L; Dalebout, Merel L; Burtenshaw, Jessica; Whitehead, Hal

    2012-03-01

    Sperm whale social groups can be assigned to vocal clans based on their production of codas, short stereotyped patterns of clicks. It is currently unclear whether genetic variation could account for these behavioural differences. We studied mitochondrial DNA (mtDNA) variation among sympatric vocal clans in the Pacific Ocean, using sequences extracted from sloughed skin samples. We sampled 194 individuals from 30 social groups belonging to one of three vocal clans. As in previous studies of sperm whales, mtDNA control region diversity was low (π = 0.003), with just 14 haplotypes present in our sample. Both hierarchical AMOVAs and partial Mantel tests showed that vocal clan was a more important factor in matrilineal population genetic structure than geography, even though our sampling spanned thousands of kilometres. The variance component attributed to vocal dialects (7.7%) was an order of magnitude higher than those previously reported in birds, while the variance component attributed to geographic area was negligible. Despite this, the two most common haplotypes were present in significant quantities in each clan, meaning that variation in the control region cannot account for behavioural variation between clans, and instead parallels the situation in humans where parent-offspring transmission of language variation has resulted in correlations with neutral genes. Our results also raise questions for the management of sperm whale populations, which has traditionally been based on dividing populations into geographic 'stocks', suggesting that culturally-defined vocal clans may be more appropriate management units.

  18. Human RECQ Helicase Pathogenic Variants, Population Variation and "Missing" Diseases.

    PubMed

    Fu, Wenqing; Ligabue, Alessio; Rogers, Kai J; Akey, Joshua M; Monnat, Raymond J

    2017-02-01

    Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes-RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases-may remain missing, as they likely incompatible with life.

  19. Genetic variation in the nuclear and organellar genomes modulates stochastic variation in the metabolome, growth, and defense.

    PubMed

    Joseph, Bindu; Corwin, Jason A; Kliebenstein, Daniel J

    2015-01-01

    Recent studies are starting to show that genetic control over stochastic variation is a key evolutionary solution of single celled organisms in the face of unpredictable environments. This has been expanded to show that genetic variation can alter stochastic variation in transcriptional processes within multi-cellular eukaryotes. However, little is known about how genetic diversity can control stochastic variation within more non-cell autonomous phenotypes. Using an Arabidopsis reciprocal RIL population, we showed that there is significant genetic diversity influencing stochastic variation in the plant metabolome, defense chemistry, and growth. This genetic diversity included loci specific for the stochastic variation of each phenotypic class that did not affect the other phenotypic classes or the average phenotype. This suggests that the organism's networks are established so that noise can exist in one phenotypic level like metabolism and not permeate up or down to different phenotypic levels. Further, the genomic variation within the plastid and mitochondria also had significant effects on the stochastic variation of all phenotypic classes. The genetic influence over stochastic variation within the metabolome was highly metabolite specific, with neighboring metabolites in the same metabolic pathway frequently showing different levels of noise. As expected from bet-hedging theory, there was more genetic diversity and a wider range of stochastic variation for defense chemistry than found for primary metabolism. Thus, it is possible to begin dissecting the stochastic variation of whole organismal phenotypes in multi-cellular organisms. Further, there are loci that modulate stochastic variation at different phenotypic levels. Finding the identity of these genes will be key to developing complete models linking genotype to phenotype.

  20. The Genetics of Human Skin Disease

    PubMed Central

    DeStefano, Gina M.; Christiano, Angela M.

    2014-01-01

    The skin is composed of a variety of cell types expressing specific molecules and possessing different properties that facilitate the complex interactions and intercellular communication essential for maintaining the structural integrity of the skin. Importantly, a single mutation in one of these molecules can disrupt the entire organization and function of these essential networks, leading to cell separation, blistering, and other striking phenotypes observed in inherited skin diseases. Over the past several decades, the genetic basis of many monogenic skin diseases has been elucidated using classical genetic techniques. Importantly, the findings from these studies has shed light onto the many classes of molecules and essential genetic as well as molecular interactions that lend the skin its rigid, yet flexible properties. With the advent of the human genome project, next-generation sequencing techniques, as well as several other recently developed methods, tremendous progress has been made in dissecting the genetic architecture of complex, non-Mendelian skin diseases. PMID:25274756

  1. Molecular genetics of human chromosome 21.

    PubMed Central

    Watkins, P C; Tanzi, R E; Cheng, S V; Gusella, J F

    1987-01-01

    Chromosome 21 is the smallest autosome, comprising only about 1.9% of human DNA, but represents one of the most intensively studied regions of the genome. Much of the interest in chromosome 21 can be attributed to its association with Down's syndrome, a genetic disorder that afflicts one in every 700 to 1000 newborns. Although only 17 genes have been assigned to chromosome 21, a very large number of cloned DNA segments of unknown function have been isolated and regionally mapped. The majority of these segments detect restriction fragment length polymorphisms (RFLPs) and therefore represent useful genetic markers. Continued molecular genetic investigation of chromosome 21 will be central to elucidating molecular events leading to meiotic non-disjunction and consequent trisomy, the contribution of specific genes to the pathology of Down's syndrome, and the possible role of chromosome 21 in Alzheimer's disease and other as yet unmapped genetic defects. PMID:2884319

  2. The role of functional data in interpreting the effects of genetic variation.

    PubMed

    Young, David L; Fields, Stanley

    2015-11-05

    Progress in DNA-sequencing technologies has provided a catalogue of millions of DNA variants in the human population, but characterization of the functional effects of these variants has lagged far behind. For example, sequencing of tumor samples is driving an urgent need to classify whether or not mutations seen in cancers affect disease progression or treatment effectiveness or instead are benign. Furthermore, mutations can interact with genetic background and with environmental effects. A new approach, termed deep mutational scanning, has enabled the quantitative assessment of the effects of thousands of mutations in a protein. However, this type of experiment is carried out in model organisms, tissue culture, or in vitro; typically addresses only a single biochemical function of a protein; and is generally performed under a single condition. The current challenge lies in using these functional data to generate useful models for the phenotypic consequences of genetic variation in humans.

  3. 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 C.; 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

  4. 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.

  5. 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)

  6. Population genetic variation in gene expression is associated withphenotypic variation in Saccharomyces cerevisiae

    SciTech Connect

    Fay, Justin C.; McCullough, Heather L.; Sniegowski, Paul D.; Eisen, Michael B.

    2004-02-25

    The relationship between genetic variation in gene expression and phenotypic variation observable in nature is not well understood. Identifying how many phenotypes are associated with differences in gene expression and how many gene-expression differences are associated with a phenotype is important to understanding the molecular basis and evolution of complex traits. Results: We compared levels of gene expression among nine natural isolates of Saccharomyces cerevisiae grown either in the presence or absence of copper sulfate. Of the nine strains, two show a reduced growth rate and two others are rust colored in the presence of copper sulfate. We identified 633 genes that show significant differences in expression among strains. Of these genes,20 were correlated with resistance to copper sulfate and 24 were correlated with rust coloration. The function of these genes in combination with their expression pattern suggests the presence of both correlative and causative expression differences. But the majority of differentially expressed genes were not correlated with either phenotype and showed the same expression pattern both in the presence and absence of copper sulfate. To determine whether these expression differences may contribute to phenotypic variation under other environmental conditions, we examined one phenotype, freeze tolerance, predicted by the differential expression of the aquaporin gene AQY2. We found freeze tolerance is associated with the expression of AQY2. Conclusions: Gene expression differences provide substantial insight into the molecular basis of naturally occurring traits and can be used to predict environment dependent phenotypic variation.

  7. Genome Architecture and Its Roles in Human Copy Number Variation

    PubMed Central

    Chen, Lu; Zhou, Weichen; Zhang, Ling

    2014-01-01

    Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs), are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability. PMID:25705150

  8. Neandertal origin of genetic variation at the cluster of OAS immunity genes.

    PubMed

    Mendez, Fernando L; Watkins, Joseph C; Hammer, Michael F

    2013-04-01

    Analyses of ancient DNA from extinct humans reveal signals of at least two independent hybridization events in the history of non-African populations. To date, there are very few examples of specific genetic variants that have been rigorously identified as introgressive. Here, we survey DNA sequence variation in the OAS gene cluster on chromosome 12 and provide strong evidence that a haplotype extending for ~185 kb introgressed from Neandertals. This haplotype is nearly restricted to Eurasians and is estimated to have diverged from the Neandertal sequence ~125 kya. Despite the potential for novel functional variation, the observed frequency of this haplotype is consistent with neutral introgression. This is the second locus in the human genome, after STAT2, carrying distinct haplotypes that appear to have introgressed separately from both Neandertals and Denisova.

  9. Parasite-host interaction in malaria: genetic clues and copy number variation

    PubMed Central

    2009-01-01

    In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction. PMID:19725943

  10. Genetic variation of germination cold tolerance in Japanese rice germplasm

    PubMed Central

    Bosetti, Fátima; Montebelli, Camila; Novembre, Ana Dionísia L.C.; Chamma, Helena Pescarin; Pinheiro, José Baldin

    2012-01-01

    Low temperatures at the initial stages of rice development prevent fast germination and seedling establishment and may cause significant productivity losses. In order to develop rice cultivars exhibiting cold tolerance, it is necessary to investigate genetic resources, providing basic knowledge to allow the introduction of genes involved in low temperature germination ability from accessions into elite cultivars. Japanese rice accessions were evaluated at the germination under two conditions: 13°C for 28 days (cold stress) and 28°C for seven days (optimal temperature). The traits studied were coleoptile and radicle length under optimal temperature, coleoptile and radicle length under cold and percentage of the reduction in coleptile and radicle length due to low temperature. Among the accessions studied, genetic variation for traits related to germination under low temperatures was observed and accessions exhibiting adequate performance for all investigated traits were identified. The use of multivariate analysis allowed the identification of the genotypes displaying cold tolerance by smaller reductions in coleoptile and radicle lenght in the presence of cold and high vigour, by higher coleoptile and radicle growth under cold. PMID:23226080

  11. Gene therapy for human genetic disease?

    PubMed

    Friedmann, T; Roblin, R

    1972-03-03

    In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue. For the foreseeable future, however, we oppose any further attempts at gene therapy in human patients because (i) our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate; (ii) our understanding of the details of the relation between the molecular defect and the disease state is rudimentary for essentially all genetic diseases; and (iii) we have no information on the short-range and long-term side effects of gene therapy. We therefore propose that a sustained effort be made to formulate a complete set of ethicoscientific criteria to guide the development and clinical application of gene therapy techniques. Such an endeavor could go a long way toward ensuring that gene therapy is used in humans only in those instances where it will prove beneficial, and toward preventing its misuse through premature application. Two recent papers have provided new demonstrations of directed genetic modification of mammalian cells. Munyon et al. (44) restored the ability to synthesize the enzyme thymidine kinase to thymidine kinase-deficient mouse cells by infection with ultraviolet-irradiated herpes simplex virus. In their experiments the DNA from herpes simplex virus, which contains a gene coding for thymidine kinase, may have formed a hereditable association with the mouse cells. Merril et al. (45) reported that treatment of fibroblasts from patients with galactosemia with exogenous DNA caused increased activity of a missing enzyme, alpha-D-galactose-l-phosphate uridyltransferase. They also provided some evidence that the change persisted after subculturing the treated cells. If this latter report can be confirmed, the feasibility of directed genetic modification of human cells would be clearly demonstrated, considerably

  12. Genetic variation of Mycobacterium tuberculosis circulating in Kharkiv Oblast, Ukraine

    PubMed Central

    2011-01-01

    Background A persistent increase of tuberculosis cases has recently been noted in the Ukraine. The reported incidence of drug-resistant isolates of M. tuberculosis is growing steadily; however, data on the genetic variation of isolates of M. tuberculosis circulating in northern Ukraine and on the spectrum and frequency of occurrence of mutations determining resistance to the principal anti-tuberculosis drugs isoniazid and rifampicin have not yet been reported. Methods Isolates of M. tuberculosis from 98 tuberculosis patients living in Kharkiv Oblast (Ukraine) were analyzed using VNTR- and RFLP-IS6110-typing methods. Mutations associated with resistance to rifampicin and isoniazid were detected by RFLP-PCR methods, and also confirmed by sequencing. Results We identified 75 different genetic profiles. Thirty four (34%) isolates belonged to the Beijing genotype and 23 (23%) isolates belonged to the LAM family. A cluster of isolates belonging to the LAM family had significant genetic heterogeneity, indicating that this family had an ancient distribution and circulation in this geographical region. Moreover, we found a significant percentage of the isolates (36%) belonged to as yet unidentified families of M. tuberculosis or had individual non-clustering genotypes. Mutations conferring rifampicin and isoniazid resistance were detected in 49% and 54% isolates, respectively. Mutations in codon 531 of the rpoB gene and codon 315 of the katG gene were predominant among drug-resistant isolates. An association was found for belonging to the LAM strain family and having multiple drug resistance (R = 0.27, p = 0.0059) and also for the presence of a mutation in codon 531 of the rpoB gene and belonging to the Beijing strain family (R = 0.2, p = 0.04). Conclusions Transmission of drug-resistant isolates seems to contribute to the spread of resistant TB in this oblast. The Beijing genotype and LAM genotype should be seen as a major cause of drug resistant TB in this region. PMID

  13. Genetic Variations in the Serotoninergic System Contribute to Body-Mass Index in Chinese Adolescents

    PubMed Central

    Chen, Chuansheng; Moyzis, Robert; He, Qinghua; Lei, Xuemei; Li, Jin; Wang, Yunxin; Liu, Bin; Xiu, Daiming; Zhu, Bi; Dong, Qi

    2013-01-01

    Objective Obesity has become a worldwide health problem in the past decades. Human and animal studies have implicated serotonin in appetite regulation, and behavior genetic studies have shown that body mass index (BMI) has a strong genetic component. However, the roles of genes related to the serotoninergic (5-hydroxytryptamine,5-HT) system in obesity/BMI are not well understood, especially in Chinese subjects. Subjects and Design With a sample of 478 healthy Chinese volunteers, this study investigated the relation between BMI and genetic variations of the serotoninergic system as characterized by 136 representative polymorphisms. We used a system-level approach to identify SNPs associated with BMI, then estimated their overall contribution to BMI by multiple regression and verified it by permutation. Results We identified 12 SNPs that made statistically significant contributions to BMI. After controlling for gender and age, four of these SNPs accounted for 7.7% additional variance of BMI. Permutation analysis showed that the probability of obtaining these findings by chance was low (p = 0.015, permuted for 1000 times). Conclusion These results showed that genetic variations in the serotoninergic system made a moderate contribution to individual differences in BMI among a healthy Chinese sample, suggesting that a similar approach can be used to study obesity. PMID:23554917

  14. Genetic specificity of a plant–insect food web: Implications for linking genetic variation to network complexity

    PubMed Central

    Barbour, Matthew A.; Fortuna, Miguel A.; Bascompte, Jordi; Nicholson, Joshua R.; Julkunen-Tiitto, Riitta; Jules, Erik S.; Crutsinger, Gregory M.

    2016-01-01

    Theory predicts that intraspecific genetic variation can increase the complexity of an ecological network. To date, however, we are lacking empirical knowledge of the extent to which genetic variation determines the assembly of ecological networks, as well as how the gain or loss of genetic variation will affect network structure. To address this knowledge gap, we used a common garden experiment to quantify the extent to which heritable trait variation in a host plant determines the assembly of its associated insect food web (network of trophic interactions). We then used a resampling procedure to simulate the additive effects of genetic variation on overall food-web complexity. We found that trait variation among host-plant genotypes was associated with resistance to insect herbivores, which indirectly affected interactions between herbivores and their insect parasitoids. Direct and indirect genetic effects resulted in distinct compositions of trophic interactions associated with each host-plant genotype. Moreover, our simulations suggest that food-web complexity would increase by 20% over the range of genetic variation in the experimental population of host plants. Taken together, our results indicate that intraspecific genetic variation can play a key role in structuring ecological networks, which may in turn affect network persistence. PMID:26858398

  15. 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

  16. Frequency variations of discrete cranial traits in major human populations. III. Hyperostotic variations

    PubMed Central

    HANIHARA, TSUNEHIKO; ISHIDA, HAJIME

    2001-01-01

    Seven discrete cranial traits usually categorised as hyperostotic characters, the medial palatine canal, hypoglossal canal bridging, precondylar tubercle, condylus tertius, jugular foramen bridging, auditory exostosis, and mylohyoid bridging were investigated in 81 major human population samples from around the world. Significant asymmetric occurrences of the bilateral traits were detected in the medial palatine canal and jugular foramen bridging in several samples. Significant intertrait associations were found between some pairs of the traits, but not consistently across the large geographical samples. The auditory exostosis showed a predominant occurrence in males. With the exception of the auditory exostosis and mylohyoid bridging in a few samples, significant sex differences were slight. The frequency distributions of the traits (except for the auditory exostosis) showed some interregional clinality and intraregional discontinuity, suggesting that genetic drift could have contributed to the observed pattern of variation. PMID:11554504

  17. Genetics of human congenital urinary bladder disease.

    PubMed

    Woolf, Adrian S; Stuart, Helen M; Newman, William G

    2014-03-01

    Lower urinary tract and/or kidney malformations are collectively the most common cause of end-stage renal disease in children, and they are also likely to account for a major subset of young adults requiring renal replacement therapy. Advances have been made regarding the discovery of the genetic causes of human kidney malformations. Indeed, testing for mutations of key nephrogenesis genes is now feasible for patients seen in nephrology clinics. Unfortunately, less is known about defined genetic bases of human lower urinary tract anomalies. The focus of this review is the genetic bases of congenital structural and functional disorders of the urinary bladder. Three are highlighted. First, prune belly syndrome, where mutations of CHRM3, encoding an acetylcholine receptor, HNF1B, encoding a transcription factor, and ACTA2, encoding a cytoskeletal protein, have been reported. Second, the urofacial syndrome, where mutations of LRIG2 and HPSE2, encoding proteins localised in nerves invading the fetal bladder, have been defined. Finally, we review emerging evidence that bladder exstrophy may have genetic bases, including variants in the TP63 promoter. These genetic discoveries provide a new perspective on a group of otherwise poorly understood diseases.

  18. Genetically modified pigs to model human diseases.

    PubMed

    Flisikowska, Tatiana; Kind, Alexander; Schnieke, Angelika

    2014-02-01

    Genetically modified mice are powerful tools to investigate the molecular basis of many human diseases. Mice are, however, of limited value for preclinical studies, because they differ significantly from humans in size, general physiology, anatomy and lifespan. Considerable efforts are, thus, being made to develop alternative animal models for a range of human diseases. These promise powerful new resources that will aid the development of new diagnostics, medicines and medical procedures. Here, we provide a comprehensive review of genetically modified porcine models described in the scientific literature: various cancers, cystic fibrosis, Duchenne muscular dystrophy, autosomal polycystic kidney disease, Huntington’s disease, spinal muscular atrophy, haemophilia A, X-linked severe combined immunodeficiency, retinitis pigmentosa, Stargardt disease, Alzheimer’s disease, various forms of diabetes mellitus and cardiovascular diseases.

  19. Human Genetic Disorders of Axon Guidance

    PubMed Central

    Engle, Elizabeth C.

    2010-01-01

    This article reviews symptoms and signs of aberrant axon connectivity in humans, and summarizes major human genetic disorders that result, or have been proposed to result, from defective axon guidance. These include corpus callosum agenesis, L1 syndrome, Joubert syndrome and related disorders, horizontal gaze palsy with progressive scoliosis, Kallmann syndrome, albinism, congenital fibrosis of the extraocular muscles type 1, Duane retraction syndrome, and pontine tegmental cap dysplasia. Genes mutated in these disorders can encode axon growth cone ligands and receptors, downstream signaling molecules, and axon transport motors, as well as proteins without currently recognized roles in axon guidance. Advances in neuroimaging and genetic techniques have the potential to rapidly expand this field, and it is feasible that axon guidance disorders will soon be recognized as a new and significant category of human neurodevelopmental disorders. PMID:20300212

  20. Molecular genetics of human lactase deficiencies.

    PubMed

    Järvelä, Irma; Torniainen, Suvi; Kolho, Kaija-Leena

    2009-01-01

    Lactase non-persistence (adult-type hypolactasia) is present in more than half of the human population and is caused by the down-regulation of lactase enzyme activity during childhood. Congenital lactase deficiency (CLD) is a rare severe gastrointestinal disorder of new-borns enriched in the Finnish population. Both lactase deficiencies are autosomal recessive traits and characterized by diminished expression of lactase activity in the intestine. Genetic variants underlying both forms have been identified. Here we review the current understanding of the molecular defects of human lactase deficiencies and their phenotype-genotype correlation, the implications on clinical practice, and the understanding of their function and role in human evolution.

  1. Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia

    PubMed Central

    2010-01-01

    Background Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis. Methods As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations. Results Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10-3). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019). Conclusions Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation. PMID:20858243

  2. Novel genetic capacitors and potentiators for the natural genetic variation of sensory bristles and their trait specificity in Drosophila melanogaster.

    PubMed

    Takahashi, Kazuo H

    2015-11-01

    Cryptic genetic variation (CGV) is defined as the genetic variation that has little effect on phenotypic variation under a normal condition, but contributes to heritable variation under environmental or genetic perturbations. Genetic buffering systems that suppress the expression of CGV and store it in a population are called genetic capacitors, and the opposite systems are called genetic potentiators. One of the best-known candidates for a genetic capacitor and potentiator is the molecular chaperone protein, HSP90, and one of its characteristics is that it affects the genetic variation in various morphological traits. However, it remains unclear whether the wide-ranging effects of HSP90 on a broad range of traits are a general feature of genetic capacitors and potentiators. In the current study, I searched for novel genetic capacitors and potentiators for quantitative bristle traits of Drosophila melanogaster and then investigated the trait specificity of their genetic buffering effect. Three bristle traits of D. melanogaster were used as the target traits, and the genomic regions with genetic buffering effects were screened using the 61 genomic deficiencies examined previously for genetic buffering effects in wing shape. As a result, four and six deficiencies with significant effects on increasing and decreasing the broad-sense heritability of the bristle traits were identified, respectively. Of the 18 deficiencies with significant effects detected in the current study and/or by the previous study, 14 showed trait-specific effects, and four affected the genetic buffering of both bristle traits and wing shape. This suggests that most genetic capacitors and potentiators exert trait-specific effects, but that general capacitors and potentiators with effects on multiple traits also exist.

  3. Genetic Heterogeneity in Algerian Human Populations

    PubMed Central

    Deba, Tahria; Calafell, Francesc; Benhamamouch, Soraya; Comas, David

    2015-01-01

    The demographic history of human populations in North Africa has been characterized by complex processes of admixture and isolation that have modeled its current gene pool. Diverse genetic ancestral components with different origins (autochthonous, European, Middle Eastern, and sub-Saharan) and genetic heterogeneity in the region have been described. In this complex genetic landscape, Algeria, the largest country in Africa, has been poorly covered, with most of the studies using a single Algerian sample. In order to evaluate the genetic heterogeneity of Algeria, Y-chromosome, mtDNA and autosomal genome-wide makers have been analyzed in several Berber- and Arab-speaking groups. Our results show that the genetic heterogeneity found in Algeria is not correlated with geography or linguistics, challenging the idea of Berber groups being genetically isolated and Arab groups open to gene flow. In addition, we have found that external sources of gene flow into North Africa have been carried more often by females than males, while the North African autochthonous component is more frequent in paternally transmitted genome regions. Our results highlight the different demographic history revealed by different markers and urge to be cautious when deriving general conclusions from partial genomic information or from single samples as representatives of the total population of a region. PMID:26402429

  4. Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in Aggressiveness of Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0453 TITLE: Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in Aggressiveness of...COVERED 15 Sep 2014 - 14 Sep 2015 4. TITLE AND SUBTITLE Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in...proposed studies are expected to (1) identify genetic variations in the genes of androgen transporters that are associated with the racial differences in

  5. Population Genetics of Euphydryas Butterflies. I. Genetic Variation and the Neutrality Hypothesis

    PubMed Central

    McKechnie, Stephen W.; Ehrlich, Paul R.; White, Raymond R.

    1975-01-01

    Twenty-one populations of the checkerspot butterfly, Euphydryas editha, and ten populations of Euphydryas chalcedona were sampled for genetic variation at eight polymorphic enzyme loci. Both species possessed loci that were highly variable from population to population and loci that were virtually identical across all populations sampled. Our data indicate that the neutrality hypothesis is untenable for the loci studied, and therefore selection is indicated as the major factor responsible for producing these patterns. Thorough ecological work allowed gene flow to be ruled out (in almost all instances) as a factor maintaining similar gene frequencies across populations. The Lewontin-Krakauer test indicated magnitudes of heterogeneity among standardized variances of gene frequencies inconsistent with the neutrality hypothesis. The question of whether or not to correct this statistic for sample size is discussed. Observed equitability of gene frequencies of multiple allelic loci was found to be greater than that predicted under the neutrality hypothesis. Genetic differentiation presisting through two generations was found between the one pair of populations known to exchange significant numbers of individuals per generation. Two matrices of genetic distance between populations, based on the eight loci sampled, were found to be significantly correlated with a matrix of environmental distance, based on measures of fourteen environmental parameters. Correlations between gene frequencies and environmental parameters, results of multiple regression analysis, and results of principle component analysis showed strong patterns of association and of "explained" variation. The correlation analyses suggest which factors might be further investigated as proximate selective agents. PMID:1205135

  6. Impact of genetic variation on synaptic protein levels in genetically diverse mice.

    PubMed

    Loos, Maarten; Li, Ka Wan; van der Schors, Roel; Gouwenberg, Yvonne; van der Loo, Rolinka; Williams, Robert W; Smit, August B; Spijker, Sabine

    2016-04-01

    The relative abundance of synaptic proteins shapes protein complex formation and is essential for synapse function and behavioral fitness. Here, we have used a panel of highly diverse inbred strains of mice-NOD/LtJ, A/J, 129S1/SvImJ, FVB/NJ, C57BL/6J, WSB/EiJ, PWK/PhJ, and CAST/EiJ-to quantify the effects of genetic variation on the synaptic proteome between strains. Using iTRAQ-based quantitative proteome analyses, we detected significant differences in ∼20% of 400 core synaptic proteins. Surprisingly, the differentially abundant proteins showed a modest range of variation across strains, averaging about 1.3-fold. Analysis of protein abundance covariation across the eight strains identified known protein-protein relations (proteins of Arp2/3 complex), as well as novel relations (e.g. Dlg family, Fscn1). Moreover, covariation of synaptic proteins was substantially tighter (∼fourfold more dense than chance level) than corresponding networks of synaptic transcripts (∼twofold more dense than chance). The tight stoichiometry and coherent synaptic protein covariation networks suggest more intense evolutionary selection at this level of molecular organization. In conclusion, genetic diversity in the mouse genome differentially affects the transcriptome and proteome, and only partially penetrates the synaptic proteome. Protein abundance correlation analyses in genetically divergent strains can complement protein-protein interaction network analyses, to provide insight into protein interactomes.

  7. Naturally occurring human genetic variation in the 3’-untranslated region of the secretory protein chromogranin A (CHGA) is associated with autonomic blood pressure regulation and hypertension in sex-dependent fashion

    PubMed Central

    Chen, Yuqing; Rao, Fangwen; Rodriguez-Flores, Juan L.; Mahata, Manjula; Fung, Maple M.; Stridsberg, Mats; Vaingankar, Sucheta M.; Wen, Gen; Salem, Rany M.; Das, Madhusudan; Cockburn, Myles G.; Schork, Nicholas J.; Ziegler, Michael G.; Hamilton, Bruce A.; Mahata, Sushil K.; Taupenot, Laurent; O’Connor, Daniel T.

    2008-01-01

    Objective Determination whether common variation at the CHGA locus increases susceptibility to hypertension. Background Chromogranin A (CHGA) regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. Methods Dense genotyping across the CHGA locus in >1000 individuals with the most extreme BPs in the population, as well twin pairs with autonomic phenotypes. Characterizing function of a trait-associated 3'-UTR variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. Results CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurred in the 3'-UTR at C+87T, accounting for up to ~12/~9 mmHg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by ~10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the SBP response to stress by ~12 mmHg, and the response was smaller in women (by ~6 mmHg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by ~30%. In cultured chromaffin cells, reducing endogenous Chga expression by si-RNA caused ~2/3 depletion of catecholamine storage vesicles. Conclusions Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and propose steps ("intermediate phenotypes") whereby in sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension. PMID:19017515

  8. Genetic Susceptibility to Fungal Infections in Humans.

    PubMed

    Lionakis, Michail S

    2012-03-01

    Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a "normal" host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed.

  9. Genetic Susceptibility to Fungal Infections in Humans

    PubMed Central

    Lionakis, Michail S.

    2012-01-01

    Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a “normal” host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed. PMID:23087779

  10. Population Structure in a Comprehensive Genomic Data Set on Human Microsatellite Variation

    PubMed Central

    Pemberton, Trevor J.; DeGiorgio, Michael; Rosenberg, Noah A.

    2013-01-01

    Over the past two decades, microsatellite genotypes have provided the data for landmark studies of human population-genetic variation. However, the various microsatellite data sets have been prepared with different procedures and sets of markers, so that it has been difficult to synthesize available data for a comprehensive analysis. Here, we combine eight human population-genetic data sets at the 645 microsatellite loci they share in common, accounting for procedural differences in the production of the different data sets, to assemble a single data set containing 5795 individuals from 267 worldwide populations. We perform a systematic analysis of genetic relatedness, detecting 240 intra-population and 92 inter-population pairs of previously unidentified close relatives and proposing standardized subsets of unrelated individuals for use in future studies. We then augment the human data with a data set of 84 chimpanzees at the 246 loci they share in common with the human samples. Multidimensional scaling and neighbor-joining analyses of these data sets offer new insights into the structure of human populations and enable a comparison of genetic variation patterns in chimpanzees with those in humans. Our combined data sets are the largest of their kind reported to date and provide a resource for use in human population-genetic studies. PMID:23550135

  11. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

    PubMed

    Scott, Eric M; Halees, Anason; Itan, Yuval; Spencer, Emily G; He, Yupeng; Azab, Mostafa Abdellateef; Gabriel, Stacey B; Belkadi, Aziz; Boisson, Bertrand; Abel, Laurent; Clark, Andrew G; Alkuraya, Fowzan S; Casanova, Jean-Laurent; Gleeson, Joseph G

    2016-09-01

    The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

  12. Temporal variation of genetic composition in Atlantic salmon populations from the Western White Sea Basin: influence of anthropogenic factors?

    PubMed Central

    2013-01-01

    Background Studies of the temporal patterns of population genetic structure assist in evaluating the consequences of demographic and environmental changes on population stability and persistence. In this study, we evaluated the level of temporal genetic variation in 16 anadromous and 2 freshwater salmon populations from the Western White Sea Basin (Russia) using samples collected between 1995 and 2008. To assess whether the genetic stability was affected by human activity, we also evaluated the effect of fishing pressure on the temporal genetic variation in this region. Results We found that the genetic structure of salmon populations in this region was relatively stable over a period of 1.5 to 2.5 generations. However, the level of temporal variation varied among geographical regions: anadromous salmon of the Kola Peninsula exhibited a higher stability compared to that of the anadromous and freshwater salmon from the Karelian White Sea coast. This discrepancy was most likely attributed to the higher census, and therefore effective, population sizes of the populations inhabiting the rivers of the Kola Peninsula compared to salmon of the Karelian White Sea coast. Importantly, changes in the genetic diversity observed in a few anadromous populations were best explained by the increased level of fishing pressure in these populations rather than environmental variation or the negative effects of hatchery escapees. The observed population genetic patterns of isolation by distance remained consistent among earlier and more recent samples, which support the stability of the genetic structure over the period studied. Conclusions Given the increasing level of fishing pressure in the Western White Sea Basin and the higher level of temporal variation in populations exhibiting small census and effective population sizes, further genetic monitoring in this region is recommended, particularly on populations from the Karelian rivers. PMID:24053319

  13. Anatomical Variation of Human Collector Channel Orifices

    PubMed Central

    Bentley, Michael D.; Hann, Cheryl R.; Fautsch, Michael P.

    2016-01-01

    Purpose To examine the anatomical variation of normal human collector channel orifices and their relationship with Schlemm's canal. Methods Ten human anterior segments fixed by immersion or perfusion were dissected radially and further divided by fine dissection into corresponding inner and outer wall segments. The tissues were dehydrated, critical-point dried, sputter coated, and examined by scanning electron microscopy. Images were obtained at magnifications from ×200 to ×10,000. Selected radial collector channel regions were processed for plastic embedding. Results Two classes of collector channel orifices were identified. Simple oval orifices (54.7 ± 4.6–μm diameter) were lined with endothelial cells and most often occurred on a planar region of Schlemm's canal outer wall. Complex orifices (62.7 ± 3.4–μm diameter) were often found associated with septal columns and bridges, and typically covered with flap-like structures (10–40 μm) that extended between the inner and outer wall and over the collector channel orifices. Both simple and complex orifices had complete or partial lip-like rims. In orifices with partial rims, a trough-like groove was often visible on the outer wall surface opposite the lip. Transected septa and inner and outer wall adhesion sites were often found in association with complex collector channel orifices. Conclusions Collector channel orifice structure varied from simple ovals to complex tethered flaps and bridges. Collector channel orifices with complex flaps connect the inner and outer walls of Schlemm's canal, and may serve to enhance and regulate aqueous outflow in these regions. PMID:26975026

  14. Human Genetics Education: A Look to the Future.

    ERIC Educational Resources Information Center

    Biological Sciences Curriculum Study Journal, 1979

    1979-01-01

    Examines the status of human genetics education. Provides an updated report of the work being done at the BSCS Center for Education in Human and Medical Genetics. Includes reports of regional conferences and of West German educational programs. (MA)

  15. Human Genetic Engineering: A Survey of Student Value Stances

    ERIC Educational Resources Information Center

    Wilson, Sara McCormack; And Others

    1975-01-01

    Assesses the values of high school and college students relative to human genetic engineering and recommends that biology educators explore instructional strategies merging human genetic information with value clarification techniques. (LS)

  16. Genetic variation and recurrent parasitaemia in Peruvian Plasmodium vivax populations

    PubMed Central

    2014-01-01

    Background Plasmodium vivax is a predominant species of malaria in parts of South America and there is increasing resistance to drugs to treat infections by P. vivax. The existence of latent hypnozoites further complicates the ability to classify recurrent infections as treatment failures due to relapse, recrudescence of hyponozoites or re-infections. Antigen loci are putatively under natural selection and may not be an optimal molecular marker to define parasite haplotypes in paired samples. Putatively neutral microsatellite loci, however, offer an assessment of neutral haplotypes. The objective here was to assess the utility of neutral microsatellite loci to reconcile cases of recurrent parasitaemia in Amazonian P. vivax populations in Peru. Methods Patient blood samples were collected from three locations in or around Iquitos in the Peruvian Amazon. Five putatively neutral microsatellite loci were characterized from 445 samples to ascertain the within and amongst population variation. A total of 30 day 0 and day of recurrent parasitaemia samples were characterized at microsatellite loci and five polymorphic antigen loci for haplotype classification. Results The genetic diversity at microsatellite loci was consistent with neutral levels of variation measured in other South American P. vivax populations. Results between antigen and microsatellite loci for the 30 day 0 and day of recurrent parasitaemia samples were the same for 80% of the pairs. The majority of non-concordant results were the result of differing alleles at microsatellite loci. This analysis estimates that 90% of the paired samples with the same microsatellite haplotype are unlikely to be due to a new infection. Conclusions A population-level approach was used to yield a better estimate of the probability of a new infection versus relapse or recrudescence of homologous hypnozoites; hypnozoite activation was common for this cohort. Population studies are critical with the evaluation of genetic

  17. Human genetic technology: who shall control?

    PubMed

    Blank, R H

    1984-01-01

    The biotechnical "revolution" has fast come upon us. It promises to produce both substantial benefits and difficult dilemmas for individuals and society. Despite the growing attention being paid to biotechnology, a major unanswered question is who shall control the development and use of the powerful array of human genetic and reproductive innovations. Should the decisions be left to individual consumers and private industry or should they be made by the government or other social institutions? After briefly reviewing development in human genetics and reproduction and describing trends toward commercialization of them, this article discusses the dilemmas these trends raise for a democratic society. It argues for the urgent need to delineate societal goals and priorities for the future and for technology assessment as early as possible in the developmental process. The article concludes by presenting some examples of the social policy problems now emerging.

  18. Genetic basis of human circadian rhythm disorders.

    PubMed

    Jones, Christopher R; Huang, Angela L; Ptáček, Louis J; Fu, Ying-Hui

    2013-05-01

    Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health.

  19. Gene Conversion in Human Genetic Disease

    PubMed Central

    Chen, Jian-Min; Férec, Claude; Cooper, David N.

    2010-01-01

    Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102

  20. Moose body mass variation revisited: disentangling effects of environmental conditions and genetics.

    PubMed

    Herfindal, Ivar; Haanes, Hallvard; Solberg, Erling J; Røed, Knut H; Høgda, Kjell Arild; Sæther, Bernt-Erik

    2014-02-01

    Large-scale geographical variation in phenotypic traits within species is often correlated to local environmental conditions and population density. Such phenotypic variation has recently been shown to also be influenced by genetic structuring of populations. In ungulates, large-scale geographical variation in phenotypic traits, such as body mass, has been related to environmental conditions and population density, but little is known about the genetic influences. Research on the genetic structure of moose suggests two distinct genetic lineages in Norway, structured along a north-south gradient. This corresponds with many environmental gradients, thus genetic structuring provides an additional factor affecting geographical phenotypic variation in Norwegian moose. We investigated if genetic structure explained geographical variation in body mass in Norwegian moose while accounting for environmental conditions, age and sex, and if it captured some of the variance in body mass that previously was attributed to environmental factors. Genetic structuring of moose was the most important variable in explaining the geographic variation in body mass within age and sex classes. Several environmental variables also had strong explanatory power, related to habitat diversity, environmental seasonality and winter harshness. The results suggest that environmental conditions, landscape characteristics, and genetic structure should be evaluated together when explaining large-scale patterns in phenotypic characters or life history traits. However, to better understand the role of genetic and environmental effects on phenotypic traits in moose, an extended individual-based study of variation in fitness-related characters is needed, preferably in an area of convergence between different genetic lineages.

  1. The genomic signature of parallel adaptation from shared genetic variation

    PubMed Central

    Roesti, Marius; Gavrilets, Sergey; Hendry, Andrew P.; Salzburger, Walter; Berner, Daniel

    2014-01-01

    Parallel adaptation is common and may often occur from shared genetic variation, but the genomic consequences of this process remain poorly understood. We first use individual-based simulations to demonstrate that comparisons among populations adapted in parallel from shared variation reveal a characteristic genomic signature around a selected locus: a low divergence valley centered at the locus and flanked by twin peaks of high divergence. This signature is initiated by the hitchhiking of haplotype tracts differing among derived populations in the broader neighborhood of the selected locus (driving the high divergence twin peaks) and shared haplotype tracts in the tight neighborhood of the locus (driving the low divergence valley). This initial hitchhiking signature is reinforced over time because the selected locus acts as a barrier to gene flow from the source to the derived populations, thus promoting divergence by drift in its close neighborhood. We next empirically confirm the peak-valley-peak signature by combining targeted and RAD sequence data at three candidate adaptation genes in multiple marine (source) and freshwater (derived) populations of threespine stickleback. Finally, we use a genome-wide screen for the peak-valley-peak signature to discover additional genome regions involved in parallel marine-freshwater divergence. Our findings offer a new explanation for heterogeneous genomic divergence and thus challenge the standard view that peaks in population divergence harbor divergently selected loci, and that low-divergence regions result from balancing selection or localized introgression. We anticipate that genome scans for peak-valley-peak divergence signatures will promote the discovery of adaptation genes in other organisms. PMID:24635356

  2. Advances in gene technology: Human genetic disorders

    SciTech Connect

    Scott, W.A.; Ahmad, F.; Black, S.; Schultz, J.; Whelan, W.J.

    1984-01-01

    This book discusses the papers presented at the conference on the subject of ''advances in Gene technology: Human genetic disorders''. Molecular biology of various carcinomas and inheritance of metabolic diseases is discussed and technology advancement in diagnosis of hereditary diseases is described. Some of the titles discussed are-Immunoglobulin genes translocation and diagnosis; hemophilia; oncogenes; oncogenic transformations; experimental data on mice, hamsters, birds carcinomas and sarcomas.

  3. Genetic variation in polyploid forage grass: Assessing the molecular genetic variability in the Paspalum genus

    PubMed Central

    2013-01-01

    Background Paspalum (Poaceae) is an important genus of the tribe Paniceae, which includes several species of economic importance for foraging, turf and ornamental purposes, and has a complex taxonomical classification. Because of the widespread interest in several species of this genus, many accessions have been conserved in germplasm banks and distributed throughout various countries around the world, mainly for the purposes of cultivar development and cytogenetic studies. Correct identification of germplasms and quantification of their variability are necessary for the proper development of conservation and breeding programs. Evaluation of microsatellite markers in different species of Paspalum conserved in a germplasm bank allowed assessment of the genetic differences among them and assisted in their proper botanical classification. Results Seventeen new polymorphic microsatellites were developed for Paspalum atratum Swallen and Paspalum notatum Flüggé, twelve of which were transferred to 35 Paspalum species and used to evaluate their variability. Variable degrees of polymorphism were observed within the species. Based on distance-based methods and a Bayesian clustering approach, the accessions were divided into three main species groups, two of which corresponded to the previously described Plicatula and Notata Paspalum groups. In more accurate analyses of P. notatum accessions, the genetic variation that was evaluated used thirty simple sequence repeat (SSR) loci and revealed seven distinct genetic groups and a correspondence of these groups to the three botanical varieties of the species (P. notatum var. notatum, P. notatum var. saurae and P. notatum var. latiflorum). Conclusions The molecular genetic approach employed in this study was able to distinguish many of the different taxa examined, except for species that belong to the Plicatula group, which has historically been recognized as a highly complex group. Our molecular genetic approach represents a

  4. Genetics of single-cell protein abundance variation in large yeast populations

    NASA Astrophysics Data System (ADS)

    Albert, Frank W.; Treusch, Sebastian; Shockley, Arthur H.; Bloom, Joshua S.; Kruglyak, Leonid

    2014-02-01

    Variation among individuals arises in part from differences in DNA sequences, but the genetic basis for variation in most traits, including common diseases, remains only partly understood. Many DNA variants influence phenotypes by altering the expression level of one or several genes. The effects of such variants can be detected as expression quantitative trait loci (eQTL). Traditional eQTL mapping requires large-scale genotype and gene expression data for each individual in the study sample, which limits sample sizes to hundreds of individuals in both humans and model organisms and reduces statistical power. Consequently, many eQTL are probably missed, especially those with smaller effects. Furthermore, most studies use messenger RNA rather than protein abundance as the measure of gene expression. Studies that have used mass-spectrometry proteomics reported unexpected differences between eQTL and protein QTL (pQTL) for the same genes, but these studies have been even more limited in scope. Here we introduce a powerful method for identifying genetic loci that influence protein expression in the yeast Saccharomyces cerevisiae. We measure single-cell protein abundance through the use of green fluorescent protein tags in very large populations of genetically variable cells, and use pooled sequencing to compare allele frequencies across the genome in thousands of individuals with high versus low protein abundance. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci that we detected were clustered in `hotspots' that influence multiple proteins, and some hotspots were found to influence more than half of the proteins that we examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell

  5. Genetic Variation Underlying Protein Expression in Eggs of the Marine Mussel Mytilus edulis*S⃞

    PubMed Central

    Diz, Angel P.; Dudley, Edward; MacDonald, Barry W.; Piña, Benjamin; Kenchington, Ellen L. R.; Zouros, Eleftherios; Skibinski, David O. F.

    2009-01-01

    Study of the genetic basis of gene expression variation is central to attempts to understand the causes of evolutionary change. Although there are many transcriptomics studies estimating genetic variance and heritability in model organisms such as humans there is a lack of equivalent proteomics studies. In the present study, the heritability underlying egg protein expression was estimated in the marine mussel Mytilus. We believe this to be the first such measurement of genetic variation for gene expression in eggs of any organism. The study of eggs is important in evolutionary theory and life history analysis because maternal effects might have profound effects on the rate of evolution of offspring traits. Evidence is presented that the egg proteome varies significantly between individual females and that heritability of protein expression in mussel eggs is moderate to high suggesting abundant genetic variation on which natural selection might act. The study of the mussel egg proteome is also important because of the unusual system of mitochondrial DNA inheritance in mussels whereby different mitochondrial genomes are transmitted independently through female and male lineages (doubly uniparental inheritance). It is likely that the mechanism underlying this system involves the interaction of specific egg factors with sperm mitochondria following fertilization, and its elucidation might be advanced by study of the proteome in females having different progeny sex ratios. Putative identifications are presented here for egg proteins using MS/MS in Mytilus lines differing in sex ratio. Ontology terms relating to stress response and protein folding occur more frequently for proteins showing large expression differences between the lines. The distribution of ontology terms in mussel eggs was compared with those for previous mussel proteomics studies (using other tissues) and with mammal eggs. Significant differences were observed between mussel eggs and mussel tissues but

  6. Learned vocal variation is associated with abrupt cryptic genetic change in a parrot species complex.

    PubMed

    Ribot, Raoul F H; Buchanan, Katherine L; Endler, John A; Joseph, Leo; Bennett, Andrew T D; Berg, Mathew L

    2012-01-01

    Contact zones between subspecies or closely related species offer valuable insights into speciation processes. A typical feature of such zones is the presence of clinal variation in multiple traits. The nature of these traits and the concordance among clines are expected to influence whether and how quickly speciation will proceed. Learned signals, such as vocalizations in species having vocal learning (e.g. humans, many birds, bats and cetaceans), can exhibit rapid change and may accelerate reproductive isolation between populations. Therefore, particularly strong concordance among clines in learned signals and population genetic structure may be expected, even among continuous populations in the early stages of speciation. However, empirical evidence for this pattern is often limited because differences in vocalisations between populations are driven by habitat differences or have evolved in allopatry. We tested for this pattern in a unique system where we may be able to separate effects of habitat and evolutionary history. We studied geographic variation in the vocalizations of the crimson rosella (Platycercus elegans) parrot species complex. Parrots are well known for their life-long vocal learning and cognitive abilities. We analysed contact calls across a ca 1300 km transect encompassing populations that differed in neutral genetic markers and plumage colour. We found steep clinal changes in two acoustic variables (fundamental frequency and peak frequency position). The positions of the two clines in vocal traits were concordant with a steep cline in microsatellite-based genetic variation, but were discordant with the steep clines in mtDNA, plumage and habitat. Our study provides new evidence that vocal variation, in a species with vocal learning, can coincide with areas of restricted gene flow across geographically continuous populations. Our results suggest that traits that evolve culturally can be strongly associated with reduced gene flow between

  7. dbSNP: the NCBI database of genetic variation.

    PubMed

    Sherry, S T; Ward, M H; Kholodov, M; Baker, J; Phan, L; Smigielski, E M; Sirotkin, K

    2001-01-01

    In response to a need for a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, the National Center for Biotechnology Information (NCBI) has established the dbSNP database [S.T.Sherry, M.Ward and K. Sirotkin (1999) Genome Res., 9, 677-679]. Submissions to dbSNP will be integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data. The complete contents of dbSNP are available to the public at website: http://www.ncbi.nlm.nih.gov/SNP. The complete contents of dbSNP can also be downloaded in multiple formats via anonymous FTP at ftp://ncbi.nlm.nih.gov/snp/.

  8. Overview of genetic analysis of human opioid receptors.

    PubMed

    Spampinato, Santi M

    2015-01-01

    The human μ-opioid receptor gene (OPRM1), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies. The μ-opioid receptor (MOR), encoded by OPRM1, contributes to regulate the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic polymorphisms of opioid receptors are candidates for the variability of clinical opioid effects. The non-synonymous polymorphism A118G of the OPRM1 has been repeatedly associated with the efficacy of opioid treatments for pain and various types of dependence. Genetic analysis of human opioid receptors has evidenced the presence of numerous polymorphisms either in exonic or in intronic sequences as well as the presence of synonymous coding variants that may have important effects on transcription, mRNA stability, and splicing, thus affecting gene function despite not directly disrupting any specific residue. Genotyping of opioid receptors is still in its infancy and a relevant progress in this field can be achieved by using advanced gene sequencing techniques described in this review that allow the researchers to obtain vast quantities of data on human genomes and transcriptomes in a brief period of time and with affordable costs.

  9. Genetic Diversity in Cytokines Associated with Immune Variation and Resistance to Multiple Pathogens in a Natural Rodent Population

    PubMed Central

    Turner, Andrew K.; Begon, Mike; Jackson, Joseph A.; Bradley, Janette E.; Paterson, Steve

    2011-01-01

    Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans. PMID:22039363

  10. The influence of mitonuclear genetic variation on personality in seed beetles

    PubMed Central

    Løvlie, Hanne; Immonen, Elina; Gustavsson, Emil; Kazancioğlu, Erem; Arnqvist, Göran

    2014-01-01

    There is a growing awareness of the influence of mitochondrial genetic variation on life-history phenotypes, particularly via epistatic interactions with nuclear genes. Owing to their direct effect on traits such as metabolic and growth rates, mitonuclear interactions may also affect variation in behavioural types or personalities (i.e. behavioural variation that is consistent within individuals, but differs among individuals). However, this possibility is largely unexplored. We used mitonuclear introgression lines, where three mitochondrial genomes were introgressed into three nuclear genetic backgrounds, to disentangle genetic effects on behavioural variation in a seed beetle. We found within-individual consistency in a suite of activity-related behaviours, providing evidence for variation in personality. Composite measures of overall activity of individuals in behavioural assays were influenced by both nuclear genetic variation and by the interaction between nuclear and mitochondrial genomes. More importantly, the degree of expression of behavioural and life-history phenotypes was correlated and mitonuclear genetic variation affected expression of these concerted phenotypes. These results show that mitonuclear genetic variation affects both behavioural and life-history traits, and they provide novel insights into the maintenance of genetic variation in behaviour and personality. PMID:25320161

  11. The influence of mitonuclear genetic variation on personality in seed beetles.

    PubMed

    Løvlie, Hanne; Immonen, Elina; Gustavsson, Emil; Kazancioğlu, Erem; Arnqvist, Göran

    2014-12-07

    There is a growing awareness of the influence of mitochondrial genetic variation on life-history phenotypes, particularly via epistatic interactions with nuclear genes. Owing to their direct effect on traits such as metabolic and growth rates, mitonuclear interactions may also affect variation in behavioural types or personalities (i.e. behavioural variation that is consistent within individuals, but differs among individuals). However, this possibility is largely unexplored. We used mitonuclear introgression lines, where three mitochondrial genomes were introgressed into three nuclear genetic backgrounds, to disentangle genetic effects on behavioural variation in a seed beetle. We found within-individual consistency in a suite of activity-related behaviours, providing evidence for variation in personality. Composite measures of overall activity of individuals in behavioural assays were influenced by both nuclear genetic variation and by the interaction between nuclear and mitochondrial genomes. More importantly, the degree of expression of behavioural and life-history phenotypes was correlated and mitonuclear genetic variation affected expression of these concerted phenotypes. These results show that mitonuclear genetic variation affects both behavioural and life-history traits, and they provide novel insights into the maintenance of genetic variation in behaviour and personality.

  12. Child Development and Structural Variation in the Human Genome

    ERIC Educational Resources Information Center

    Zhang, Ying; Haraksingh, Rajini; Grubert, Fabian; Abyzov, Alexej; Gerstein, Mark; Weissman, Sherman; Urban, Alexander E.

    2013-01-01

    Structural variation of the human genome sequence is the insertion, deletion, or rearrangement of stretches of DNA sequence sized from around 1,000 to millions of base pairs. Over the past few years, structural variation has been shown to be far more common in human genomes than previously thought. Very little is currently known about the effects…

  13. 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 Genetic differentiation (0.202

  14. Advances in molecular identification, taxonomy, genetic variation and diagnosis of Toxocara spp.

    PubMed

    Chen, Jia; Zhou, Dong-Hui; Nisbet, Alasdair J; Xu, Min-Jun; Huang, Si-Yang; Li, Ming-Wei; Wang, Chun-Ren; Zhu, Xing-Quan

    2012-10-01

    The genus Toxocara contains parasitic nematodes of human and animal health significance, such as Toxocara canis, Toxocara cati and Toxocara vitulorum. T. canis and T. cati are among the most prevalent parasites of dogs and cats with a worldwide distribution. Human infection with T. canis and T. cati, which can cause a number of clinical manifestations such as visceral larva migrans (VLMs), ocular larva migrans (OLMs), eosinophilic meningoencephalitis (EME), covert toxocariasis (CT) and neurotoxocariasis, is considered the most prevalent neglected helminthiasis in industrialized countries. The accurate identification Toxocara spp. and their unequivocal differentiation from each other and from other ascaridoid nematodes causing VLMs and OLMs has important implications for studying their taxonomy, epidemiology, population genetics, diagnosis and control. Due to the limitations of traditional (morphological) approaches for identification and diagnosis of Toxocara spp., PCR-based techniques utilizing a range of genetic markers in the nuclear and mitochondrial genomes have been developed as useful alternative approaches because of their high sensitivity, specificity, rapidity and utility. In this article, we summarize the current state of knowledge and advances in molecular identification, taxonomy, genetic variation and diagnosis of Toxocara spp. with prospects for further studies.

  15. PATENTS IN GENOMICS AND HUMAN GENETICS

    PubMed Central

    Cook-Deegan, Robert; Heaney, Christopher

    2010-01-01

    Genomics and human genetics are scientifically fundamental and commercially valuable. These fields grew to prominence in an era of growth in government and nonprofit research funding, and of even greater growth of privately funded research and development in biotechnology and pharmaceuticals. Patents on DNA technologies are a central feature of this story, illustrating how patent law adapts---and sometimes fails to adapt---to emerging genomic technologies. In instrumentation and for therapeutic proteins, patents have largely played their traditional role of inducing investment in engineering and product development, including expensive postdiscovery clinical research to prove safety and efficacy. Patents on methods and DNA sequences relevant to clinical genetic testing show less evidence of benefits and more evidence of problems and impediments, largely attributable to university exclusive licensing practices. Whole-genome sequencing will confront uncertainty about infringing granted patents but jurisprudence trends away from upholding the broadest and potentially most troublesome patent claims. PMID:20590431

  16. Identification of spatial genetic boundaries using a multifractal model in human population genetics.

    PubMed

    Xue, Fuzhong; Wang, Jiezhen; Hu, Ping; Ma, Daoxin; Liu, Jing; Li, Guifu; Zhang, Li; Wu, Min; Sun, Guoqing; Hou, Haifeng

    2005-10-01

    There are two purposes in displaying spatial genetic structure. One is that a visual representation of the variation of the genetic variable should be provided in the contour map. The other is that spatial genetic structure should be reflected by the patterns or the gradients with genetic boundaries in the map. Nevertheless, most conventional interpolation methods, such as Cavalli-Sforza's method in genography, inverse distance-weighted methods, and the Kriging technique, focus only on the first primary purpose because of their arbitrary thresholds marked on the maps. In this paper we present an application of the contour area multifractal model (CAMM) to human population genetics. The method enables the analysis of the geographic distribution of a genetic marker and provides an insight into the spatial and geometric properties of obtained patterns. Furthermore, the CAMM may overcome some of the limitations of other interpolation techniques because no arbitrary thresholds are necessary in the computation of genetic boundaries. The CAMM is built by establishing power law relationships between the area A (> or =rho) in the contour map and the value p itself after plotting these values on a log-log graph. A series of straight-line segments can be fitted to the points on the log-log graph, each representing a power law relationship between the area A (> or =rho) and the cutoff genetic variable value for rho in a particular range. These straight-line segments can yield a group of cutoff values, which can be identified as the genetic boundaries that can classify the map of genetic variable into discrete genetic zones. These genetic zones usually correspond to spatial genetic structure on the landscape. To provide a better understanding of the interest in the CAMM approach, we analyze the spatial genetic structures of three loci (ABO, HLA-A, and TPOX) in China using the CAMM. Each synthetic principal component (SPC) contour map of the three loci is created by using both

  17. Genetic variation and plasticity of Plantago coronopus under saline conditions

    NASA Astrophysics Data System (ADS)

    Smekens, Marret J.; van Tienderen, Peter H.

    2001-08-01

    Phenotypic plasticity may allow organisms to cope with variation in the environmental conditions they encounter in their natural habitats. Salt adaptation appears to be an excellent example of such a plastic response. Many plant species accumulate organic solutes in response to saline conditions. Comparative and molecular studies suggest that this is an adaptation to osmotic stress. However, evidence relating the physiological responses to fitness parameters is rare and requires assessing the potential costs and benefits of plasticity. We studied the response of thirty families derived from plants collected in three populations of Plantago coronopus in a greenhouse experiment under saline and non-saline conditions. We indeed found a positive selection gradient for the sorbitol percentage under saline conditions: plant families with a higher proportion of sorbitol produced more spikes. No effects of sorbitol on fitness parameters were found under non-saline conditions. Populations also differed genetically in leaf number, spike number, sorbitol concentration and percentages of different soluble sugars. Salt treatment led to a reduction of vegetative biomass and spike production but increased leaf dry matter percentage and leaf thickness. Both under saline and non-saline conditions there was a negative trade-off between vegetative growth and reproduction. Families with a high plasticity in leaf thickness had a lower total spike length under non-saline conditions. This would imply that natural selection under predominantly non-saline conditions would lead to a decrease in the ability to change leaf morphology in response to exposure to salt. All other tests revealed no indication for any costs of plasticity to saline conditions.

  18. Performing monkeys of Bangladesh: characterizing their source and genetic variation.

    PubMed

    Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa; Engel, Gregory A; Akhtar, Sharmin; Kanthaswamy, Sree; Smith, David Glenn

    2016-04-01

    The acquisition and training of monkeys to perform is a centuries-old tradition in South Asia, resulting in a large number of rhesus macaques kept in captivity for this purpose. The performing monkeys are reportedly collected from free-ranging populations, and may escape from their owners or may be released into other populations. In order to determine whether this tradition involving the acquisition and movement of animals has influenced the population structure of free-ranging rhesus macaques in Bangladesh, we first characterized the source of these monkeys. Biological samples from 65 performing macaques collected between January 2010 and August 2013 were analyzed for genetic variation using 716 base pairs of mitochondrial DNA. Performing monkey sequences were compared with those of free-ranging rhesus macaque populations in Bangladesh, India and Myanmar. Forty-five haplotypes with 116 (16 %) polymorphic nucleotide sites were detected among the performing monkeys. As for the free-ranging rhesus population, most of the substitutions (89 %) were transitions, and no indels (insertion/deletion) were observed. The estimate of the mean number of pair-wise differences for the performing monkey population was 10.1264 ± 4.686, compared to 14.076 ± 6.363 for the free-ranging population. Fifteen free-ranging rhesus macaque populations were identified as the source of performing monkeys in Bangladesh; several of these populations were from areas where active provisioning has resulted in a large number of macaques. The collection of performing monkeys from India was also evident.

  19. The admixture structure and genetic variation of the archipelago of Cape Verde and its implications for admixture mapping studies.

    PubMed

    Beleza, Sandra; Campos, Joana; Lopes, Jailson; Araújo, Isabel Inês; Hoppfer Almada, Ana; Correia e Silva, António; Parra, Esteban J; Rocha, Jorge

    2012-01-01

    Recently admixed populations offer unique opportunities for studying human history and for elucidating the genetic basis of complex traits that differ in prevalence between human populations. Historical records, classical protein markers, and preliminary genetic data indicate that the Cape Verde islands in West Africa are highly admixed and primarily descended from European males and African females. However, little is known about the variation in admixture levels, admixture dynamics and genetic diversity across the islands, or about the potential of Cape Verde for admixture mapping studies. We have performed a detailed analysis of phenotypic and genetic variation in Cape Verde based on objective skin color measurements, socio-economic status (SES) evaluations and data for 50 autosomal, 34 X-chromosome, and 21 non-recombinant Y-chromosome (NRY) markers in 845 individuals from six islands of the archipelago. We find extensive genetic admixture between European and African ancestral populations (mean West African ancestry = 0.57, sd = 0.08), with individual African ancestry proportions varying considerably among the islands. African ancestry proportions calculated with X and Y-chromosome markers confirm that the pattern of admixture has been sex-biased. The high-resolution NRY-STRs reveal additional patterns of variation among the islands that are most consistent with differentiation after admixture. The differences in the autosomal admixture proportions are clearly evident in the skin color distribution across the islands (Pearson r = 0.54, P-value<2e-16). Despite this strong correlation, there are significant interactions between SES and skin color that are independent of the relationship between skin color and genetic ancestry. The observed distributions of admixture, genetic variation and skin color and the relationship of skin color with SES relate to historical and social events taking place during the settlement history of Cape Verde, and have implications for

  20. The Genetics of Sun Sensitivity in Humans

    PubMed Central

    Rees, Jonathan L.

    2004-01-01

    Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a key marker of sun sensitivity, is less heritable. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence. MC1R encodes a 317–amino acid G-coupled receptor that controls the relative amounts of the two major melanin classes, eumelanin and pheomelanin. Most persons with red hair are homozygous for alleles of the MC1R gene that show varying degrees of diminished function. More than 65 human MC1R alleles with nonsynonymous changes have been identified, and current evidence suggests that many of them vary in their physiological activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of one or two alleles) and (ii) individual differences in the pharmacological profile in response to ligand. Thus, a single locus, identified within a Mendelian framework, can contribute significantly to human pigmentary variation. PMID:15372380

  1. Genetics of human iris colour and patterns.

    PubMed

    Sturm, Richard A; Larsson, Mats

    2009-10-01

    The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6.

  2. Genetic variation in arthropod vectors of disease-causing organisms: obstacles and opportunities.

    PubMed Central

    Gooding, R H

    1996-01-01

    An overview of the genetic variation in arthropods that transmit pathogens to vertebrates is presented, emphasizing the genetics of vector-pathogen relationships and the biochemical genetics of vectors. Vector-pathogen interactions are reviewed briefly as a prelude to a discussion of the genetics of susceptibility and refractoriness in vectors. Susceptibility to pathogens is controlled by maternally inherited factors, sex-linked dominant alleles, and dominant and recessive autosomal genes. There is widespread interpopulation (including intercolony) and temporal variation in susceptibility to pathogens. The amount of biochemical genetic variation in vectors is similar to that found in other invertebrates. However, the amount varies widely among species, among populations within species, and temporally within populations. Biochemical genetic studies show that there is considerable genetic structuring of many vectors at the local, regional, and global levels. It is argued that genetic variation in vectors is critical in understanding vector-pathogen interactions and that genetic variation in vectors creates both obstacles to and opportunities for application of genetic techniques to the control of vectors. PMID:8809462

  3. Neutral genetic variation among wild North American populations of the weedy plant Arabidopsis thaliana is not geographically structured.

    PubMed

    Jørgensen, S; Mauricio, R

    2004-11-01

    We investigated neutral genetic variation within and among 53 wild-collected populations of the weedy annual plant, Arabidopsis thaliana, in North America, using amplified fragment length polymorphism (AFLP) markers. A. thaliana is thought to have been introduced to North America from Eurasia by humans; such an introduction might be expected to leave a clear geographical signal in the genetic data. To detect such patterns, we sampled populations at several hierarchical geographical levels. We collected individuals from populations in two areas of the Southeast and one in the Midwest, as well as individuals from populations in the Pacific Northwest and Northeast. To estimate within-population variation, we sampled eight individuals from each of six populations in the Southeast and Midwest. Among all 95 individuals analysed, we detected 131 polymorphic AFLP fragments. We found no evidence for continental or regional diversification. Individuals sampled from Midwestern and Southeastern populations intermingled in a neighbour-joining tree, and Mantel tests conducted within the Midwestern and Southeastern regions as well as the full data set failed to detect any significant relationship between geographical and genetic distance. These results mirror those found for most global surveys of neutral genetic variability in A. thaliana. Surprisingly, we detected substantial amounts of neutral genetic variability within populations. The levels of genetic variation within populations, coupled with the nongeographical nature of divergence among populations, are consistent with contemporary gene flow and point to a complex and dynamic population history of A. thaliana in North America.

  4. Explosive genetic evidence for explosive human population growth.

    PubMed

    Gao, Feng; Keinan, Alon

    2016-12-01

    The advent of next-generation sequencing technology has allowed the collection of vast amounts of genetic variation data. A recurring discovery from studying larger and larger samples of individuals had been the extreme, previously unexpected, excess of very rare genetic variants, which has been shown to be mostly due to the recent explosive growth of human populations. Here, we review recent literature that inferred recent changes in population size in different human populations and with different methodologies, with many pointing to recent explosive growth, especially in European populations for which more data has been available. We also review the state-of-the-art methods and software for the inference of historical population size changes that lead to these discoveries. Finally, we discuss the implications of recent population growth on personalized genomics, on purifying selection in the non-equilibrium state it entails and, as a consequence, on the genetic architecture underlying complex disease and the performance of mapping methods in discovering rare variants that contribute to complex disease risk.

  5. Impact of microRNA regulation on variation in human gene expression

    PubMed Central

    Lu, Jian; Clark, Andrew G.

    2012-01-01

    MicroRNAs (miRNAs) are endogenously expressed small RNAs that regulate expression of mRNAs at the post-transcriptional level. The consequence of miRNA regulation is hypothesized to reduce the expression variation of target genes. However, it is possible that mutations in miRNAs and target sites cause rewiring of the miRNA regulatory networks resulting in increased variation in gene expression. By examining variation in gene expression patterns in human populations and between human and other primate species, we find that miRNAs have stabilized expression of a small number of target genes during primate evolution. Compared with genes not regulated by miRNAs, however, genes regulated by miRNAs overall have higher expression variation at the population level, and they display greater variation in expression among human ethnic groups or between human and other primate species. By integrating expression data with genotypes determined in the HapMap 3 and the 1000 Genomes Projects, we found that expression variation in miRNAs, genetic variants in miRNA loci, and mutations in miRNA target sites are important sources of elevated expression variation of miRNA target genes. A reasonable case can be made that natural selection is driving this pattern of variation. PMID:22456605

  6. Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

    PubMed Central

    Simpson, Eleanor H.; Morud, Julia; Winiger, Vanessa; Biezonski, Dominik; Zhu, Judy P.; Bach, Mary Elizabeth; Malleret, Gael; Polan, H. Jonathan; Ng-Evans, Scott; Phillips, Paul E.M.; Kellendonk, Christoph; Kandel, Eric R.

    2014-01-01

    A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val158 allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val158 allele, stimulus–response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans. PMID:24639487

  7. Understanding and monitoring the consequences of human impacts on intraspecific variation.

    PubMed

    Mimura, Makiko; Yahara, Tetsukazu; Faith, Daniel P; Vázquez-Domínguez, Ella; Colautti, Robert I; Araki, Hitoshi; Javadi, Firouzeh; Núñez-Farfán, Juan; Mori, Akira S; Zhou, Shiliang; Hollingsworth, Peter M; Neaves, Linda E; Fukano, Yuya; Smith, Gideon F; Sato, Yo-Ichiro; Tachida, Hidenori; Hendry, Andrew P

    2017-02-01

    Intraspecific variation is a major component of biodiversity, yet it has received relatively little attention from governmental and nongovernmental organizations, especially with regard to conservation plans and the management of wild species. This omission is ill-advised because phenotypic and genetic variations within and among populations can have dramatic effects on ecological and evolutionary processes, including responses to environmental change, the maintenance of species diversity, and ecological stability and resilience. At the same time, environmental changes associated with many human activities, such as land use and climate change, have dramatic and often negative impacts on intraspecific variation. We argue for the need for local, regional, and global programs to monitor intraspecific genetic variation. We suggest that such monitoring should include two main strategies: (i) intensive monitoring of multiple types of genetic variation in selected species and (ii) broad-brush modeling for representative species for predicting changes in variation as a function of changes in population size and range extent. Overall, we call for collaborative efforts to initiate the urgently needed monitoring of intraspecific variation.

  8. Using Genome Query Language to uncover genetic variation

    PubMed Central

    Kozanitis, Christos; Heiberg, Andrew; Varghese, George; Bafna, Vineet

    2014-01-01

    Motivation: With high-throughput DNA sequencing costs dropping <$1000 for human genomes, data storage, retrieval and analysis are the major bottlenecks in biological studies. To address the large-data challenges, we advocate a clean separation between the evidence collection and the inference in variant calling. We define and implement a Genome Query Language (GQL) that allows for the rapid collection of evidence needed for calling variants. Results: We provide a number of cases to showcase the use of GQL for complex evidence collection, such as the evidence for large structural variations. Specifically, typical GQL queries can be written in 5–10 lines of high-level code and search large datasets (100 GB) in minutes. We also demonstrate its complementarity with other variant calling tools. Popular variant calling tools can achieve one order of magnitude speed-up by using GQL to retrieve evidence. Finally, we show how GQL can be used to query and compare multiple datasets. By separating the evidence and inference for variant calling, it frees all variant detection tools from the data intensive evidence collection and focuses on statistical inference. Availability: GQL can be downloaded from http://cseweb.ucsd.edu/~ckozanit/gql. Contact: ckozanit@ucsd.edu or vbafna@cs.ucsd.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23751181

  9. Genetic Testing and Its Implications: Human Genetics Researchers Grapple with Ethical Issues.

    ERIC Educational Resources Information Center

    Rabino, Isaac

    2003-01-01

    Contributes systematic data on the attitudes of scientific experts who engage in human genetics research about the pros, cons, and ethical implications of genetic testing. Finds that they are highly supportive of voluntary testing and the right to know one's genetic heritage. Calls for greater genetic literacy. (Contains 87 references.) (Author/NB)

  10. Genetic susceptibility to radiogenic cancer in humans.

    PubMed

    Allan, James M

    2008-11-01

    The clinical benefits associated with the use of ionizing radiation for diagnostic and therapeutic purposes are well established, particularly in cancer medicine. Unfortunately, it is now clear that prior exposure to radiation is associated with an excess risk of developing malignancy in the exposure field. Indeed, the development of a second primary malignancy is a devastating side effect that can often be attributed to radiotherapy for a first cancer. Research has focused on elucidating the relationship between therapeutic radiation dose and site-specific cancer risk, and how this relationship is affected by host factors such as age, sex, and exposure to other potential carcinogens. By contrast, there is a relative paucity of data on host genetic susceptibility to cancer following cytotoxic and mutagenic radiation exposure. Animal model systems suggest a strong genetic basis underlying susceptibility to radiogenic cancer. In humans, research has focused on investigating loci with relatively rare putative high penetrance risk alleles. However, genetic susceptibility to radiogenic cancer and other late effects of radiation exposure may be determined predominantly by co-inheritance of low penetrance risk alleles, and how these interact with each other (gene-gene interactions), with radiation dose (gene-exposure interactions) and other risk factors.

  11. 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.

  12. Challenges and prospects in genome-wide quantitative trait loci mapping of standing genetic variation in natural populations.

    PubMed

    Schielzeth, Holger; Husby, Arild

    2014-07-01

    A considerable challenge in evolutionary genetics is to understand the genetic mechanisms that facilitate or impede evolutionary adaptation in natural populations. For this, we must understand the genetic loci contributing to trait variation and the selective forces acting on them. The decreased costs and increased feasibility of obtaining genotypic data on a large number of individuals have greatly facilitated gene mapping in natural populations, particularly because organisms whose genetics have been historically difficult to study are now within reach. Here we review the methods available to evolutionary ecologists interested in dissecting the genetic basis of traits in natural populations. Our focus lies on standing genetic variation in outbred populations. We present an overview of the current state of research in the field, covering studies on both plants and animals. We also draw attention to particular challenges associated with the discovery of quantitative trait loci and discuss parallels to studies on crops, livestock, and humans. Finally, we point to some likely future developments in genetic mapping studies.

  13. Spatial and temporal patterns of neutral and adaptive genetic variation in the endangered African wild dog (Lycaon pictus).

    PubMed

    Marsden, Clare D; Woodroffe, Rosie; Mills, Michael G L; McNutt, J Weldon; Creel, Scott; Groom, Rosemary; Emmanuel, Masenga; Cleaveland, Sarah; Kat, Pieter; Rasmussen, Gregory S A; Ginsberg, Joshua; Lines, Robin; André, Jean-Marc; Begg, Colleen; Wayne, Robert K; Mable, Barbara K

    2012-03-01

    Deciphering patterns of genetic variation within a species is essential for understanding population structure, local adaptation and differences in diversity between populations. Whilst neutrally evolving genetic markers can be used to elucidate demographic processes and genetic structure, they are not subject to selection and therefore are not informative about patterns of adaptive variation. As such, assessments of pertinent adaptive loci, such as the immunity genes of the major histocompatibility complex (MHC), are increasingly being incorporated into genetic studies. In this study, we combined neutral (microsatellite, mtDNA) and adaptive (MHC class II DLA-DRB1 locus) markers to elucidate the factors influencing patterns of genetic variation in the African wild dog (Lycaon pictus); an endangered canid that has suffered extensive declines in distribution and abundance. Our genetic analyses found all extant wild dog populations to be relatively small (N(e)  < 30). Furthermore, through coalescent modelling, we detected a genetic signature of a recent and substantial demographic decline, which correlates with human expansion, but contrasts with findings in some other African mammals. We found strong structuring of wild dog populations, indicating the negative influence of extensive habitat fragmentation and loss of gene flow between habitat patches. Across populations, we found that the spatial and temporal structure of microsatellite diversity and MHC diversity were correlated and strongly influenced by demographic stability and population size, indicating the effects of genetic drift in these small populations. Despite this correlation, we detected signatures of selection at the MHC, implying that selection has not been completely overwhelmed by genetic drift.

  14. Aphid wing dimorphisms: linking environmental and genetic control of trait variation

    PubMed Central

    Brisson, Jennifer A.

    2010-01-01

    Both genetic and environmental factors underlie phenotypic variation. While research at the interface of evolutionary and developmental biology has made excellent advances in understanding the contribution of genes to morphology, less well understood is the manner in which environmental cues are incorporated during development to influence the phenotype. Also virtually unexplored is how evolutionary transitions between environmental and genetic control of trait variation are achieved. Here, I review investigations into molecular mechanisms underlying phenotypic plasticity in the aphid wing dimorphism system. Among aphids, some species alternate between environmentally sensitive (polyphenic) and genetic (polymorphic) control of wing morph determination in their life cycle. Therefore, a traditional molecular genetic approach into understanding the genetically controlled polymorphism may provide a unique avenue into not only understanding the molecular basis of polyphenic variation in this group, but also the opportunity to compare and contrast the mechanistic basis of environmental and genetic control of similar dimorphisms. PMID:20083636

  15. Deep genetic structure and ecological divergence in a widespread human commensal toad.

    PubMed

    Wogan, Guinevere O U; Stuart, Bryan L; Iskandar, Djoko T; McGuire, Jimmy A

    2016-01-01

    The Asian common toad (Duttaphrynus melanostictus) is a human commensal species that occupies a wide variety of habitats across tropical Southeast Asia. We test the hypothesis that genetic variation in D. melanostictus is weakly associated with geography owing to natural and human-mediated dispersal facilitated by its commensal nature. Phylogenetic and population genetic analyses of mitochondrial and nuclear DNA sequence variation, and predictive species distribution modelling, unexpectedly recovered three distinct evolutionary lineages that differ genetically and ecologically, corresponding to the Asian mainland, coastal Myanmar and the Sundaic islands. The persistence of these three divergent lineages, despite ample opportunities for recent human-mediated and geological dispersal, suggests that D. melanostictus actually consists of multiple species, each having narrower geographical ranges and ecological niches, and higher conservation value, than is currently recognized. These findings also have implications for the invasion potential of this human commensal elsewhere, such as in its recently introduced ranges on the islands of Borneo, Sulawesi, Seram and Madagascar.

  16. Molecular genetics of speciation and human origins.

    PubMed Central

    Ayala, F J; Escalante, A; O'Huigin, C; Klein, J

    1994-01-01

    The major histocompatibility complex (MHC) plays a cardinal role in the defense of vertebrates against parasites and other pathogens. In some genes there are extensive and ancient polymorphisms that have passed from ancestral to descendant species and are shared among contemporary species. The polymorphism at the DRB1 locus, represented by 58 known alleles in humans, has existed for at least 30 million years and is shared by humans, apes, and other primates. The coalescence theory of populations genetics leads to the conclusion that the DRB1 polymorphism requires that the population ancestral to modern humans has maintained a mean effective size of 100,000 individuals over the 30-million-year persistence of this polymorphism. We explore the possibility of occasional population bottlenecks and conclude that the ancestral population could not have at any time consisted of fewer than several thousand individuals. The MHC polymorphisms exclude the theory claiming, on the basis of mitochondrial DNA polymorphisms, that a constriction down to one or few women occurred in Africa, at the transition from archaic to anatomically modern humans, some 200,000 years ago. The data are consistent with, but do not provide specific support for, the claim that human populations throughout the World were at that time replaced by populations migrating from Africa. The MHC and other molecular polymorphisms are consistent with a "multiregional" theory of Pleistocene human evolution that proposes regional continuity of human populations since the time of migrations of Homo erectus to the present, with distinctive regional selective pressures and occasional migrations between populations. PMID:8041698

  17. Genetics of human sensitivity to ultraviolet radiation

    NASA Astrophysics Data System (ADS)

    Cleaver, James E.

    1994-07-01

    the major human health effects of solar and artificial UV light occur from the UVB and UVC wavelength ranges and involve a variety of short-term and long-term deleterious changes to the skin and eyes. the more important initial damage to cellular macromolecules involves dimerization of adjacent pyrimidines in DNA to produce cyclobutane pyrimidine dimes, (6-4) pyrimidine- pyrimidone, and (6-4) dewar photoproducts. these photoproducts can be repaired by a genetically regulated enzyme system (nucleotide excision repair) which removes oligonucleotides 29-30 nucleotides long that contain the photoproducts, and synthesizes replacement patches. At least a dozen gene products are involved in the process of recognizing photoproducts in DNA, altering local DNA helicity and cleaving the polynucleotide chain at defined positions either side of a photoproduct. Hereditary mutations in many of these genes are recognized in the human genetic disorders xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Several of the gene products have other functions involving the regulation of gene transcription which accounts for the complex clinical presentation of repair deficient diseases that involve sensitivity of the skin and eyes to UV light, increased solar carcinogenesis (in XP), demyelination, and ganglial calcification (in CS), hair abnormalities (in TTD), and developmental and neurological abnormalities

  18. Genetic variation in South Asia: assessing the influences of geography, language and ethnicity for understanding history and disease risk.

    PubMed

    Ayub, Qasim; Tyler-Smith, Chris

    2009-09-01

    South Asia is home to more than 1.5 billion humans representing many diverse ethnicities, linguistic and religious groups and representing almost one-quarter of humanity. Modern humans arrived here soon after their departure from Africa approximately 50,000-70,000 years before present (YBP) and several subsequent human migrations and invasions, as well as the unique social structure of the region, have helped shape the pattern of genetic diversity currently observed in these populations. Over the last few decades population geneticists and molecular anthropologists have analyzed DNA variation in indigenous populations from this region in order to catalog their genetic relationships and histories. The emphasis is gradually shifting from the study of population origins to high resolution surveys of DNA variation to address issues of population stratification and genetic susceptibility or resistance to diseases in genome-wide association surveys. We present a historical overview of the genetic studies carried out on populations from this region in order to understand the influence of geographic, linguistic and religious factors on population diversity in this region, and discuss future prospects in light of developments in high throughput genotyping and next generation sequencing technologies.

  19. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies.

    PubMed

    Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D

    2012-02-01

    Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

  20. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

    PubMed Central

    Acland, Gregory M.

    2014-01-01

    Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision. PMID:22065099

  1. Genetic Variation and Population Genetics of Taenia saginata in North and Northeast Thailand in relation to Taenia asiatica

    PubMed Central

    Anantaphruti, Malinee; Thaenkham, Urusa; Kusolsuk, Teera; Maipanich, Wanna; Saguankiat, Surapol; Pubampen, Somjit; Phuphisut, Orawan

    2013-01-01

    Taenia saginata is the most common human Taenia in Thailand. By cox1 sequences, 73 isolates from four localities in north and northeast were differentiated into 14 haplotypes, 11 variation sites and haplotype diversity of 0.683. Among 14 haplotypes, haplotype A was the major (52.1%), followed by haplotype B (21.9%). Clustering diagram of Thai and GenBank sequences indicated mixed phylogeny among localities. By MJ analysis, haplotype clustering relationships showed paired-stars-like network, having two main cores surrounded by minor haplotypes. Tajima's D values were significantly negative in T. saginata world population, suggesting population expansion. Significant Fu's Fs values in Thai, as well as world population, also indicate that population is expanding and may be hitchhiking as part of selective sweep. Haplotype B and its dispersion were only found in populations from Thailand. Haplotype B may evolve and ultimately become an ancestor of future populations in Thailand. Haplotype A seems to be dispersion haplotype, not just in Thailand, but worldwide. High genetic T. saginata intraspecies divergence was found, in contrast to its sister species, T. asiatica; among 30 samples from seven countries, its haplotype diversity was 0.067, while only 2 haplotypes were revealed. This extremely low intraspecific variation suggests that T. asiatica could be an endangered species. PMID:23864933

  2. Genetic variation, inbreeding and chemical exposure—combined effects in wildlife and critical considerations for ecotoxicology

    PubMed Central

    Brown, A. Ross; Hosken, David J.; Balloux, François; Bickley, Lisa K.; LePage, Gareth; Owen, Stewart F.; Hetheridge, Malcolm J.; Tyler, Charles R.

    2009-01-01

    Exposure to environmental chemicals can have negative consequences for wildlife and even cause localized population extinctions. Resistance to chemical stress, however, can evolve and the mechanisms include desensitized target sites, reduced chemical uptake and increased metabolic detoxification and sequestration. Chemical resistance in wildlife populations can also arise independently of exposure and may be spread by gene flow between populations. Inbreeding—matings between closely related individuals—can have negative fitness consequences for natural populations, and there is evidence of inbreeding depression in many wildlife populations. In some cases, reduced fitness in inbred populations has been shown to be exacerbated under chemical stress. In chemical testing, both inbred and outbred laboratory animals are used and for human safety assessments, iso-genic strains (virtual clones) of mice and rats are often employed that reduce response variation, the number of animals used and associated costs. In contrast, for environmental risk assessment, strains of animals are often used that have been selectively bred to maintain heterozygosity, with the assumption that they are better able to predict adverse effects in wild, genetically variable, animals. This may not necessarily be the case however, as one outbred strain may not be representative of another or of a wild population. In this paper, we critically discuss relationships between genetic variation, inbreeding and chemical effects with the intention of seeking to support more effective chemical testing for the protection of wildlife. PMID:19833649

  3. Cyclic Variations in Sustained Human Performance

    ERIC Educational Resources Information Center

    Aue, William R.; Arruda, James E.; Kass, Steven J.; Stanny, Claudia J.

    2009-01-01

    Biological rhythms play a prominent role in the modulation of human physiology and behavior. [Smith, K., Valentino, D., & Arruda, J. (2003). "Rhythmic oscillations in the performance of a sustained attention task." "Journal of Clinical and Experimental Neuropsychology," 25, 561-570] suggested that sustained human performance may systematically…

  4. The Grandest Genetic Experiment Ever Performed on Man? - A Y-Chromosomal Perspective on Genetic Variation in India.

    PubMed

    Carvalho-Silva, Denise R; Tyler-Smith, Chris

    2008-05-01

    We have analysed Y-chromosomal data from Indian caste, Indian tribal and East Asian populations in order to investigate the impact of the caste system on male genetic variation. We find that variation within populations is lower in India than in East Asia, while variation between populations is overall higher. This observation can be explained by greater subdivision within the Indian population, leading to more genetic drift. However, the effect is most marked in the tribal populations, and the level of variation between caste populations is similar to the level between Chinese populations. The caste system has therefore had a detectable impact on Y-chromosomal variation, but this has been less strong than the influence of the tribal system, perhaps because of larger population sizes in the castes, more gene flow or a shorter period of time.

  5. Human Genetics and Islam: Scientific and Medical Aspects

    PubMed Central

    Ghareeb, Bilal A.A.

    2011-01-01

    Objective: To relate diverse aspects of genetics and its applications to concepts in the Glorious Qur’an and the ḥadīth. Study Design: The author compared passages from the Glorious Qur’an and ḥadīth with modern concepts in genetics, such as recessive inheritance, genetic counseling, genetic variation, cytoplasmic inheritance, sex chromosomes, genetics-environment interactions, gender determination, and the hypothesis of “pairing in the universe.” Conclusions: A fresh understanding of Islamic scripture reveals references to principles of genetics that predate contemporary discoveries. This highlights the need for further exploration of possible links between science and religion. PMID:23610491

  6. Mitochondrial Genetic Variation in Iranian Infertile Men with Varicocele

    PubMed Central

    Heidari, Mohammad Mehdi; Khatami, Mehri; Danafar, Amirhossein; Dianat, Tahere; Farahmand, Ghazaleh; Talebi, Ali Reza

    2016-01-01

    Background: Several recent studies have shown that mitochondrial DNA mutations lead to major disabilities and premature death in carriers. More than 150 mutations in human mitochondrial DNA (mtDNA) genes have been associated with a wide spectrum of disorders. Varicocele, one of the causes of infertility in men wherein abnormal inflexion and distension of veins of the pampiniform plexus is observed within spermatic cord, can increase reactive oxygen species (ROS) production in semen and cause oxidative stress and sperm dysfunction in patients. Given that mitochondria are the source of ROS production in cells, the aim of this study was to scan nine mitochondrial genes (MT-COX2, MT-tRNALys , MT-ATP8, MT-ATP6, MT-COX3, MT-tRNAGly , MT-ND3, MT-tRNAArg and MT-ND4L) for mutations in infertile patients with varicocele. Materials and Methods: In this cross-sectional study, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing were used to detect and identify point mutations respectively in 9 mitochondrial genes in 72 infertile men with varicocele and 159 fertile men. In brief, the samples showing altered electrophoretic patterns of DNA in the SSCP gel were sent for DNA sequencing to identify the exact nucleotide variation. Results: Ten type nucleotide variants were detected exclusively in mitochondrial DNA of infertile men. These include six novel nucleotide changes and four variants previously reported for other disorders. Conclusion: Mutations in mitochondrial genes may affect respiratory complexes in combination with environmental risk factors. Therefore these nucleotide variants probably lead to impaired ATP synthesis and mitochondrial function ultimately interfering with sperm motility and infertility. PMID:27695613

  7. Whole-Genome Sequencing Reveals Genetic Variation in the Asian House Rat

    PubMed Central

    Teng, Huajing; Zhang, Yaohua; Shi, Chengmin; Mao, Fengbiao; Hou, Lingling; Guo, Hongling; Sun, Zhongsheng; Zhang, Jianxu

    2016-01-01

    Whole-genome sequencing of wild-derived rat species can provide novel genomic resources, which may help decipher the genetics underlying complex phenotypes. As a notorious pest, reservoir of human pathogens, and colonizer, the Asian house rat, Rattus tanezumi, is successfully adapted to its habitat. However, little is known regarding genetic variation in this species. In this study, we identified over 41,000,000 single-nucleotide polymorphisms, plus insertions and deletions, through whole-genome sequencing and bioinformatics analyses. Moreover, we identified over 12,000 structural variants, including 143 chromosomal inversions. Further functional analyses revealed several fixed nonsense mutations associated with infection and immunity-related adaptations, and a number of fixed missense mutations that may be related to anticoagulant resistance. A genome-wide scan for loci under selection identified various genes related to neural activity. Our whole-genome sequencing data provide a genomic resource for future genetic studies of the Asian house rat species and have the potential to facilitate understanding of the molecular adaptations of rats to their ecological niches. PMID:27172215

  8. Genetic variation in vitamin B-12 content of bovine milk and its association with SNP along the bovine genome.

    PubMed

    Rutten, Marc J M; Bouwman, Aniek C; Sprong, R Corinne; van Arendonk, Johan A M; Visker, Marleen H P W

    2013-01-01

    Vitamin B-12 (also called cobalamin) is essential for human health and current intake levels of vitamin B-12 are considered to be too low. Natural enrichment of the vitamin B-12 content in milk, an important dietary source of vitamin B-12, may help to increase vitamin B-12 intake. Natural enrichment of the milk vitamin B-12 content could be achieved through genetic selection, provided there is genetic variation between cows with respect to the vitamin B-12 content in their milk. A substantial amount of genetic variation in vitamin B-12 content was detected among raw milk samples of 544 first-lactation Dutch Holstein Friesian cows. The presence of genetic variation between animals in vitamin B-12 content in milk indicates that the genotype of the cow affects the amount of vitamin B-12 that ends up in her milk and, consequently, that the average milk vitamin B-12 content of the cow population can be increased by genetic selection. A genome-wide association study revealed significant association between 68 SNP and vitamin B-12 content in raw milk of 487 first-lactation Dutch Holstein Friesian cows. This knowledge facilitates genetic selection for milk vitamin B-12 content. It also contributes to the understanding of the biological mechanism responsible for the observed genetic variation in vitamin B-12 content in milk. None of the 68 significantly associated SNP were in or near known candidate genes involved in transport of vitamin B-12 through the gastrointestinal tract, uptake by ileum epithelial cells, export from ileal cells, transport through the blood, uptake from the blood, intracellular processing, or reabsorption by the kidneys. Probably, associations relate to genes involved in alternative pathways of well-studied processes or to genes involved in less well-studied processes such as ruminal production of vitamin B-12 or secretion of vitamin B-12 by the mammary gland.

  9. Genetic Variation in Vitamin B-12 Content of Bovine Milk and Its Association with SNP along the Bovine Genome

    PubMed Central

    Rutten, Marc J. M.; Bouwman, Aniek C.; Sprong, R. Corinne; van Arendonk, Johan A. M.; Visker, Marleen H. P. W.

    2013-01-01

    Vitamin B-12 (also called cobalamin) is essential for human health and current intake levels of vitamin B-12 are considered to be too low. Natural enrichment of the vitamin B-12 content in milk, an important dietary source of vitamin B-12, may help to increase vitamin B-12 intake. Natural enrichment of the milk vitamin B-12 content could be achieved through genetic selection, provided there is genetic variation between cows with respect to the vitamin B-12 content in their milk. A substantial amount of genetic variation in vitamin B-12 content was detected among raw milk samples of 544 first-lactation Dutch Holstein Friesian cows. The presence of genetic variation between animals in vitamin B-12 content in milk indicates that the genotype of the cow affects the amount of vitamin B-12 that ends up in her milk and, consequently, that the average milk vitamin B-12 content of the cow population can be increased by genetic selection. A genome-wide association study revealed significant association between 68 SNP and vitamin B-12 content in raw milk of 487 first-lactation Dutch Holstein Friesian cows. This knowledge facilitates genetic selection for milk vitamin B-12 content. It also contributes to the understanding of the biological mechanism responsible for the observed genetic variation in vitamin B-12 content in milk. None of the 68 significantly associated SNP were in or near known candidate genes involved in transport of vitamin B-12 through the gastrointestinal tract, uptake by ileum epithelial cells, export from ileal cells, transport through the blood, uptake from the blood, intracellular processing, or reabsorption by the kidneys. Probably, associations relate to genes involved in alternative pathways of well-studied processes or to genes involved in less well-studied processes such as ruminal production of vitamin B-12 or secretion of vitamin B-12 by the mammary gland. PMID:23626813

  10. Cryptococcus neoformans isolates from Yaoundé human immunodeficiency virus-infected patients exhibited intra-individual genetic diversity and variation in antifungal susceptibility profiles between isolates from the same patient.

    PubMed

    Kammalac Ngouana, Thierry; Drakulovski, Pascal; Krasteva, Donika; Kouanfack, Charles; Reynes, Jacques; Delaporte, Eric; Boyom, Fabrice Fekam; Mallié, Michèle; Bertout, Sebastien

    2016-07-01

    Cryptococcal meningitis is a dreadful opportunistic fungal infection amongst human immunodeficiency virus (HIV)-infected patients. One complication in the management of the disease is the possible infection of a patient by two or more different strains of Cryptococcus neoformans. This study investigated the intra-individual genetic diversity and antifungal susceptibility of C. neoformans isolates from Yaoundé (Cameroon) HIV-infected patients with cryptococcal meningitis. Twenty-five clinical isolates were obtained during a prospective study. Five colonies were randomly collected from each initial sample. The 150 isolates obtained (125 colonies and 25 initial samples) were submitted to serotyping by multiplex PCR. Genotyping analyses were achieved using RFLP, and minisatellite- and microsatellite-length polymorphism. The antifungal susceptibility testing was carried out using a Sensititre YeastOne kit. Seven antifungals were tested: itraconazole, fluconazole, amphotericin B, ketoconazole, 5-fluorocytosine, posaconazole and voriconazole. The 150 isolates were identified as C. neoformans serotype A and genotype VNI. The microsatellite and minisatellite sequence analyses generated 15 genotypes. Six out of 25 (24 %) patients were found to be infected by two different genotypes. Antifungal susceptibility showed several profiles: posaconazole (0.015-0.25 µg ml-1), amphotericin B (0.06-1 µg ml-1), fluconazole (0.5-16 µg ml-1), itraconazole (0.008-0.12 µg ml-1), ketoconazole (0.008-0.12 µg ml-1), 5-fluorocytosine (0.25-16 µg ml-1) and voriconazole (0.008-0.12 µg ml-1). It was noted that isolates from the same patient might present different susceptibility profiles to an antifungal drug with differences of more than four dilutions. The results achieved highlighted the possible presence of isolates with different genotypes in a patient with dissimilar antifungal susceptibility profiles during a single episode of cryptococcal meningitis.

  11. Human genetic differentiation across the Strait of Gibraltar

    PubMed Central

    2010-01-01

    Background The Strait of Gibraltar is a crucial area in the settlement history of modern humans because it represents a possible connection between Africa and Europe. So far, genetic data were inconclusive about the fact that this strait constitutes a barrier to gene flow, as previous results were highly variable depending on the genetic locus studied. The present study evaluates the impact of the Gibraltar region in reducing gene flow between populations from North-Western Africa and South-Western Europe, by comparing formally various genetic loci. First, we compute several statistics of population differentiation. Then, we use an original simulation approach in order to infer the most probable evolutionary scenario for the settlement of the area, taking into account the effects of both demography and natural selection at some loci. Results We show that the genetic patterns observed today in the region of the Strait of Gibraltar may reflect an ancient population genetic structure which has not been completely erased by more recent events such as Neolithic migrations. Moreover, the differences observed among the loci (i.e. a strong genetic boundary revealed by the Y-chromosome polymorphism and, at the other extreme, no genetic differentiation revealed by HLA-DRB1 variation) across the strait suggest specific evolutionary histories like sex-mediated migration and natural selection. By considering a model of balancing selection for HLA-DRB1, we here estimate a coefficient of selection of 2.2% for this locus (although weaker in Europe than in Africa), which is in line with what was estimated from synonymous versus non-synonymous substitution rates. Selection at this marker thus appears strong enough to leave a signature not only at the DNA level, but also at the population level where drift and migration processes were certainly relevant. Conclusions Our multi-loci approach using both descriptive analyses and Bayesian inferences lead to better characterize the role of

  12. 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.

  13. Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations.

    PubMed

    Mendez, Fernando L; Watkins, Joseph C; Hammer, Michael F

    2012-06-01

    Recent analysis of DNA extracted from two Eurasian forms of archaic human shows that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. Although these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We resequenced a 7-kb region encompassing the OAS1 gene in 88 individuals from six Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5' region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 myr, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1,500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.

  14. Medical genetics

    SciTech Connect

    Jorde, L.B.; Carey, J.C.; White, R.L.

    1995-10-01

    This book on the subject of medical genetics is a textbook aimed at a very broad audience: principally, medical students, nursing students, graduate, and undergraduate students. The book is actually a primer of general genetics as applied to humans and provides a well-balanced introduction to the scientific and clinical basis of human genetics. The twelve chapters include: Introduction, Basic Cell Biology, Genetic Variation, Autosomal Dominant and Recessive Inheritance, Sex-linked and Mitochondrial Inheritance, Clinical Cytogenetics, Gene Mapping, Immunogenetics, Cancer Genetics, Multifactorial Inheritance and Common Disease, Genetic Screening, Genetic Diagnosis and Gene Therapy, and Clinical Genetics and Genetic Counseling.

  15. Anatomical variations in human carotid bodies.

    PubMed Central

    Khan, Q; Heath, D; Smith, P

    1988-01-01

    The variations in anatomical structure and position of both carotid bodies were noted in 100 consecutive subjects who came to necropsy. Considerable variations in form were found. Although most carotid bodies (83% on the right and 86% on the left) were of the classic ovoid type, an appreciable minority was bilobed (9% on the right and 7% on the left) or double (7% on the right and 6% on the left); 1% were leaf shaped. All these anatomical variants have to be distinguished from the pathologically enlarged carotid body that may have a smooth or finely nodular surface. Anatomical variants (such as the bilobed) may themselves enlarge as a consequence of carotid body hyperplasia. Images Fig 1 Fig 2 Fig 3 Fig 4 Fig 5 Fig 6 Fig 7 Fig 8 PMID:3209707

  16. Migration distance rather than migration rate explains genetic diversity in human patrilocal groups.

    PubMed

    Marks, Sarah J; Levy, Hila; Martinez-Cadenas, Conrado; Montinaro, Francesco; Capelli, Cristian

    2012-10-01

    In patrilocal groups, females preferentially move to join their mate's paternal relatives. The gender-biased gene flow generated by this cultural practice is expected to affect genetic diversity across human populations. Greater female than male migration is predicted to result in a larger decrease in between-group differentiation for mitochondrial DNA (mtDNA) than for the non-recombining part of the Y chromosome (NRY). We address the question of how patrilocality affects the distribution of genetic variation in human populations controlling for confounding factors such as ethno-linguistic heterogeneity and geographic distance which possibly explain the contradictory results observed in previous studies. By combining genetic and bio-demographic data from Lesotho and Spain, we show that preferential female migration over short distances appears to minimize the impact of a generally higher female migration rate in patrilocal communities, suggesting patrilocality might influence genetic variation only at short ranges.

  17. Analysis of Genetic Variation and Potential Applications in Genome-Scale Metabolic Modeling

    PubMed Central

    Cardoso, João G. R.; Andersen, Mikael Rørdam; Herrgård, Markus J.; Sonnenschein, Nikolaus

    2015-01-01

    Genetic variation is the motor of evolution and allows organisms to overcome the environmental challenges they encounter. It can be both beneficial and harmful in the process of engineering cell factories for the production of proteins and chemicals. Throughout the history of biotechnology, there have been efforts to exploit genetic variation in our favor to create strains with favorable phenotypes. Genetic variation can either be present in natural populations or it can be artificially created by mutagenesis and selection or adaptive laboratory evolution. On the other hand, unintended genetic variation during a long term production process may lead to significant economic losses and it is important to understand how to control this type of variation. With the emergence of next-generation sequencing technologies, genetic variation in microbial strains can now be determined on an unprecedented scale and resolution by re-sequencing thousands of strains systematically. In this article, we review challenges in the integration and analysis of large-scale re-sequencing data, present an extensive overview of bioinformatics methods for predicting the effects of genetic variants on protein function, and discuss approaches for interfacing existing bioinformatics approaches with genome-scale models of cellular processes in order to predict effects of sequence variation on cellular phenotypes. PMID:25763369

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The choice of populations for quantitative genetics experiments impacts inferences about genetic architecture and prospective selection gains. Plant breeding and quantitative genetics studies are often conducted in one or a few among many possible biparental families. Trait genotypic variation withi...

  19. Interindividual variation with respect to DNA repair in human cells

    SciTech Connect

    Leonard, R.C.; Leonard, J.C.; Bender, M.A.; Wieland, J.; Setlow, R.B.

    1989-01-01

    Ecogenetics is the study of genetically determined differences among individuals in their susceptibility to the actions of physical, chemical, and biological agents in the environment. An individual's most basic level of response to these environmental agents may be the ability to repair physical and chemical damage to DNA. We have been engaged in a survey of DNA-repair measurements in a healthy working population in order to determine the extent of the population variability in these endpoints and to assess the value of these screening protocols in identifying individuals who are at the extremes of the distribution. In addition, we are measuring intraindividual variation over time, as well as the correlations between measurements of different repair systems. The endpoints that we have chosen to use are cytogenetic responses (SCE's and micronucleus formation) and DNA excision repair (unscheduled DNA synthesis and removal of O{sup 6} guanine methylation) in human peripheral lymphocytes exposed to 254 nm ultraviolet light, x-rays, the bifunctional alkylating agent mitomycin C, or the monofunctional alkylating agent N-methyl-N-nitro-nitrosoguanidine (MNNG). These four test mutagens produce spectra of DNA lesions eliciting different types of DNA repair. 3 refs., 1 tab.

  20. The Evolution of Personality Variation in Humans and Other Animals

    ERIC Educational Resources Information Center

    Nettle, Daniel

    2006-01-01

    A comprehensive evolutionary framework for understanding the maintenance of heritable behavioral variation in humans is yet to be developed. Some evolutionary psychologists have argued that heritable variation will not be found in important, fitness-relevant characteristics because of the winnowing effect of natural selection. This article…

  1. A genetic basis of variation in eccrine sweat gland and hair follicle density.

    PubMed

    Kamberov, Yana G; Karlsson, Elinor K; Kamberova, Gerda L; Lieberman, Daniel E; Sabeti, Pardis C; Morgan, Bruce A; Tabin, Clifford J

    2015-08-11

    Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin's surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin.

  2. A genetic basis of variation in eccrine sweat gland and hair follicle density

    PubMed Central

    Kamberov, Yana G.; Karlsson, Elinor K.; Kamberova, Gerda L.; Lieberman, Daniel E.; Sabeti, Pardis C.; Morgan, Bruce A.; Tabin, Clifford J.

    2015-01-01

    Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin’s surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin. PMID:26195765

  3. Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

    DTIC Science & Technology

    2011-06-01

    the androgen axis, including those encoding enzymes of testosterone synthesis ( cytochrome P450c17) and conversion (steroid-5--reductase type 2...J., Gronberg, H., 2006. Germ- line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450 , and steroid-5-alpha...4 Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy INTRODUCTION Androgen

  4. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  5. Genetic Variation of Major Histocompatibility Complex and Microsatellite Loci: A Comparison in Bighorn Sheep

    PubMed Central

    Boyce, W. M.; Hedrick, P. W.; Muggli-Cockett, N. E.; Kalinowski, S.; Penedo, MCT.; Ramey-II, R. R.

    1997-01-01

    Examining and comparing genetic variation for major histocompatibility complex (MHC) and microsatellite (MS) loci in the same individuals provides an opportunity to understand the forces influencing genetic variation. We examined five MHC and three MS loci in 235 bighorn sheep (Ovis canadensis) from 14 populations and found that both types of loci were highly variable and were in Hardy-Weinberg proportions. Mean F(ST) values for both markers were very similar and MHC and MS genetic variability was predominantly distributed within rather than among populations. However, analyses of genetic distances and tree topologies revealed different spatial patterns of variation for the two types of loci. Collectively, these results indicated that neutral forces substantially influenced MS and MHC variation, and they provided limited evidence for selection acting on the MHC. PMID:9071595

  6. Genetic variation of major histocompatibility complex and microsatellite loci: a comparison in bighorn sheep.

    PubMed

    Boyce, W M; Hedrick, P W; Muggli-Cockett, N E; Kalinowski, S; Penedo, M C; Ramey, R R

    1997-02-01

    Examining and comparing genetic variation for major histocompatibility complex (MHC) and micro-satellite (MS) loci in the same individuals provides an opportunity to understand the forces influencing genetic variation. We examined five MHC and three MS loci in 235 bighorn sheep (Ovis canadensis) from 14 populations and found that both types of loci were highly variable and were in Hardy-Weinberg proportions. Mean FST values for both markers were very similar and MHC and MS genetic variability was predominantly distributed within rather than among populations. However, analyses of genetic distances and tree topologies revealed different spatial patterns of variation for the two types of loci. Collectively, these results indicated that neutral forces substantially influenced MS and MHC variation, and they provided limited evidence for selection acting on the MHC.

  7. Genetic variation and RNA binding proteins: tools and techniques to detect functional polymorphisms.

    PubMed

    Soemedi, Rachel; Vega, Hugo; Belmont, Judson M; Ramachandran, Sohini; Fairbrother, William G

    2014-01-01

    At its most fundamental level the goal of genetics is to connect genotype to phenotype. This question is asked at a basic level evaluating the role of genes and pathways in genetic model organism. Increasingly, this question is being asked in the clinic. Genomes of individuals and populations are being sequenced and compared. The challenge often comes at the stage of analysis. The variant positions are analyzed with the hope of understanding human disease. However after a genome or exome has been sequenced, the researcher is often deluged with hundreds of potentially relevant variations. Traditionally, amino-acid changing mutations were considered the tractable class of disease-causing mutations; however, mutations that disrupt noncoding elements are the subject of growing interest. These noncoding changes are a major avenue of disease (e.g., one in three hereditary disease alleles are predicted to affect splicing). Here, we review some current practices of medical genetics, the basic theory behind biochemical binding and functional assays, and then explore technical advances in how variations that alter RNA protein recognition events are detected and studied. These advances are advances in scale-high-throughput implementations of traditional biochemical assays that are feasible to perform in any molecular biology laboratory. This chapter utilizes a case study approach to illustrate some methods for analyzing polymorphisms. The first characterizes a functional intronic SNP that deletes a high affinity PTB site using traditional low-throughput biochemical and functional assays. From here we demonstrate the utility of high-throughput splicing and spliceosome assembly assays for screening large sets of SNPs and disease alleles for allelic differences in gene expression. Finally we perform three pilot drug screens with small molecules (G418, tetracycline, and valproic acid) that illustrate how compounds that rescue specific instances of differential pre-mRNA processing

  8. Human Gut Microbiota: Repertoire and Variations

    PubMed Central

    Lagier, Jean-Christophe; Million, Matthieu; Hugon, Perrine; Armougom, Fabrice; Raoult, Didier

    2012-01-01

    The composition of human gut microbiota and their relationship with the host and, consequently, with human health and disease, presents several challenges to microbiologists. Originally dominated by culture-dependent methods for exploring this ecosystem, the advent of molecular tools has revolutionized our ability to investigate these relationships. However, many biases that have led to contradictory results have been identified. Microbial culturomics, a recent concept based on a use of several culture conditions with identification by MALDI-TOF followed by the genome sequencing of the new species cultured had allowed a complementarity with metagenomics. Culturomics allowed to isolate 31 new bacterial species, the largest human virus, the largest bacteria, and the largest Archaea from human. Moreover, some members of this ecosystem, such as Eukaryotes, giant viruses, Archaea, and Planctomycetes, have been neglected by the majority of studies. In addition, numerous factors, such as age, geographic provenance, dietary habits, antibiotics, or probiotics, can influence the composition of the microbiota. Finally, in addition to the countless biases associated with the study techniques, a considerable limitation to the interpretation of studies of human gut microbiota is associated with funding sources and transparency disclosures. In the future, studies independent of food industry funding and using complementary methods from a broad range of both culture-based and molecular tools will increase our knowledge of the repertoire of this complex ecosystem and host-microbiota mutualism. PMID:23130351

  9. Human gut microbiota: repertoire and variations.

    PubMed

    Lagier, Jean-Christophe; Million, Matthieu; Hugon, Perrine; Armougom, Fabrice; Raoult, Didier

    2012-01-01

    The composition of human gut microbiota and their relationship with the host and, consequently, with human health and disease, presents several challenges to microbiologists. Originally dominated by culture-dependent methods for exploring this ecosystem, the advent of molecular tools has revolutionized our ability to investigate these relationships. However, many biases that have led to contradictory results have been identified. Microbial culturomics, a recent concept based on a use of several culture conditions with identification by MALDI-TOF followed by the genome sequencing of the new species cultured had allowed a complementarity with metagenomics. Culturomics allowed to isolate 31 new bacterial species, the largest human virus, the largest bacteria, and the largest Archaea from human. Moreover, some members of this ecosystem, such as Eukaryotes, giant viruses, Archaea, and Planctomycetes, have been neglected by the majority of studies. In addition, numerous factors, such as age, geographic provenance, dietary habits, antibiotics, or probiotics, can influence the composition of the microbiota. Finally, in addition to the countless biases associated with the study techniques, a considerable limitation to the interpretation of studies of human gut microbiota is associated with funding sources and transparency disclosures. In the future, studies independent of food industry funding and using complementary methods from a broad range of both culture-based and molecular tools will increase our knowledge of the repertoire of this complex ecosystem and host-microbiota mutualism.

  10. Genetic modification of preimplantation embryos: toward adequate human research policies.

    PubMed

    Dresser, Rebecca

    2004-01-01

    Citing advances in transgenic animal research and setbacks in human trials of somatic cell genetic interventions, some scientists and others want to begin planning for research involving the genetic modification of human embryos. Because this form of genetic modification could affect later-born children and their offspring, the protection of human subjects should be a priority in decisions about whether to proceed with such research. Yet because of gaps in existing federal policies, embryo modification proposals might not receive adequate scientific and ethical scrutiny. This article describes current policy shortcomings and recommends policy actions designed to ensure that the investigational genetic modification of embryos meets accepted standards for research on human subjects.

  11. Mouse Genetic Models of Human Brain Disorders

    PubMed Central

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  12. NORMAL HUMAN VARIATION: REFOCUSSING THE ENHANCEMENT DEBATE

    PubMed Central

    Kahane, Guy; Savulescu, Julian

    2015-01-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range. PMID:23906367

  13. Normal human variation: refocussing the enhancement debate.

    PubMed

    Kahane, Guy; Savulescu, Julian

    2015-02-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range.

  14. Genetic Variation of Fatty Acid Oxidation and Obesity, A Literature Review

    PubMed Central

    Freitag Luglio, Harry

    2016-01-01

    Modulation of fat metabolism is an important component of the etiology of obesity as well as individual response to weight loss program. The influence of lipolysis process had receives many attentions in recent decades. Compared to that, fatty acid oxidation which occurred after lipolysis seems to be less exposed. There are limited publications on how fatty acid oxidation influences predisposition to obesity, especially the importance of genetic variations of fatty acid oxidation proteins on development of obesity. The aim of this review is to provide recent knowledge on how polymorphism of genes related fatty acid oxidation is obtained. Studies in human as well as animal model showed that disturbance of genes related fatty acid oxidation process gave impact on body weight and risks to obesity. Several polymorphisms on CD36, CPT, ACS and FABP had been shown to be related to obesity either by regulating enzymatic activity or directly influence fatty acid oxidation process. PMID:27127449

  15. Genetic variation among agamid lizards of the trapelus agiliscomplex in the caspian-aral basin

    SciTech Connect

    Macey, J. Robert; Ananjeva, Natalia B.

    2004-05-19

    Allozyme variation is examined in eight populations of Trapelus from the Caspian-Aral Basin of the former USSR. Thirty-one loci (15 variable) exhibit remarkably low levels of genetic variation with only a Nei's genetic distance of 0.117 across 2500 km. An isolated population on the European side of the Caspian Sea is found to phenetically cluster inside the Asian populations examined, suggesting that it should not be considered taxonomically distinct.

  16. Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics.

    PubMed

    Moore, Jason H; Boczko, Erik M; Summar, Marshall L

    2005-02-01

    Understanding how DNA sequence variations impact human health through a hierarchy of biochemical and physiological systems is expected to improve the diagnosis, prevention, and treatment of common, complex human diseases. We have previously developed a hierarchical dynamic systems approach based on Petri nets for generating biochemical network models that are consistent with genetic models of disease susceptibility. This modeling approach uses an evolutionary computation approach called grammatical evolution as a search strategy for optimal Petri net models. We have previously demonstrated that this approach routinely identifies biochemical network models that are consistent with a variety of genetic models in which disease susceptibility is determined by nonlinear interactions between two or more DNA sequence variations. We review here this approach and then discuss how it can be used to model biochemical and metabolic data in the context of genetic studies of human disease susceptibility.

  17. Variation.

    ERIC Educational Resources Information Center

    Hamilton City Board of Education (Ontario).

    Suggestions for studying the topic of variation of individuals and objects (balls) to help develop elementary school students' measurement, comparison, classification, evaluation, and data collection and recording skills are made. General suggestions of variables that can be investigated are made for the study of human variation. Twelve specific…

  18. Assessment of the Genetic Variation in Bone Fracture Healing

    DTIC Science & Technology

    2004-10-01

    variations in both structural and material properties of bone development will be recapitulated in the developmental mechanism(s) that controls the bone’s... structural geometry and material properties during fracture healing. Two goals were set out in the proposal to test this hypothesis. The first was to...determine how variations in basic bone structure and material properties in three in bred strains of mice is translated into the healing process of

  19. Somatic retrotransposition alters the genetic landscape of the human brain

    PubMed Central

    Baillie, J. Kenneth; Barnett, Mark W.; Upton, Kyle R.; Gerhardt, Daniel J.; Richmond, Todd A.; De Sapio, Fioravante; Brennan, Paul; Rizzu, Patrizia; Smith, Sarah; Fell, Mark; Talbot, Richard T.; Gustincich, Stefano; Freeman, Thomas C.; Mattick, John S.; Hume, David A.; Heutink, Peter; Carninci, Piero; Jeddeloh, Jeffrey A.; Faulkner, Geoffrey J.

    2011-01-01

    Retrotransposons are mobile genetic elements that employ a germ line “copy-and-paste” mechanism to spread throughout metazoan genomes1. At least 50% of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease2-3. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells4-5, excluding early embryo development and some malignancies6-7. Recent reports of L1 expression8-9 and copy number variation10-11 (CNV) in the human brain suggest L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germ line mutations, as well as 7,743 putative somatic L1 insertions in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 and 1,350 somatic Alu and SVA insertions, respectively. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes. PMID:22037309

  20. Variation in alternative splicing across human tissues

    PubMed Central

    Yeo, Gene; Holste, Dirk; Kreiman, Gabriel; Burge, Christopher B

    2004-01-01

    Background Alternative pre-mRNA splicing (AS) is widely used by higher eukaryotes to generate different protein isoforms in specific cell or tissue types. To compare AS events across human tissues, we analyzed the splicing patterns of genomically aligned expressed sequence tags (ESTs) derived from libraries of cDNAs from different tissues. Results Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most pronounced differences between tissues were seen for the frequencies of alternative 3' splice site and alternative 5' splice site usage, which were about 50 to 100% higher in the liver than in any other human tissue studied. Quantifying differences in splice junction usage, the brain, pancreas, liver and the peripheral nervous system had the most distinctive patterns of AS. Analysis of available microarray expression data showed that the liver had the most divergent pattern of expression of serine-arginine protein and heterogeneous ribonucleoprotein genes compared to the other human tissues studied, possibly contributing to the unusually high frequency of alternative splice site usage seen in liver. Sequence motifs enriched in alternative exons in genes expressed in the brain, testis and liver suggest specific splicing factors that may be important in AS regulation in these tissues. Conclusions This study distinguishes the human brain, testis and liver as having unusually high levels of AS, highlights differences in the types of AS occurring commonly in different tissues, and identifies candidate cis-regulatory elements and trans-acting factors likely to have important roles in tissue-specific AS in human cells. PMID:15461793

  1. Conservation genetics of the Philippine tarsier: cryptic genetic variation restructures conservation priorities for an island archipelago primate.

    PubMed

    Brown, Rafe M; Weghorst, Jennifer A; Olson, Karen V; Duya, Mariano R M; Barley, Anthony J; Duya, Melizar V; Shekelle, Myron; Neri-Arboleda, Irene; Esselstyn, Jacob A; Dominy, Nathaniel J; Ong, Perry S; Moritz, Gillian L; Luczon, Adrian; Diesmos, Mae Lowe L; Diesmos, Arvin C; Siler, Cameron D

    2014-01-01

    Establishment of conservation priorities for primates is a particular concern in the island archipelagos of Southeast Asia, where rates of habitat destruction are among the highest in the world. Conservation programs require knowledge of taxonomic diversity to ensure success. The Philippine tarsier is a flagship species that promotes environmental awareness and a thriving ecotourism economy in the Philippines. However, assessment of its conservation status has been impeded by taxonomic uncertainty, a paucity of field studies, and a lack of vouchered specimens and genetic samples available for study in biodiversity repositories. Consequently, conservation priorities are unclear. In this study we use mitochondrial and nuclear DNA to empirically infer geographic partitioning of genetic variation and to identify evolutionarily distinct lineages for conservation action. The distribution of Philippine tarsier genetic diversity is neither congruent with expectations based on biogeographical patterns documented in other Philippine vertebrates, nor does it agree with the most recent Philippine tarsier taxonomic arrangement. We identify three principal evolutionary lineages that do not correspond to the currently recognized subspecies, highlight the discovery of a novel cryptic and range-restricted subcenter of genetic variation in an unanticipated part of the archipelago, and identify additional geographically structured genetic variation that should be the focus of future studies and conservation action. Conservation of this flagship species necessitates establishment of protected areas and targeted conservation programs within the range of each genetically distinct variant of the Philippine tarsier.

  2. Conservation Genetics of the Philippine Tarsier: Cryptic Genetic Variation Restructures Conservation Priorities for an Island Archipelago Primate

    PubMed Central

    Brown, Rafe M.; Weghorst, Jennifer A.; Olson, Karen V.; Duya, Mariano R. M.; Barley, Anthony J.; Duya, Melizar V.; Shekelle, Myron; Neri-Arboleda, Irene; Esselstyn, Jacob A.; Dominy, Nathaniel J.; Ong, Perry S.; Moritz, Gillian L.; Luczon, Adrian; Diesmos, Mae Lowe L.; Diesmos, Arvin C.; Siler, Cameron D.

    2014-01-01

    Establishment of conservation priorities for primates is a particular concern in the island archipelagos of Southeast Asia, where rates of habitat destruction are among the highest in the world. Conservation programs require knowledge of taxonomic diversity to ensure success. The Philippine tarsier is a flagship species that promotes environmental awareness and a thriving ecotourism economy in the Philippines. However, assessment of its conservation status has been impeded by taxonomic uncertainty, a paucity of field studies, and a lack of vouchered specimens and genetic samples available for study in biodiversity repositories. Consequently, conservation priorities are unclear. In this study we use mitochondrial and nuclear DNA to empirically infer geographic partitioning of genetic variation and to identify evolutionarily distinct lineages for conservation action. The distribution of Philippine tarsier genetic diversity is neither congruent with expectations based on biogeographical patterns documented in other Philippine vertebrates, nor does it agree with the most recent Philippine tarsier taxonomic arrangement. We identify three principal evolutionary lineages that do not correspond to the currently recognized subspecies, highlight the discovery of a novel cryptic and range-restricted subcenter of genetic variation in an unanticipated part of the archipelago, and identify additional geographically structured genetic variation that should be the focus of future studies and conservation action. Conservation of this flagship species necessitates establishment of protected areas and targeted conservation programs within the range of each genetically distinct variant of the Philippine tarsier. PMID:25136854

  3. The impact of genetic variation and cigarette smoke on DNA methylation in current and former smokers from the COPDGene study.

    PubMed

    Qiu, Weiliang; Wan, Emily; Morrow, Jarrett; Cho, Michael H; Crapo, James D; Silverman, Edwin K; DeMeo, Dawn L

    2015-01-01

    DNA methylation can be affected by systemic exposures, such as cigarette smoking and genetic sequence variation; however, the relative impact of each on the epigenome is unknown. We aimed to assess if cigarette smoking and genetic variation are associated with overlapping or distinct sets of DNA methylation marks and pathways. We selected 85 Caucasian current and former smokers with genome-wide single nucleotide polymorphism (SNP) genotyping available from the COPDGene study. Genome-wide methylation was obtained on DNA from whole blood using the Illumina HumanMethylation27 platform. To determine the impact of local sequence variation on DNA methylation (mQTL), we examined the association between methylation and SNPs within 50 kb of each CpG site. To examine the impact of cigarette smoking on DNA methylation, we examined the differences in methylation by current cigarette smoking status. We detected 770 CpG sites annotated to 708 genes associated at an FDR < 0.05 in the cis-mQTL analysis and 1,287 CpG sites annotated to 1,242 genes, which were nominally associated in the smoking-CpG association analysis (P(unadjusted) < 0.05). Forty-three CpG sites annotated to 40 genes were associated with both SNP variation and current smoking; this overlap was not greater than that expected by chance. Our results suggest that cigarette smoking and genetic variants impact distinct sets of DNA methylation marks, the further elucidation of which may partially explain the variable susceptibility to the health effects of cigarette smoking. Ascertaining how genetic variation and systemic exposures differentially impact the human epigenome has relevance for both biomarker identification and therapeutic target development for smoking-related diseases.

  4. Discovery of Genetic Variation that Enhances Improvement of Dairy Production and Health in Cattle and Buffalos

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The hypothesis underlying this project is that genome-wide information on genetic variation will increase accuracy of predictions of genetic merit; will enhance heritability and reliability of these predictions through improved pedigree information; and will improve detection of most quantitative tr...

  5. Genetic variation in bison (bison bison) subspecies and cattle (Bos taurus) breeds and subspecies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic variation was quantified at 29 polymorphic microsatellite DNA loci in nine herds of plains bison (Bison bison bison)