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Sample records for human genetic variation

  1. Genetic variation and human longevity.

    PubMed

    Soerensen, Mette

    2012-05-01

    The overall aim of the PhD project was to elucidate the association of human longevity with genetic variation in major candidate genes and pathways of longevity. Based on a thorough literature and database search we chose to apply a pathway approach; to explore variation in genes composing the DNA damage signaling, DNA repair, GH/IGF-1/insulin signaling and pro-/antioxidant pathways. In addition, 16 genes which did not belong to the core of either pathway, however recurrently regarded as candidate genes of longevity (e.g. APOE), were included. In this way a total of 168 genes were selected for investigation. We decided to explore the genetic variation in the form of single nucleotide polymorphisms (SNPs), a highly investigated type of genetic variation. SNPs having potential functional impact (e.g. affecting binding of transcription factors) were identified, so were specific SNPs in the candidate genes previously published to be associated with human longevity. To cover the majority of the common genetic variation in the 168 gene regions (encoding regions plus 5,000 bp upstream and 1,000 downstream) we applied the tagging SNP approach via the HapMap Consortium. Consequently 1,536 SNPs were selected. The majority of the previous publications on genetic variation and human longevity had employed a case-control study design, e.g. comparing centenarians to middle-aged controls. This type of study design is somehow prone to bias introduced by for instance cohort effects, i.e. differences in characteristics of cases and controls, a kind of bias which is avoided when a prospective cohort is under study. Therefore, we chose to investigate 1,200 individuals of the Danish 1905 birth cohort, which have been followed since 1998 when the members were 92-93 years old. The genetic contribution to human longevity has been estimated to be most profound during the late part of life, thus these oldest-old individuals are excellent for investigating such effect. The follow-up survival

  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. PMID:26432245

  3. 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

  4. 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

  5. Gene Expression and Genetic Variation in Human Atria

    PubMed Central

    Lin, Honghuang; Dolmatova, Elena V.; Morley, Michael P.; Lunetta, Kathryn L.; McManus, David D.; Magnani, Jared W.; Margulies, Kenneth B.; Hakonarson, Hakon; del Monte, Federica; Benjamin, Emelia J.; Cappola, Thomas P.; Ellinor, Patrick T.

    2013-01-01

    Background The human left and right atria have different susceptibilities to develop atrial fibrillation (AF). However, the molecular events related to structural and functional changes that enhance AF susceptibility are still poorly understood. Objective To characterize gene expression and genetic variation in human atria. Methods We studied the gene expression profiles and genetic variations in 53 left atrial and 52 right atrial tissue samples collected from the Myocardial Applied Genomics Network (MAGNet) repository. The tissues were collected from heart failure patients undergoing transplantation and from unused organ donor hearts with normal ventricular function. Gene expression was profiled using the Affymetrix GeneChip Human Genome U133A Array. Genetic variation was profiled using the Affymetrix Genome-Wide Human SNP Array 6.0. Results We found that 109 genes were differentially expressed between left and right atrial tissues. A total of 187 and 259 significant cis-associations between transcript levels and genetic variants were identified in left and right atrial tissues, respectively. We also found that a SNP at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right atrial tissues. Conclusion We found a distinct transcriptional profile between the right and left atrium, and extensive cis-associations between atrial transcripts and common genetic variants. Our results implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF. PMID:24177373

  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. The Evolution of Human Genetic and Phenotypic Variation in Africa

    PubMed Central

    Campbell, Michael C.

    2010-01-01

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

  8. Human genetic variation database, a reference database of genetic variations in the Japanese population

    PubMed Central

    Higasa, Koichiro; Miyake, Noriko; Yoshimura, Jun; Okamura, Kohji; Niihori, Tetsuya; Saitsu, Hirotomo; Doi, Koichiro; Shimizu, Masakazu; Nakabayashi, Kazuhiko; Aoki, Yoko; Tsurusaki, Yoshinori; Morishita, Shinichi; Kawaguchi, Takahisa; Migita, Osuke; Nakayama, Keiko; Nakashima, Mitsuko; Mitsui, Jun; Narahara, Maiko; Hayashi, Keiko; Funayama, Ryo; Yamaguchi, Daisuke; Ishiura, Hiroyuki; Ko, Wen-Ya; Hata, Kenichiro; Nagashima, Takeshi; Yamada, Ryo; Matsubara, Yoichi; Umezawa, Akihiro; Tsuji, Shoji; Matsumoto, Naomichi; Matsuda, Fumihiko

    2016-01-01

    Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/. PMID:26911352

  9. 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

  10. 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. PMID:24878678

  11. Beyond race: towards a whole-genome perspective on human populations and genetic variation.

    PubMed

    Foster, Morris W; Sharp, Richard R

    2004-10-01

    The renewed emphasis on population-specific genetic variation, exemplified most prominently by the International HapMap Project, is complicated by a longstanding, uncritical reliance on existing population categories in genetic research. Race and other pre-existing population definitions (ethnicity, religion, language, nationality, culture and so on) tend to be contentious concepts that have polarized discussions about the ethics and science of research into population-specific human genetic variation. By contrast, a broader consideration of the multiple historical sources of genetic variation provides a whole-genome perspective on the ways i n which existing population definitions do, and do not, account for how genetic variation is distributed among individuals. Although genetics will continue to rely on analytical tools that make use of particular population histories, it is important to interpret findings in a broader genomic context. PMID:15510170

  12. Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

    PubMed Central

    Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

    2014-01-01

    Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

  13. Interpreting noncoding genetic variation in complex traits and human disease.

    PubMed

    Ward, Lucas D; Kellis, Manolis

    2012-11-01

    Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has focused primarily on protein-coding variants, owing to the difficulty of interpreting noncoding mutations. This picture has changed with advances in the systematic annotation of functional noncoding elements. Evolutionary conservation, functional genomics, chromatin state, sequence motifs and molecular quantitative trait loci all provide complementary information about the function of noncoding sequences. These functional maps can help with prioritizing variants on risk haplotypes, filtering mutations encountered in the clinic and performing systems-level analyses to reveal processes underlying disease associations. Advances in predictive modeling can enable data-set integration to reveal pathways shared across loci and alleles, and richer regulatory models can guide the search for epistatic interactions. Lastly, new massively parallel reporter experiments can systematically validate regulatory predictions. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis and treatment. PMID:23138309

  14. Genetic Mechanism of Human Neutrophil Antigen 2 Deficiency and Expression Variations

    PubMed Central

    Li, Yunfang; Mair, David C.; Schuller, Randy M.; Li, Ling; Wu, Jianming

    2015-01-01

    Human neutrophil antigen 2 (HNA-2) deficiency is a common phenotype as 3–5% humans do not express HNA-2. HNA-2 is coded by CD177 gene that associates with human myeloproliferative disorders. HNA-2 deficient individuals are prone to produce HNA-2 alloantibodies that cause a number of disorders including transfusion-related acute lung injury and immune neutropenia. In addition, the percentages of HNA-2 positive neutrophils vary significantly among individuals and HNA-2 expression variations play a role in human diseases such as myelodysplastic syndrome, chronic myelogenous leukemia, and gastric cancer. The underlying genetic mechanism of HNA-2 deficiency and expression variations has remained a mystery. In this study, we identified a novel CD177 nonsense single nucleotide polymorphism (SNP 829A>T) that creates a stop codon within the CD177 coding region. We found that all 829TT homozygous individuals were HNA-2 deficient. In addition, the SNP 829A>T genotypes were significantly associated with the percentage of HNA-2 positive neutrophils. Transfection experiments confirmed that HNA-2 expression was absent on cells expressing the CD177 SNP 829T allele. Our data clearly demonstrate that the CD177 SNP 829A>T is the primary genetic determinant for HNA-2 deficiency and expression variations. The mechanistic delineation of HNA-2 genetics will enable the development of genetic tests for diagnosis and prognosis of HNA-2-related human diseases. PMID:26024230

  15. 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

  16. 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

  17. Inter-chromosomal variation in the pattern of human population genetic structure.

    PubMed

    Baye, Tesfaye M

    2011-05-01

    Emerging technologies now make it possible to genotype hundreds of thousands of genetic variations in individuals, across the genome. The study of loci at finer scales will facilitate the understanding of genetic variation at genomic and geographic levels. We examined global and chromosomal variations across HapMap populations using 3.7 million single nucleotide polymorphisms to search for the most stratified genomic regions of human populations and linked these regions to ontological annotation and functional network analysis. To achieve this, we used five complementary statistical and genetic network procedures: principal component (PC), cluster, discriminant, fixation index (FST) and network/pathway analyses. At the global level, the first two PC scores were sufficient to account for major population structure; however, chromosomal level analysis detected subtle forms of population structure within continental populations, and as many as 31 PCs were required to classify individuals into homogeneous groups. Using recommended population ancestry differentiation measures, a total of 126 regions of the genome were catalogued. Gene ontology and networks analyses revealed that these regions included the genes encoding oculocutaneous albinism II (OCA2), hect domain and RLD 2 (HERC2), ectodysplasin A receptor (EDAR) and solute carrier family 45, member 2 (SLC45A2). These genes are associated with melanin production, which is involved in the development of skin and hair colour, skin cancer and eye pigmentation. We also identified the genes encoding interferon-γ (IFNG) and death-associated protein kinase 1 (DAPK1), which are associated with cell death, inflammatory and immunological diseases. An in-depth understanding of these genomic regions may help to explain variations in adaptation to different environments. Our approach offers a comprehensive strategy for analysing chromosome-based population structure and differentiation, and demonstrates the application of

  18. Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

    PubMed Central

    Burchell, B; Coughtrie, M W

    1997-01-01

    Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and leed to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leeding to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in men with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will leed to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. PMID:9255555

  19. Common Genetic Variation and the Control of HIV-1 in Humans

    PubMed Central

    Shianna, Kevin V.; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T.; Urban, Thomas J.; Zhang, Kunlin; Gumbs, Curtis E.; Smith, Jason P.; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F.; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M.; Obel, Niels; Wolinsky, Steven M.; Martinson, Jeremy J.; Detels, Roger; Margolick, Joseph B.; Jacobson, Lisa P.; Descombes, Patrick; Antonarakis, Stylianos E.; Beckmann, Jacques S.; O'Brien, Stephen J.; Letvin, Norman L.; McMichael, Andrew J.; Haynes, Barton F.; Carrington, Mary; Feng, Sheng; Telenti, Amalio; Goldstein, David B.

    2009-01-01

    To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians. PMID:20041166

  20. Impact of human management on the genetic variation of wild pepper, Capsicum annuum var. glabriusculum.

    PubMed

    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

  1. 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. PMID:17519928

  2. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

    PubMed

    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

    2012-10-01

    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

  3. 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

  4. Human metabolic profiles are stably controlled by genetic and environmental variation.

    PubMed

    Nicholson, George; Rantalainen, Mattias; Maher, Anthony D; Li, Jia V; Malmodin, Daniel; Ahmadi, Kourosh R; Faber, Johan H; Hallgrímsdóttir, Ingileif B; Barrett, Amy; Toft, Henrik; Krestyaninova, Maria; Viksna, Juris; Neogi, Sudeshna Guha; Dumas, Marc-Emmanuel; Sarkans, Ugis; The Molpage Consortium; Silverman, Bernard W; Donnelly, Peter; Nicholson, Jeremy K; Allen, Maxine; Zondervan, Krina T; Lindon, John C; Spector, Tim D; McCarthy, Mark I; Holmes, Elaine; Baunsgaard, Dorrit; Holmes, Chris C

    2011-01-01

    ¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR-based biomarkers quantifying predisposition to disease. PMID:21878913

  5. 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. PMID:27535533

  6. 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

  7. 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. PMID:23128226

  8. Intersection of population variation and autoimmunity genetics in human T cell activation.

    PubMed

    Ye, Chun Jimmie; Feng, Ting; Kwon, Ho-Keun; Raj, Towfique; Wilson, Michael T; Asinovski, Natasha; McCabe, Cristin; Lee, Michelle H; Frohlich, Irene; Paik, Hyun-il; Zaitlen, Noah; Hacohen, Nir; Stranger, Barbara; De Jager, Philip; Mathis, Diane; Regev, Aviv; Benoist, Christophe

    2014-09-12

    T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans and its genetic or environmental roots. We analyzed gene expression in CD4(+) T cells during unbiased activation or in T helper 17 (T(H)17) conditions from 348 healthy participants representing European, Asian, and African ancestries. We observed interindividual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple T(H)1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, interindividual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease. PMID:25214635

  9. Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

    PubMed Central

    Barman, Adriana; Assmann, Anne; Richter, Sylvia; Soch, Joram; Schütze, Hartmut; Wüstenberg, Torsten; Deibele, Anna; Klein, Marieke; Richter, Anni; Behnisch, Gusalija; Düzel, Emrah; Zenker, Martin; Seidenbecher, Constanze I.; Schott, Björn H.

    2014-01-01

    The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans. PMID:24808846

  10. Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory.

    PubMed

    Barman, Adriana; Assmann, Anne; Richter, Sylvia; Soch, Joram; Schütze, Hartmut; Wüstenberg, Torsten; Deibele, Anna; Klein, Marieke; Richter, Anni; Behnisch, Gusalija; Düzel, Emrah; Zenker, Martin; Seidenbecher, Constanze I; Schott, Björn H

    2014-01-01

    The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans. PMID:24808846

  11. Probabilistic models of genetic variation in structured populations applied to global human studies

    PubMed Central

    Hao, Wei; Song, Minsun; Storey, John D.

    2016-01-01

    Motivation: Modern population genetics studies typically involve genome-wide genotyping of individuals from a diverse network of ancestries. An important problem is how to formulate and estimate probabilistic models of observed genotypes that account for complex population structure. The most prominent work on this problem has focused on estimating a model of admixture proportions of ancestral populations for each individual. Here, we instead focus on modeling variation of the genotypes without requiring a higher-level admixture interpretation. Results: We formulate two general probabilistic models, and we propose computationally efficient algorithms to estimate them. First, we show how principal component analysis can be utilized to estimate a general model that includes the well-known Pritchard–Stephens–Donnelly admixture model as a special case. Noting some drawbacks of this approach, we introduce a new ‘logistic factor analysis’ framework that seeks to directly model the logit transformation of probabilities underlying observed genotypes in terms of latent variables that capture population structure. We demonstrate these advances on data from the Human Genome Diversity Panel and 1000 Genomes Project, where we are able to identify SNPs that are highly differentiated with respect to structure while making minimal modeling assumptions. Availability and Implementation: A Bioconductor R package called lfa is available at http://www.bioconductor.org/packages/release/bioc/html/lfa.html. Contact: jstorey@princeton.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26545820

  12. Human variation databases

    PubMed Central

    Küntzer, Jan; Eggle, Daniela; Klostermann, Stefan; Burtscher, Helmut

    2010-01-01

    More than 100 000 human genetic variations have been described in various genes that are associated with a wide variety of diseases. Such data provides invaluable information for both clinical medicine and basic science. A number of locus-specific databases have been developed to exploit this huge amount of data. However, the scope, format and content of these databases differ strongly and as no standard for variation databases has yet been adopted, the way data is presented varies enormously. This review aims to give an overview of current resources for human variation data in public and commercial resources. PMID:20639550

  13. Population Variation and Genetic Control of Modular Chromatin Architecture in Humans.

    PubMed

    Waszak, Sebastian M; Delaneau, Olivier; Gschwind, Andreas R; Kilpinen, Helena; Raghav, Sunil K; Witwicki, Robert M; Orioli, Andrea; Wiederkehr, Michael; Panousis, Nikolaos I; Yurovsky, Alisa; Romano-Palumbo, Luciana; Planchon, Alexandra; Bielser, Deborah; Padioleau, Ismael; Udin, Gilles; Thurnheer, Sarah; Hacker, David; Hernandez, Nouria; Reymond, Alexandre; Deplancke, Bart; Dermitzakis, Emmanouil T

    2015-08-27

    Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain. PMID:26300124

  14. 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. PMID:23786442

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

    PubMed Central

    Hightower, C. Makena; Zhang, Kuixing; Miramontes-González, José Pablo; 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.

    2013-01-01

    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, though 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 (h2) and genetic covariance (pleiotropy; shared h2) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and 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. Additionally, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release. PMID:23786442

  16. Genetic variation in a member of the laminin gene family affects variation in body composition in Drosophila and humans

    PubMed Central

    De Luca, Maria; Chambers, Michelle Moses; Casazza, Krista; Lok, Kerry H; Hunter, Gary R; Gower, Barbara A; Fernández, José R

    2008-01-01

    Background The objective of the present study was to map candidate loci influencing naturally occurring variation in triacylglycerol (TAG) storage using quantitative complementation procedures in Drosophila melanogaster. Based on our results from Drosophila, we performed a human population-based association study to investigate the effect of natural variation in LAMA5 gene on body composition in humans. Results We identified four candidate genes that contributed to differences in TAG storage between two strains of D. melanogaster, including Laminin A (LanA), which is a member of the α subfamily of laminin chains. We confirmed the effects of this gene using a viable LanA mutant and showed that female flies homozygous for the mutation had significantly lower TAG storage, body weight, and total protein content than control flies. Drosophila LanA is closely related to human LAMA5 gene, which maps to the well-replicated obesity-linkage region on chromosome 20q13.2-q13.3. We tested for association between three common single nucleotide polymorphisms (SNPs) in the human LAMA5 gene and variation in body composition and lipid profile traits in a cohort of unrelated women of European American (EA) and African American (AA) descent. In both ethnic groups, we found that SNP rs659822 was associated with weight (EA: P = 0.008; AA: P = 0.05) and lean mass (EA: P= 0.003; AA: P = 0.03). We also found this SNP to be associated with height (P = 0.01), total fat mass (P = 0.01), and HDL-cholesterol (P = 0.003) but only in EA women. Finally, significant associations of SNP rs944895 with serum TAG levels (P = 0.02) and HDL-cholesterol (P = 0.03) were observed in AA women. Conclusion Our results suggest an evolutionarily conserved role of a member of the laminin gene family in contributing to variation in weight and body composition. PMID:18694491

  17. 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.

  18. Genetic Variation among Human Isolates of Uninucleated Cyst-Producing Entamoeba Species

    PubMed Central

    Verweij, Jaco J.; Polderman, Anton M.; Clark, C. Graham

    2001-01-01

    Twelve human infections with Entamoeba spp. producing uninucleated cysts were studied. DNA was extracted from infected feces and used to amplify part of the ameba small-subunit rRNA gene. Sequence analysis identified four distinct types of Entamoeba, all of which are related to Entamoeba polecki and E. chattoni and two of which have not been reported previously. Whether these genetic types represent different species is unclear. We propose that the agent of all human infections with uninucleated cyst-producing Entamoeba species be reported as “E. polecki-like.” PMID:11283106

  19. Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models

    PubMed Central

    Chen, Xu; Kuja-Halkola, Ralf; Rahman, Iffat; Arpegård, Johannes; Viktorin, Alexander; Karlsson, Robert; Hägg, Sara; Svensson, Per; Pedersen, Nancy L.; Magnusson, Patrik K.E.

    2015-01-01

    In order to further illuminate the potential role of dominant genetic variation in the “missing heritability” debate, we investigated the additive (narrow-sense heritability, h2) and dominant (δ2) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of δ2 were evident for 14 traits in twin models (average δ2twin = 0.25, range 0.14–0.49), two of which also displayed significant δ2 in the GREMLd analyses (triglycerides δ2SNP = 0.28 and waist circumference δ2SNP = 0.19). On average, the proportion of h2SNP/h2twin was 70% for ADE-fitted traits (for which the best-fitting model included additive and dominant genetic and unique environmental components) and 31% for AE-fitted traits (for which the best-fitting model included additive genetic and unique environmental components). Independent evidence for contribution from shared environment, also in ADE-fitted traits, was obtained from self-reported within-pair contact frequency and age at separation. We conclude that despite the fact that additive genetics appear to constitute the bulk of genetic influences for most complex traits, dominant genetic variation might often be masked by shared environment in twin and family studies and might therefore have a more prominent role than what family-based estimates often suggest. The risk of erroneously attributing all inherited genetic influences (additive and dominant) to the h2 in too-small twin studies might also lead to exaggerated “missing heritability” (the proportion of h2 that remains unexplained by SNPs). PMID:26544805

  20. The role of community review in evaluating the risks of human genetic variation research.

    PubMed

    Foster, M W; Sharp, R R; Freeman, W L; Chino, M; Bernsten, D; Carter, T H

    1999-06-01

    The practicality and moral value of community review of human genetic research has become a focus of debate. Examples from two Native American communities are used to address four aspects of that debate: (1) the value of community review in larger, geographically dispersed populations; (2) the identification of culturally specific risks; (3) the potential conflict between individual and group assessments of research-related risks; and (4) the confusion of social categories with biological categories. Our experiences working with these two communities suggest that: (1) successful community review may require the involvement of private social units (e.g., families); (2) culturally specific implications of genetic research may be identifiable only by community members and are of valid concern in their moral universes; (3) community concerns can be incorporated into existing review mechanisms without necessarily giving communities the power to veto research proposals; and (4) the conflation of social and biological categories presents recruitment problems for genetic studies. These conclusions argue for the use of community review to identify and minimize research-related risks posed by genetic studies. Community review also can assist in facilitating participant recruitment and retention, as well as in developing partnerships between researchers and communities. PMID:10330360

  1. Genomic and Network Patterns of Schizophrenia Genetic Variation in Human Evolutionary Accelerated Regions

    PubMed Central

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

    2015-01-01

    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. PMID:25681384

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

    PubMed

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

    2014-12-01

    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

  3. 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

  4. 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

  5. Genetic variation in human NPY expression affects stress response and emotion

    PubMed Central

    Zhou, Zhifeng; Zhu, Guanshan; Hariri, Ahmad R.; Enoch, Mary-Anne; Scott, David; Sinha, Rajita; Virkkunen, Matti; Mash, Deborah C.; Lipsky, Robert H.; Hu, Xian-Zhang; Hodgkinson, Colin A.; Xu, Ke; Buzas, Beata; Yuan, Qiaoping; Shen, Pei-Hong; Ferrell, Robert E.; Manuck, Stephen B.; Brown, Sarah M.; Hauger, Richard L.; Stohler, Christian S.; Zubieta, Jon-Kar; Goldman, David

    2009-01-01

    Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic1,2 and its release is induced by stress3. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories4–6. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases. PMID:18385673

  6. Genetic variation in human NPY expression affects stress response and emotion.

    PubMed

    Zhou, Zhifeng; Zhu, Guanshan; Hariri, Ahmad R; Enoch, Mary-Anne; Scott, David; Sinha, Rajita; Virkkunen, Matti; Mash, Deborah C; Lipsky, Robert H; Hu, Xian-Zhang; Hodgkinson, Colin A; Xu, Ke; Buzas, Beata; Yuan, Qiaoping; Shen, Pei-Hong; Ferrell, Robert E; Manuck, Stephen B; Brown, Sarah M; Hauger, Richard L; Stohler, Christian S; Zubieta, Jon-Kar; Goldman, David

    2008-04-24

    Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases. PMID:18385673

  7. 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

  8. Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

    PubMed Central

    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

  9. 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

    2015-01-01

    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 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. PMID:25731744

  10. 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

  11. 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

  12. Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity.

    PubMed

    Van Camp, Jasmijn K; De Freitas, Fenna; Zegers, Doreen; Beckers, Sigri; Verhulst, Stijn L; Van Hoorenbeeck, Kim; Massa, Guy; Verrijken, An; Desager, Kristine N; Van Gaal, Luc F; Van Hul, Wim

    2016-05-01

    The aim of this study was to confirm the previously identified link between BAMBI and human obesity by means of a genetic and functional analysis. We performed both a mutation analysis, using high-resolution melting curve analysis, and a genetic association study, including 8 common tagSNPs in the BAMBI gene region. Three of the identified genetic variants (R151W, H201R, and C229R) were evaluated for their Wnt signaling enhancing capacity in a Wnt luciferase reporter assay. Mutation screening of the BAMBI coding region and exon-intron boundaries on our population of 677 obese children and adolescents and 529 lean control subjects resulted in the identification of 18 variants, 10 of which were not previously reported and 12 of which were exclusively found in obese individuals. The difference in variant frequency, not taking into account common polymorphisms, between obese (3.1 %) and lean (0.9 %) subjects was statistically significant (p = 0.004). Our Wnt luciferase assay, using WT and mutant BAMBI constructs, showed a significantly reduced activity for all of the investigated variants. Logistic and linear regression analysis on our Caucasian population of 1022 obese individuals and 606 lean controls, did not identify associations with obesity parameters (p values >0.05). We found several rare genetic variations, which represent the first naturally occurring missense variants of BAMBI in obese patients. Three variants (R151W, H201R, and C229R) were shown to reduce Wnt signaling enhancing capacity of BAMBI and we believe this result should encourage further study of this gene in other obese populations. In addition, we did not find evidence for the involvement of BAMBI common variation in human obesity in our population. PMID:26499194

  13. 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

  14. 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. PMID:27247418

  15. Genetic variation in the major mitotic checkpoint genes associated with chromosomal aberrations in healthy humans.

    PubMed

    Försti, Asta; Frank, Christoph; Smolkova, Bozena; Kazimirova, Alena; Barancokova, Magdalena; Vymetalkova, Veronika; Kroupa, Michal; Naccarati, Alessio; Vodickova, Ludmila; Buchancova, Janka; Dusinska, Maria; Musak, Ludovit; Vodicka, Pavel; Hemminki, Kari

    2016-10-01

    Non-specific chromosomal aberrations (CAs) are microscopically detected in about 1% of lymphocytes drawn from healthy persons. Causes of CAs in general population are not known but they may be related to risk of cancer. In view of the importance of the mitotic checkpoint machinery on maintaining chromosomal integrity we selected 9 variants in main checkpoint related genes (BUB1B, BUB3, MAD2L1, CENPF, ESPL1/separase, NEK2, PTTG1/securin, ZWILCH and ZWINT) for a genotyping study on samples from healthy individuals (N = 330 to 729) whose lymphocytes had an increased number of CAs compared to persons with a low number of CAs. Genetic variation in individual genes played a minor importance, consistent with the high conservation and selection pressure of the checkpoint system. However, gene pairs were significantly associated with CAs: PTTG1-ZWILCH and PTTG1-ZWINT. MAD2L1 and PTTG1 were the most common partners in any of the two-way interactions. The results suggest that interactions at the level of cohesin (PTTG1) and kinetochore function (ZWINT, ZWILCH and MAD2L1) contribute to the frequency of CAs, suggesting that gene variants at different checkpoint functions appeared to be required for the formation of CAs. PMID:27424524

  16. 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

  17. Genetic variations of human papillomavirus type 16: implications for cervical carcinogenesis.

    PubMed

    Kukimoto, Iwao; Muramatsu, Masamichi

    2015-01-01

    Human papillomaviruses (HPVs) are the causative agent of cervical cancer, and among approximately 15 high-risk genotypes, HPV16 accounts for more than half the cases of cervical cancer worldwide. Recent progress in determining HPV genomic sequences from clinical samples has revealed a wide variety in HPV16 genome sequences, and has allowed for comprehensive classification of intratype HPV16 variants. These consist of four variant lineages containing nucleotide variations in 1.0%-10.0% of the complete viral genome sequence. Epidemiological data suggest that the non-European-Asian lineages of HPV16 entail a higher risk of progression to invasive cervical cancer than the European-Asian lineage. Deep sequencing analysis has recently demonstrated that HPV16 genome sequences are highly homogeneous in individual clinical specimens compared with those of RNA viruses. However, an extremely sensitive PCR method, differential DNA denaturation PCR, has detected hypermutations from C to T or G to A in the E2 gene and the long control region of the HPV16 genome, which suggests the involvement of cellular apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins in this hypermutation. The quasispecies status of the HPV16 genome in the infected cervix may affect the development of cervical cancer and warrants further investigation. PMID:25766614

  18. 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.

  19. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis.

    PubMed Central

    Ye, S.; Watts, G. F.; Mandalia, S.; Humphries, S. E.; Henney, A. M.

    1995-01-01

    Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identified a common polymorphism in the stromelysin gene promoter located 1171 bp upstream from the start of transcription in which one allele has a run of six adenosines (6A) and another has five adenosines (5A). 72 men with coronary heart disease, were genotyped. They were participants in the St Thomas' Atherosclerosis Regression Study who were randomised to receive usual care (UC), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 months. In these patients the frequency of the 5A allele was 0.49 (95% CI from 0.41 to 0.57) and was not significantly different from that in a sample of 354 healthy UK men. In the UC group, patients who were homozygous for the 6A allele showed greater progression of angiographic disease than those with other genotypes: the minimum absolute width of coronary segments decreased by 0.04 (SEM 0.10) mm for 5A5A, 0.20 (0.07) mm for 5A6A, and 0.67 (0.19) mm for 6A6A (P < 0.01). The findings were similar but slightly less significant for the change in mean absolute width of coronary segments (P < 0.05). No significant associations were seen in patients in the D or DC groups. In data pooled from the three treatment groups, the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percentage diameter stenosis greater than or equal to 20%. These results provide the first evidence of a link between genetic variation in stromelysin and progression of coronary atherosclerosis and support the

  20. 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. PMID:27156976

  1. Cryptic Genetic Variation in Evolutionary Developmental Genetics.

    PubMed

    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

  2. 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

  3. 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

  4. Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients

    PubMed Central

    Qin, Xian-Yang; Sone, Hideko; Kojima, Yoshiyuki; Mizuno, Kentaro; Ueoka, Katsuhiko; Muroya, Koji; Miyado, Mami; Hisada, Aya; Zaha, Hiroko; Fukuda, Tomokazu; Yoshinaga, Jun; Yonemoto, Junzo; Kohri, Kenjiro; Hayashi, Yutaro; Fukami, Maki; Ogata, Tsutomu

    2012-01-01

    Background/Purpose We hypothesized that polymorphic differences among individuals might cause variations in the effect that environmental endocrine disruptors (EEDs) have on male genital malformations (MGMs). In this study, individual variation in the genetic response to low-dose bisphenol A (BPA) was investigated in human foreskin fibroblast cells (hFFCs) derived from child cryptorchidism (CO) and hypospadias (HS) patients. Methodology/Principal Findings hFFCs were collected from control children without MGMs (n = 5) and child CO and HS patients (n = 8 and 21, respectively). BPA exposure (10 nM) was found to inhibit matrix metalloproteinase-11 (MMP11) expression in the HS group (0.74-fold, P = 0.0034) but not in the control group (0.93-fold, P = 0.84) and CO group (0.94-fold, P = 0.70). Significantly lower levels of MMP11 expression were observed in the HS group compared with the control group (0.80-fold, P = 0.0088) and CO group (0.79-fold, P = 0.039) in response to 10 nM BPA. The effect of single-nucleotide polymorphism rs5000770 (G>A), located within the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) locus, on individual sensitivity to low-dose BPA was investigated in the HS group. A significant difference in neurotensin receptor 1 (NTSR1) expression in response to 10 nM BPA was observed between AA and AG/GG groups (n = 6 and 15, respectively. P = 0.031). However, no significant difference in ARNT2 expression was observed (P = 0.18). Conclusions/Significance This study advances our understanding of the specificity of low-dose BPA effects on human reproductive health. Our results suggest that genetic variability among individuals affects susceptibility to the effects of EEDs exposure as a potential cause of HS. PMID:23285176

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

    PubMed

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

    2016-02-01

    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

  6. 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

  7. Characterisation of the influence of genetic variations on the enzyme activity of a recombinant human glycine N-acyltransferase.

    PubMed

    van der Sluis, Rencia; Badenhorst, Christoffel P S; van der Westhuizen, Francois H; van Dijk, Alberdina A

    2013-02-25

    Human glycine N-acyltransferase (human GLYAT) detoxifies a wide range of endogenous and xenobiotic metabolites, including benzoate and salicylate. Significant inter-individual variation exists in glycine conjugation capacity. The molecular basis for this variability is not known. To investigate the influence of single nucleotide polymorphisms (SNPs) in the GLYAT coding sequence on enzyme activity, we expressed and characterised a recombinant human GLYAT. Site-directed mutagenesis was used to generate six non-synonymous SNP variants of the enzyme (K16N; S17T; R131H; N156S; F168L; R199C). The variants were expressed, purified, and enzymatically characterised. The enzyme activities of the K16N, S17T and R131H variants were similar to that of the wild-type, whereas the N156S variant was more active, the F168L variant less active, and the R199C variant was inactive. We also generated an E227Q mutant, which lacks the catalytic residue proposed by Badenhorst et al. (2012). This mutant was inactive compared to the wild-type recombinant human GLYAT. A molecular model of human GLYAT containing coenzyme A (CoA) was generated which revealed that the inactivity of the R199C variant could be due to the substitution of the highly conserved Arg(199) and destabilisation of an α-loop-α motif which is important for substrate binding in the GNAT superfamily. The finding that SNP variations in the human GLYAT gene influence the kinetic properties of the enzyme may explain some of the inter-individual variation in glycine conjugation capacity, which is relevant to the metabolism of xenobiotics such as aspirin and the industrial solvent xylene, and to the treatment of some metabolic disorders. PMID:23237781

  8. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans

    PubMed Central

    Rétey, J. V.; Adam, M.; Honegger, E.; Khatami, R.; Luhmann, U. F. O.; Jung, H. H.; Berger, W.; Landolt, H.-P.

    2005-01-01

    Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and declines during sleep. Animal studies suggested that sleep need is genetically controlled, yet the physiological mechanisms remain unknown. Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep. In contrast, a distinct polymorphism of the adenosine A2A receptor gene, which was associated with interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers, affects the electroencephalogram during sleep and wakefulness in a non-state-specific manner. Our findings indicate a direct role of adenosine in human sleep homeostasis. Moreover, our data suggest that genetic variability in the adenosinergic system contributes to the interindividual variability in brain electrical activity during sleep and wakefulness. PMID:16221767

  9. 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.

  10. [Human genetics and ethics].

    PubMed

    Zergollern, L

    1990-01-01

    Many new problems and dilemmas have occurred in the practice of medical geneticists with the development of human genetics and its subdisciplines--molecular genetics, ethic genetics and juridical genetics. Devoid of the possibility to get adequate education, genetic informer or better to say, counsellor, although a scientist and a professional who has already formed his ethic attitudes, often finds himself in a dilemma when he has to decide whether a procedure made possible by progress of science is ethical or not. Thus, due to different attitudes, same decision is ethical for some, while for the others it is not. Ethic committees are groups of moral and good people trying to find an objective approach to certain genetic and ethic problems. There are more and more ethically unanswered questions in modern human genetics, and particularly in medical genetics. Medical geneticist-ethicist still encounters numerous problems in his work. These are, for example, experiments with human gametes and embryos, possibilities of hybridization of human gametes with animal gametes, in vitro fertilization, detection of heterozygotes and homozygotes for monogene diseases. early detection of chromosomopathies, substitute mothers, homo and hetero insemination, transplantation of fetal and cadeveric organs, uncontrolled consumption of alcohol and drugs, environmental pollution, etc. It is almost impossible to create a single attitude which shall be shared by all those engaged in human health protection. Therefore, it is best to have a neutral eugenetic attitude which allows free ethical choice of each individual, in any case, for the well-being of man. PMID:2366624

  11. 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

  12. 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

  13. 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

    2011-06-03

    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.

  14. 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.

  15. 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...

  16. Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets

    PubMed Central

    Olsson, Anders H.; Volkov, Petr; Bacos, Karl; Dayeh, Tasnim; Hall, Elin; Nilsson, Emma A.; Ladenvall, Claes; Rönn, Tina; Ling, Charlotte

    2014-01-01

    Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic

  17. 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

  18. Personalized medicine and human genetic diversity.

    PubMed

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

    2014-09-01

    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

  19. 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

  20. 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

  1. 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.

  2. Networks of spatial genetic variation across species

    PubMed Central

    Fortuna, Miguel A.; Albaladejo, Rafael G.; Fernández, Laura; Aparicio, Abelardo; Bascompte, Jordi

    2009-01-01

    Spatial patterns of genetic variation provide information central to many ecological, evolutionary, and conservation questions. This spatial variability has traditionally been analyzed through summary statistics between pairs of populations, therefore missing the simultaneous influence of all populations. More recently, a network approach has been advocated to overcome these limitations. This network approach has been applied to a few cases limited to a single species at a time. The question remains whether similar patterns of spatial genetic variation and similar functional roles for specific patches are obtained for different species. Here we study the networks of genetic variation of four Mediterranean woody plant species inhabiting the same habitat patches in a highly fragmented forest mosaic in Southern Spain. Three of the four species show a similar pattern of genetic variation with well-defined modules or groups of patches holding genetically similar populations. These modules can be thought of as the long-sought-after, evolutionarily significant units or management units. The importance of each patch for the cohesion of the entire network, though, is quite different across species. This variation creates a tremendous challenge for the prioritization of patches to conserve the genetic variation of multispecies assemblages. PMID:19861546

  3. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome.

    PubMed

    Ollikainen, Miina; Smith, Katherine R; Joo, Eric Ji-Hoon; Ng, Hong Kiat; Andronikos, Roberta; Novakovic, Boris; Abdul Aziz, Nur Khairunnisa; Carlin, John B; Morley, Ruth; Saffery, Richard; Craig, Jeffrey M

    2010-11-01

    Mounting evidence from both animal and human studies suggests that the epigenome is in constant drift over the life course in response to stochastic and environmental factors. In humans, this has been highlighted by a small number of studies that have demonstrated discordant DNA methylation patterns in adolescent or adult monozygotic (MZ) twin pairs. However, to date, it remains unclear when such differences emerge, and how prevalent they are across different tissues. To address this, we examined the methylation of four differentially methylated regions associated with the IGF2/H19 locus in multiple birth tissues derived from 91 twin pairs: 56 MZ and 35 dizygotic (DZ). Tissues included cord blood-derived mononuclear cells and granulocytes, human umbilical vein endothelial cells, buccal epithelial cells and placental tissue. Considerable variation in DNA methylation was observed between tissues and between unrelated individuals. Most interestingly, methylation discordance was also present within twin pairs, with DZ pairs showing greater discordance than MZ pairs. These data highlight the variable contribution of both intrauterine environmental exposures and underlying genetic factors to the establishment of the neonatal epigenome of different tissues and confirm the intrauterine period as a sensitive time for the establishment of epigenetic variability in humans. This has implications for the effects of maternal environment on the development of the newborn epigenome and supports an epigenetic mechanism for the previously described phenomenon of 'fetal programming' of disease risk. PMID:20699328

  4. Genetic variation in walnuts (Juglans regia, j. sigillata and Juglandaceae) species distinctions, human impacts, and the conservation of agrobiodiversity in yunnan, china

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Walnuts are a major crop of many countries and mostly cultivated in large-scale plantations with few cultivars. Landraces provide important genetic reservoirs; thus, understanding factors influencing the geographic distribution of genetic variation in crop resources is a fundamental goal of agrobiod...

  5. DNA methylation contributes to natural human variation

    PubMed Central

    Heyn, Holger; Moran, Sebastian; Hernando-Herraez, Irene; Sayols, Sergi; Gomez, Antonio; Sandoval, Juan; Monk, Dave; Hata, Kenichiro; Marques-Bonet, Tomas; Wang, Liewei; Esteller, Manel

    2013-01-01

    DNA methylation patterns are important for establishing cell, tissue, and organism phenotypes, but little is known about their contribution to natural human variation. To determine their contribution to variability, we have generated genome-scale DNA methylation profiles of three human populations (Caucasian-American, African-American, and Han Chinese-American) and examined the differentially methylated CpG sites. The distinctly methylated genes identified suggest an influence of DNA methylation on phenotype differences, such as susceptibility to certain diseases and pathogens, and response to drugs and environmental agents. DNA methylation differences can be partially traced back to genetic variation, suggesting that differentially methylated CpG sites serve as evolutionarily established mediators between the genetic code and phenotypic variability. Notably, one-third of the DNA methylation differences were not associated with any genetic variation, suggesting that variation in population-specific sites takes place at the genetic and epigenetic levels, highlighting the contribution of epigenetic modification to natural human variation. PMID:23908385

  6. Nonautosomal genetic variation in carotenoid coloration.

    PubMed

    Evans, Simon R; Schielzeth, Holger; Forstmeier, Wolfgang; Sheldon, Ben C; Husby, Arild

    2014-09-01

    Carotenoid-based coloration plays an important role in signaling, is often sexually dimorphic, and is potentially subject to directional and/or sex-specific selection. To understand the evolutionary dynamics of such color traits, it is essential to quantify patterns of inheritance, yet nonautosomal sources of genetic variation are easily overlooked by classical heritability analyses. Carotenoid metabolism has recently been linked to mitochondria, highlighting the potential for color variation to be explained by cytoplasmically inherited factors. In this study, we used quantitative genetic animal models to estimate the importance of mitochondrial and sex chromosome-linked sources of genetic variation in coloration in two songbird populations in which dietary carotenoids are either unmodified (great tit plumage) or metabolized into alternative color forms (zebra finch beak). We found no significant Z-linked genetic variance in great tit plumage coloration, while zebra finch beak coloration exhibited significant W linkage and cytoplasmic inheritance. Our results support cytoplasmic inheritance of color in the zebra finch, a trait based on endogenously metabolized carotenoids, and demonstrate the potential for nonautosomal sources to account for a considerable share of genetic variation in coloration. Although often overlooked, such nonautosomal genetic variation exhibits sex-dependent patterns of inheritance and potentially influences the evolution of sexual dichromatism. PMID:25141146

  7. 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)

  8. 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

  9. 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. PMID:25135957

  10. American Society of Human Genetics

    MedlinePlus

    ... Research Awards August 9, 2016 Media Advisory: American Society of Human Genetics 2016 Annual Meeting July 26, ... McKusick Leadership Award June 30, 2016 The American Society of Human Genetics, Incorporated 9650 Rockville Pike • Bethesda, ...

  11. Genetics for the Human Race

    SciTech Connect

    Myles Axton; Francis Collins; Charles Rotimi; Charmaine Royal; David Goldstein, Daniel Drell; Georgia Dunston; Rick Kittles; Lynn Jorde; Mildred Cho; Joanna Mountain; Ari Patrinos; Neil Risch; Shomarka Keita; Kenneth Kidd; Mark Shriver; Sarah Tishkoff

    2004-11-01

    This supplement has its origins on May 15, 2003, when the National Human Genome Center at Howard University held a small but important workshop in Washington DC. The workshop, Human Genome Variation and 'Race', and this special issue of Nature Genetics were proposed by scientists at Howard University and financially supported by the Genome Programs of the US Department of Energy, through its Office of Science; the Irving Harris Foundation; the National Institutes of Health, through the National Human Genome Research Institute; and Howard University. As summarized by Francis Collins, director of the National Human Genome Research Institute, the workshop focused on several key questions: ''What does the current body of scientific information say about the connections among race, ethnicity, genetics and health? What remains unknown? What additional research is needed? How can this information be applied to benefit human health? How might this information be applied in nonmedical settings? How can we adopt policies that will achieve beneficial societal outcomes?'' This supplement, supported by the Department of Energy through a grant to Howard University, contains articles based on the presentations at this workshop.

  12. 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

  13. Advances in human genetics

    SciTech Connect

    Harris, H.; Hirschhorn, K.

    1993-01-01

    This book has five chapters covering peroxisomal diseases, X-linked immunodeficiencies, genetic mutations affecting human lipoproteins and their receptors and enzymes, genetic aspects of cancer, and Gaucher disease. The chapter on peroxisomes covers their discovery, structure, functions, disorders, etc. The chapter on X-linked immunodeficiencies discusses such diseases as agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, animal models, linkage analysis, etc. Apolipoprotein formation, synthesis, gene regulation, proteins, etc. are the main focus of chapter 3. The chapter on cancer covers such topics as oncogene mapping and the molecular characterization of some recessive oncogenes. Gaucher disease is covered from its diagnosis, classification, and prevention, to its organ system involvement and molecular biology.

  14. Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans

    PubMed Central

    Walum, Hasse; Westberg, Lars; Henningsson, Susanne; Neiderhiser, Jenae M.; Reiss, David; Igl, Wilmar; Ganiban, Jody M.; Spotts, Erica L.; Pedersen, Nancy L.; Eriksson, Elias; Lichtenstein, Paul

    2008-01-01

    Pair-bonding has been suggested to be a critical factor in the evolutionary development of the social brain. The brain neuropeptide arginine vasopressin (AVP) exerts an important influence on pair-bonding behavior in voles. There is a strong association between a polymorphic repeat sequence in the 5′ flanking region of the gene (avpr1a) encoding one of the AVP receptor subtypes (V1aR), and proneness for monogamous behavior in males of this species. It is not yet known whether similar mechanisms are important also for human pair-bonding. Here, we report an association between one of the human AVPR1A repeat polymorphisms (RS3) and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, and show that the RS3 genotype of the males also affects marital quality as perceived by their spouses. These results suggest an association between a single gene and pair-bonding behavior in humans, and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans. PMID:18765804

  15. Comprehensive variation discovery in single human genomes

    PubMed Central

    Weisenfeld, Neil I.; Yin, Shuangye; Sharpe, Ted; Lau, Bayo; Hegarty, Ryan; Holmes, Laurie; Sogoloff, Brian; Tabbaa, Diana; Williams, Louise; Russ, Carsten; Nusbaum, Chad; Lander, Eric S.; MacCallum, Iain; Jaffe, David B.

    2014-01-01

    Complete knowledge of the genetic variation in individual human genomes is a crucial foundation for understanding the etiology of disease. Genetic variation is typically characterized by sequencing individual genomes and comparing reads to a reference. Existing methods do an excellent job of detecting variants in approximately 90% of the human genome, however calling variants in the remaining 10% of the genome (largely low-complexity sequence and segmental duplications) is challenging. To improve variant calling, we developed a new algorithm, DISCOVAR, and examined its performance on improved, low-cost sequence data. Using a newly created reference set of variants from finished sequence of 103 randomly chosen Fosmids, we find that some standard variant call sets miss up to 25% of variants. We show that the combination of new methods and improved data increases sensitivity several-fold, with the greatest impact in challenging regions of the human genome. PMID:25326702

  16. 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)

  17. Genetic Variation in GPX1 Is Associated with GPX1 Activity in a Comprehensive Analysis of Genetic Variations in Selenoenzyme Genes and Their Activity and Oxidative Stress in Humans12

    PubMed Central

    Takata, Yumie; King, Irena B.; Lampe, Johanna W.; Burk, Raymond F.; Hill, Kristina E.; Santella, Regina M.; Kristal, Alan R.; Duggan, David J.; Vaughan, Thomas L.; Peters, Ulrike

    2012-01-01

    Previous studies suggest some effects of selenium on risk of several chronic diseases, which may be mediated through a small number of selenoenzymes with antioxidant properties. In this cross-sectional analysis of 195 participants from the Seattle Barrett’s Esophagus Study who were free of esophageal cancer at the time of blood draw, we examined whether the number of the minor alleles in 26 tagging single nucleotide polymorphisms (SNP) of five selenoenzyme genes [i.e., glutathione peroxidase 1–4 (GPX1–4) and selenoprotein P (SEPP1)] was associated with activity of GPX1 in white blood cells and GPX3 in plasma, and concentrations of SEPP1 and markers of oxidative stress [malondialdehyde (MDA) and protein carbonyl content] in plasma. At the gene level, associations were observed between overall variation in GPX1 and GPX1 activity (P = 0.02) as well as between overall variation in GPX2 and SEPP1 concentrations (P = 0.03). By individual SNP, two variants in GPX1 (rs8179164 and rs1987628) showed a suggestive association with GPX1 activity (P = 0.10 and 0.08, respectively) and two GPX2 variants (rs4902346 and rs2071566) were associated with SEPP1 concentration (P = 0.004 and 0.002, respectively). Furthermore, two SNP in the SEPP1 gene (rs230813 and rs230819) were associated with MDA concentrations (P = 0.03 and 0.02, respectively). Overall, our study supports the hypothesis that common genetic variants in selenoenzymes affect their activity. PMID:22259188

  18. Thoughts on Human Genetics Education.

    ERIC Educational Resources Information Center

    Epstein, Charles J.

    1980-01-01

    The director of the Birth Defects Center at the University of California at San Francisco addresses the reasons for developing good ways of teaching human genetics. Genetic counseling is discussed within the context of several case histories. (SA)

  19. Research strategies in human behaviour genetics.

    PubMed Central

    Vogel, F

    1987-01-01

    Genetic variation influencing normal and abnormal human behaviour has been studied since Francis Galton's work in the second half of the 19th century. However, most of these studies have consisted of biometric analysis of complex phenotypes; the genotype has been treated as a 'black box'. The concepts and analytical tools of modern genetics have rarely been used. In this lecture, some examples are given of approaches combining tools from genetics, cytogenetics, and various fields of neurobiology which might help in the analysis of genetic mechanisms leading, in interaction with the environment, to individual differences in behaviour, mental performance, and susceptibility to mental diseases. PMID:2883319

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

    PubMed Central

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

    2015-01-01

    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. PMID:26100892

  1. The Genetics of Canine Skull Shape Variation

    PubMed Central

    Schoenebeck, Jeffrey J.; Ostrander, Elaine A.

    2013-01-01

    A dog’s craniofacial diversity is the result of continual human intervention in natural selection, a process that began tens of thousands of years ago. To date, we know little of the genetic underpinnings and developmental mechanisms that make dog skulls so morphologically plastic. In this Perspectives, we discuss the origins of dog skull shapes in terms of history and biology and highlight recent advances in understanding the genetics of canine skull shapes. Of particular interest are those molecular genetic changes that are associated with the development of distinct breeds. PMID:23396475

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

    PubMed Central

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

    2012-01-01

    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 [11C]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. PMID:22832851

  3. Pharmacogenetics and human genetic polymorphisms.

    PubMed

    Daly, Ann K

    2010-08-01

    The term pharmacogenetics was first used in the late 1950s and can be defined as the study of genetic factors affecting drug response. Prior to formal use of this term, there was already clinical data available in relation to variable patient responses to the drugs isoniazid, primaquine and succinylcholine. The subject area developed rapidly, particularly with regard to genetic factors affecting drug disposition. There is now comprehensive understanding of the molecular basis for variable drug metabolism by the cytochromes P450 and also for variable glucuronidation, acetylation and methylation of certain drugs. Some of this knowledge has already been translated to the clinic. The molecular basis of variation in drug targets, such as receptors and enzymes, is generally less well understood, although there is consistent evidence that polymorphisms in the genes encoding the beta-adrenergic receptors and the enzyme vitamin K epoxide reductase is of clinical importance. The genetic basis of rare idiosyncratic adverse drug reactions had also been examined. Susceptibility to reactions affecting skin and liver appears to be determined in part by the HLA (human leucocyte antigen) genotype, whereas reactions affecting the heart and muscle may be determined by polymorphisms in genes encoding ion channels and transporters respectively. Genome-wide association studies are increasingly being used to study drug response and susceptibility to adverse drug reactions, resulting in identification of some novel pharmacogenetic associations. PMID:20626352

  4. Mapping genetic influences on human brain structure.

    PubMed

    Thompson, Paul; Cannon, Tyrone D; Toga, Arthur W

    2002-01-01

    Recent advances in brain imaging and genetics have empowered the mapping of genetic and environmental influences on the human brain. These techniques shed light on the 'nature/nurture' debate, revealing how genes determine individual differences in intelligence quotient (IQ) or risk for disease. They visualize which aspects of brain structure and function are heritable, and to what degree, linking these features with behavioral or cognitive traits or disease phenotypes. In genetically transmitted disorders such as schizophrenia, patterns of brain structure can be associated with increased disease liability, and sites can be mapped where non-genetic triggers may initiate disease. We recently developed a large-scale computational brain atlas, including data components from the Finnish Twin registry, to store information on individual variations in brain structure and their heritability. Algorithms from random field theory, anatomical modeling, and population genetics were combined to detect a genetic continuum in which brain structure is heavily genetically determined in some areas but not others. These algorithmic advances motivate studies of disease in which the normative atlas acts as a quantitative reference for the heritability of structural differences and deficits in patient populations. The resulting genetic brain maps isolate biological markers for inherited traits and disease susceptibility, which may serve as targets for genetic linkage and association studies. Computational methods from brain imaging and genetics can be fruitfully merged, to shed light on the inheritance of personality differences and behavioral traits, and the genetic transmission of diseases that affect the human brain. PMID:12553492

  5. 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

  6. Genetic Mapping in Human Disease

    PubMed Central

    Altshuler, David; Daly, Mark J.; Lander, Eric S.

    2009-01-01

    Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead. PMID:18988837

  7. Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes.

    PubMed

    Mohrenweiser, Harvey W; Wilson, David M; Jones, Irene M

    2003-05-15

    Individual risk and the population incidence of disease result from the interaction of genetic susceptibility and exposure. DNA repair is an example of a cellular process where genetic variation in families with extreme predisposition is documented to be associated with high disease likelihood, including syndromes of premature aging and cancer. Although the identification and characterization of new genes or variants in cancer families continues to be important, the focus of this paper is the current status of efforts to define the impact of polymorphic amino acid substitutions in DNA repair genes on individual and population cancer risk. There is increasing evidence that mild reductions in DNA repair capacity, assumed to be the consequence of common genetic variation, affect cancer predisposition. The extensive variation being found in the coding regions of DNA repair genes and the large number of genes in each of the major repair pathways results in complex genotypes with potential to impact cancer risk in the general population. The implications of this complexity for molecular epidemiology studies, as well as concepts that may make these challenges more manageable, are discussed. The concepts include both experimental and computational approaches that could be employed to develop predictors of disease susceptibility based on DNA repair genotype, focusing initially on studies to assess functional impact on individual proteins and pathways and then on molecular epidemiology studies to assess exposure-dependent health risk. In closing, we raise some of the non-technical challenges to the utilization of the full richness of the genetic variation to reduce disease occurrence and ultimately improve health care. PMID:12714187

  8. 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). PMID:27273322

  9. Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

    PubMed

    Hill, W D; Davies, G; van de Lagemaat, L N; Christoforou, A; Marioni, R E; Fernandes, C P D; Liewald, D C; Croning, M D R; Payton, A; Craig, L C A; Whalley, L J; Horan, M; Ollier, W; Hansell, N K; Wright, M J; Martin, N G; Montgomery, G W; Steen, V M; Le Hellard, S; Espeseth, T; Lundervold, A J; Reinvang, I; Starr, J M; Pendleton, N; Grant, S G N; Bates, T C; Deary, I J

    2014-01-01

    Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence. PMID:24399044

  10. Human genetics: international projects and personalized medicine.

    PubMed

    Apellaniz-Ruiz, Maria; Gallego, Cristina; Ruiz-Pinto, Sara; Carracedo, Angel; Rodríguez-Antona, Cristina

    2016-03-01

    In this article, we present the progress driven by the recent technological advances and new revolutionary massive sequencing technologies in the field of human genetics. We discuss this knowledge in relation with drug response prediction, from the germline genetic variation compiled in the 1000 Genomes Project or in the Genotype-Tissue Expression project, to the phenome-genome archives, the international cancer projects, such as The Cancer Genome Atlas or the International Cancer Genome Consortium, and the epigenetic variation and its influence in gene expression, including the regulation of drug metabolism. This review is based on the lectures presented by the speakers of the Symposium "Human Genetics: International Projects & New Technologies" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held on the 20th and 21st of April 2015. PMID:26581075

  11. Cryptic genetic variation and paraphyly in ravens.

    PubMed Central

    Omland, K E; Tarr, C L; Boarma, W I; Marzluff, J M; Fleischer, R C

    2000-01-01

    Widespread species that are morphologically uniform may be likely to harbour cryptic genetic variation. Common ravens (Corvus corax) have an extensive range covering nearly the entire Northern Hemisphere, but show little discrete phenotypic variation. We obtained tissue samples from throughout much of this range and collected mitochondrial sequence and nuclear microsatellite data. Our study revealed a deep genetic break between ravens from the western United States and ravens from throughout the rest of the world. These two groups, the 'California clade' and the 'Holarctic clade' are well supported and over 4% divergent in mitochondrial coding sequence. Microsatellites also reveal significant differentiation between these two groups. Ravens from Minnesota, Maine and Alaska are more similar to ravens from Asia and Europe than they are to ravens from California. The two clades come in contact over a huge area of the western United States, with mixtures of the two mitochondrial groups present in Washington, Idaho and California. In addition, the restricted range Chihuahuan raven (Corvus cryptoleucus) of the south-west United States and Mexico is genetically nested within the paraphyletic common raven. Our findings suggest that the common raven may have formerly consisted of two allopatric groups that may be in the process of remerging. PMID:11197122

  12. Normal Genetic Variation, Cognition, and Aging

    PubMed Central

    Greenwood, P. M.; Parasuraman, Raja

    2005-01-01

    This article reviews the modulation of cognitive function by normal genetic variation. Although the heritability of “g” is well established, the genes that modulate specific cognitive functions are largely unidentified. Application of the allelic association approach to individual differences in cognition has begun to reveal the effects of single nucleotide polymorphisms on specific and general cognitive functions. This article proposes a framework for relating genotype to cognitive phenotype by considering the effect of genetic variation on the protein product of specific genes within the context of the neural basis of particular cognitive domains. Specificity of effects is considered, from genes controlling part of one receptor type to genes controlling agents of neuronal repair, and evidence is reviewed of cognitive modulation by polymorphisms in dopaminergic and cholinergic receptor genes, dopaminergic enzyme genes, and neurotrophic genes. Although allelic variation in certain genes can be reliably linked to cognition—specifically to components of attention, working memory, and executive function in healthy adults—the specificity, generality, and replicability of the effects are not fully known. PMID:15006290

  13. 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

  14. 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,…

  15. Y genetic variation and phenotypic diversity in health and disease.

    PubMed

    Case, Laure K; Teuscher, Cory

    2015-01-01

    Sexually dimorphic traits arise through the combined effects of sex hormones and sex chromosomes on sex-biased gene expression, and experimental mouse models have been instrumental in determining their relative contribution in modulating sex differences. A role for the Y chromosome (ChrY) in mediating sex differences outside of development and reproduction has historically been overlooked due to its unusual genetic composition and the predominant testes-specific expression of ChrY-encoded genes. However, ample evidence now exists supporting ChrY as a mediator of other physiological traits in males, and genetic variation in ChrY has been linked to several diseases, including heart disease, cancer, and autoimmune diseases in experimental animal models, as well as humans. The genetic and molecular mechanisms by which ChrY modulates phenotypic variation in males remain unknown but may be a function of copy number variation between homologous X-Y multicopy genes driving differential gene expression. Here, we review the literature identifying an association between ChrY polymorphism and phenotypic variation and present the current evidence depicting the mammalian ChrY as a member of the regulatory genome in males and as a factor influencing paternal parent-of-origin effects in female offspring. PMID:25866616

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

    PubMed Central

    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.

    2014-01-01

    Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterisation of African genetic diversity is needed. The African Genome Variation Project (AGVP) provides a resource to help design, implement and interpret genomic studies in sub-Saharan Africa (SSA) and worldwide. The AGVP represents dense genotypes from 1,481 and whole genome sequences (WGS) from 320 individuals across SSA. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across SSA. We identify new loci under selection, including for malaria and hypertension. We show that modern imputation panels can identify association signals at highly differentiated loci across populations in SSA. Using WGS, we show further improvement in imputation accuracy supporting efforts for large-scale sequencing of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa, showing for the first time that such designs are feasible. PMID:25470054

  17. 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

  18. Human genetics shape the gut microbiome

    PubMed Central

    Goodrich, Julia K.; Waters, Jillian L.; Poole, Angela C.; Sutter, Jessica L.; Koren, Omry; Blekhman, Ran; Beaumont, Michelle; Van Treuren, William; Knight, Rob; Bell, Jordana T.; Spector, Timothy D.; Clark, Andrew G.; Ley, Ruth E.

    2014-01-01

    Summary Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear. Here, we compared microbiotas across > 1,000 fecal samples obtained from the TwinsUK population, including 416 twin-pairs. We identified many microbial taxa whose abundances were influenced by host genetics. The most heritable taxon, the family Christensenellaceae, formed a cooccurrence network with other heritable Bacteria and with methanogenic Archaea. Furthermore, Christensenellaceae and its partners were enriched in individuals with low body mass index (BMI). An obese-associated microbiome was amended with Christensenella minuta, a cultured member of the Christensenellaceae, and transplanted to germfree mice. C. minuta amendment reduced weight gain and altered the microbiome of recipient mice. Our findings indicate that host genetics influence the composition of the human gut microbiome and can do so in ways that impact host metabolism. PMID:25417156

  19. Population genetics of malaria resistance in humans.

    PubMed

    Hedrick, P W

    2011-10-01

    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

  20. 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

  1. 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

  2. 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

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

    PubMed

    Mih, Nathan; Brunk, Elizabeth; Bordbar, Aarash; Palsson, Bernhard O

    2016-07-01

    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

  4. Fractal and Transgenerational Genetic Effects on Phenotypic Variation and Disease Risk

    NASA Astrophysics Data System (ADS)

    Nadeau, Joe

    To understand human biology and to manage heritable diseases, a complete picture of the genetic basis for phenotypic variation and disease risk is needed. Unexpectedly however, most of these genetic variants, even for highly heritable traits, continue to elude discovery for poorly understood reasons. The genetics community is actively exploring the usual explanations for missing heritability. But given the extraordinary work that has already been done and the exceptional magnitude of the problem, it seems likely that unconventional genetic properties are involved.

  5. 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. PMID:25579139

  6. Genetic & epigenetic approach to human obesity

    PubMed Central

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

    2014-01-01

    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. PMID:25579139

  7. DNA diagnosis of human genetic individuality.

    PubMed

    Pena, S D; Prado, V F; Epplen, J T

    1995-11-01

    DNA studies of the human genome have shown polymorphic variation at thousands of sites, defining an absolute genetic uniqueness for each individual. There are many circumstances in which it may be desirable to diagnose this molecular individuality, as for instance, in criminal investigations or paternity testing. Several techniques can be used for this DNA diagnosis and we can choose among them the one that best suits the specific problem at hand. In this review we describe the main methodologies in current use to investigate human DNA polymorphisms, discussing the best application of each option, as well as their advantages and disadvantages. PMID:8751139

  8. 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.

  9. 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.

  10. Global genetic variation at nine short tandem repeat loci and implications on forensic genetics.

    PubMed

    Sun, Guangyun; McGarvey, Stephen T; Bayoumi, Riad; Mulligan, Connie J; Barrantes, Ramiro; Raskin, Salmo; Zhong, Yixi; Akey, Joshua; Chakraborty, Ranajit; Deka, Ranjan

    2003-01-01

    We have studied genetic variation at nine autosomal short tandem repeat loci in 20 globally distributed human populations defined by geographic and ethnic origins, viz., African, Caucasian, Asian, Native American and Oceanic. The purpose of this study is to evaluate the utility and applicability of these nine loci in forensic analysis in worldwide populations. The levels of genetic variation measured by number of alleles, allele size variance and heterozygosity are high in all populations irrespective of their effective sizes. Single- as well as multi-locus genotype frequencies are in conformity with the assumptions of Hardy-Weinberg equilibrium. Further, alleles across the entire set of nine loci are mutually independent in all populations. Gene diversity analysis shows that pooling of population data by major geographic groupings does not introduce substructure effects beyond the levels recommended by the National Research Council, validating the establishment of population databases based on major geographic and ethnic groupings. A network tree based on genetic distances further supports this assertion, in which populations of common ancestry cluster together. With respect to the power of discrimination and exclusion probabilities, even the relatively reduced levels of genetic variation at these nine STR loci in smaller and isolated populations provide an exclusionary power over 99%. However, in paternity testing with unknown genotype of the mother, the power of exclusion could fall below 80% in some isolated populations, and in such cases use of additional loci supplementing the battery of the nine loci is recommended. PMID:12529704

  11. Fatty acid metabolism: Implications for diet, genetic variation, and disease

    PubMed Central

    Suburu, Janel; Gu, Zhennan; Chen, Haiqin; Chen, Wei; Zhang, Hao; Chen, Yong Q.

    2014-01-01

    Cultures across the globe, especially Western societies, are burdened by chronic diseases such as obesity, metabolic syndrome, cardiovascular disease, and cancer. Several factors, including diet, genetics, and sedentary lifestyle, are suspected culprits to the development and progression of these health maladies. Fatty acids are primary constituents of cellular physiology. Humans can acquire fatty acids by de novo synthesis from carbohydrate or protein sources or by dietary consumption. Importantly, regulation of their metabolism is critical to sustain balanced homeostasis, and perturbations of such can lead to the development of disease. Here, we review de novo and dietary fatty acid metabolism and highlight recent advances in our understanding of the relationship between dietary influences and genetic variation in fatty acid metabolism and their role in chronic diseases. PMID:24511462

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

    PubMed Central

    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

    2012-01-01

    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. PMID:22207615

  13. The role of mutation in genetic copy number variation

    NASA Astrophysics Data System (ADS)

    Clark, B. K.; Weidner, Jacob; Wabick, Kevin

    2010-03-01

    Until very recently, the standard model of DNA included two genes for each trait. This dated model has given way to a model that includes copies of some genes well in excess of the canonical two. Copy number variations in the human genome play critical roles in causing or aggravating a number of syndromes and diseases while providing increased resistance to others. We explore the role of mutation, crossover, inversion, and reproduction in determining copy number variations in a numerical simulation of a population. The numerical model consists of a population of individuals, where each individual is represented by a single strand of DNA with the same number of genes. Each gene is initially assigned to one of two traits. Fitness of the individual is determined by the two most fit genes for trait one, and trait two genetic material is treated as a reservoir of junk DNA. After a sufficient number of generations, during which the genetic distribution is allowed to reach a steady-state, the mean number of genes per trait and the copy number variation are recorded. Here, we focus on the role of mutation and compare simulation results to theory.

  14. 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. PMID:25470054

  15. 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.

  16. Human cooperation in groups: variation begets variation.

    PubMed

    van den Berg, Pieter; 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

  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. Ploidy Variation and Genetic Diversity in Dichroa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent evidence suggests a close genetic relationship between Hydrangea macrophylla and D. febrifuga, which supports previous morphological and DNA sequence data. This relationship was confirmed by the production of fertile intergeneric hybrids. Here we characterize the genetic diversity of availab...

  19. Cytoplasmic genetic variation and extensive cytonuclear interactions influence natural variation in the metabolome

    PubMed Central

    Joseph, Bindu; Corwin, Jason A; Li, Baohua; Atwell, Suzi; Kliebenstein, Daniel J

    2013-01-01

    Understanding genome to phenotype linkages has been greatly enabled by genomic sequencing. However, most genome analysis is typically confined to the nuclear genome. We conducted a metabolomic QTL analysis on a reciprocal RIL population structured to examine how variation in the organelle genomes affects phenotypic variation. This showed that the cytoplasmic variation had effects similar to, if not larger than, the largest individual nuclear locus. Inclusion of cytoplasmic variation into the genetic model greatly increased the explained phenotypic variation. Cytoplasmic genetic variation was a central hub in the epistatic network controlling the plant metabolome. This epistatic influence manifested such that the cytoplasmic background could alter or hide pairwise epistasis between nuclear loci. Thus, cytoplasmic genetic variation plays a central role in controlling natural variation in metabolomic networks. This suggests that cytoplasmic genomes must be included in any future analysis of natural variation. DOI: http://dx.doi.org/10.7554/eLife.00776.001 PMID:24150750

  20. 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. PMID:9262474

  1. 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…

  2. 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

  3. Propagation of genetic variation in gene regulatory networks

    NASA Astrophysics Data System (ADS)

    Plahte, Erik; Gjuvsland, Arne B.; Omholt, Stig W.

    2013-08-01

    A future quantitative genetics theory should link genetic variation to phenotypic variation in a causally cohesive way based on how genes actually work and interact. We provide a theoretical framework for predicting and understanding the manifestation of genetic variation in haploid and diploid regulatory networks with arbitrary feedback structures and intra-locus and inter-locus functional dependencies. Using results from network and graph theory, we define propagation functions describing how genetic variation in a locus is propagated through the network, and show how their derivatives are related to the network’s feedback structure. Similarly, feedback functions describe the effect of genotypic variation of a locus on itself, either directly or mediated by the network. A simple sign rule relates the sign of the derivative of the feedback function of any locus to the feedback loops involving that particular locus. We show that the sign of the phenotypically manifested interaction between alleles at a diploid locus is equal to the sign of the dominant feedback loop involving that particular locus, in accordance with recent results for a single locus system. Our results provide tools by which one can use observable equilibrium concentrations of gene products to disclose structural properties of the network architecture. Our work is a step towards a theory capable of explaining the pleiotropy and epistasis features of genetic variation in complex regulatory networks as functions of regulatory anatomy and functional location of the genetic variation.

  4. Adaptive genetic variation and heart disease risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose of review: Obesity, dyslipidemia and cardiovascular disease are complex and determined by both genetic and environmental factors and their interrelationships. Many associations from genome-wide association studies (GWAS) and candidate gene approaches have described a multitude of polymorphis...

  5. 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)

  6. 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…

  7. Genetic variation in the east Midlands.

    PubMed

    Mastana, S S; Sokol, R J

    1998-01-01

    According to history, the population of the British Isles derives its genepool from a succession of invaders and immigrants. The settlement pattern of these invaders gave rise to a patchwork of genepools, shown in previous genetic surveys. Specimens from 1117 blood donors of regionally subdivided East Midlands (Derbyshire, Nottinghamshire and Leicestershire) were analysed for 18 conventional genetic systems (blood groups, serum proteins and red cell enzymes), according to place of residence. Significant differences exist among the five geographically defined sub-populations, and it is argued that these are derived from the historical settlement of continental European populations in the region, especially the Danes and the Vikings. PMID:9483207

  8. [HIV infection and human genetics].

    PubMed

    Bobkova, M R

    2009-01-01

    The review summarizes data of recent studies on the impact of human gene polymorphisms on the possibility of HIV infection, as well as the specific features of its pathogenesis, the efficiency of HIV infection treatment and the likelihood of its complication. Main information on the mechanisms responsible for viral penetration into the sensitive cells, for immune response development and involvement of HLA and KIR molecules in this process are briefly outlined. Idea on major cell proteins affecting drug metabolism and excretion and encoding for their genes are generalized. There are many examples that show how different human gene alleles and their combinations affect the nature of the pathogenetic process and the occurrence and degree of adverse reactions. The first example of successfully using the prognostic genetic analysis (HLA-B*5701) registered in 2008 to upgrade the quality of HIV infection treatment is described in detail. Basic requirements for further genetic tests to use the optimal antiretroviral therapy schemes and to reduce its hazardous effects are formulated. PMID:20481056

  9. 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.

  10. Genetic Interactions Between Transcription Factors Cause Natural Variation in Yeast

    PubMed Central

    Gerke, Justin; Lorenz, Kim; Cohen, Barak

    2016-01-01

    Our understanding of the genetic basis of phenotypic diversity is limited by the paucity of examples in which multiple, interacting loci have been identified. We show that natural variation in the efficiency of sporulation, the program in yeast that initiates the sexual phase of the life cycle, between oak tree and vineyard strains is due to allelic variation between four nucleotide changes in three transcription factors: IME1, RME1, and RSF1. Furthermore, we identified that selection has shaped quantitative variation in yeast sporulation between strains. These results illustrate how genetic interactions between transcription factors are a major source of phenotypic diversity within species. PMID:19164747

  11. Models to explore genetics of human aging.

    PubMed

    Karasik, David; Newman, Anne

    2015-01-01

    Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on “successful” or “healthy” aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of

  12. Patterns of Genetic Variation Within and Between Gibbon Species

    PubMed Central

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

    2011-01-01

    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. PMID:21368318

  13. A genome-wide survey of genetic variation in gorillas using reduced representation sequencing.

    PubMed

    Scally, Aylwyn; Yngvadottir, Bryndis; Xue, Yali; Ayub, Qasim; Durbin, Richard; Tyler-Smith, Chris

    2013-01-01

    All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations. PMID:23750230

  14. A Genome-Wide Survey of Genetic Variation in Gorillas Using Reduced Representation Sequencing

    PubMed Central

    Xue, Yali; Ayub, Qasim; Durbin, Richard; Tyler-Smith, Chris

    2013-01-01

    All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations. PMID:23750230

  15. 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

  16. Child externalizing behavior problems linked to genetic and non-genetic variation in dental caries.

    PubMed

    Lorber, Michael F; Smith Slep, Amy M; Heyman, Richard E; Bretz, Walter A

    2014-01-01

    The association of environmental and genetic variation in caries with child externalizing behavior problems (inattention, hyperactivity, impulsivity, and defiance) was studied in a sample of 239 pairs of 3- to 8-year-old impoverished Brazilian twins. It was hypothesized that externalizing problems would show a stronger positive association with environmental than genetic variation in caries. Univariate twin models were estimated to parse variation in caries into three components: additive genetic (A), shared environment (C) and non-shared environment/error (E). Age-adjusted associations between externalizing problems and each variance component were tested. Contrary to the hypothesis, modest but very consistent negative associations were found between externalizing problems and both genetic and environmental variation in caries. Mutans streptococci and sweetness preference did not explain the negative associations of caries and externalizing problems. Externalizing problems in non-medicated children were associated with less dental decay that could be explained by both genetic and environmental factors. PMID:24852763

  17. Genetic and epigenetic variation in the lineage specification of regulatory T cells

    PubMed Central

    Arvey, Aaron; van der Veeken, Joris; Plitas, George; Rich, Stephen S; Concannon, Patrick; Rudensky, Alexander Y

    2015-01-01

    Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease. DOI: http://dx.doi.org/10.7554/eLife.07571.001 PMID:26510014

  18. Intraspecific genetic variation and species coexistence in plant communities.

    PubMed

    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

  19. Human genetic databases and liberty.

    PubMed

    Adalsteinsson, Ragnar

    2004-01-01

    This paper examines an act of the Icelandic Parliament on health-sector databases. Both the legislation itself and the manner in which it was presented by the Government to the Parliament and the general public raise various questions about democratic parliamentary procedures, community consultation, autonomy, privacy, professional confidence, control of health data in hospitals and business relationships between medical doctors and biotechnology corporations. A major question to be asked is: In whose interest is it that such sensitive data are handed over to for-profit corporations? Furthermore, is it within the authority of the legislature to authorize politically appointed boards of health institutes to transfer such data without the direct informed consent of the patient and without the relevant physicians' having a say? Does experience teach us to entrust private companies with sensitive personal data? Should the Government be involved in the research policy-making of the biotechnology companies that have been given access to the genetic data of a population, or should the profit motive be the sole deciding influence? That is, should the interest of the shareholders of the companies prevail over the interest of underprivileged groups who are most in need of new methods or medicine to alleviate their situation due to incurable diseases? Or is the invisible hand of the market the only competent decision-maker? Finally, will the proliferation of databases containing sensitive personal data, such as human genetic data, limit our personal liberty? PMID:16755701

  20. Genetics of Human and Canine Dilated Cardiomyopathy

    PubMed Central

    Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F. N.; Cobb, Malcolm; Mongan, Nigel P.; Rutland, Catrin S.

    2015-01-01

    Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed. PMID:26266250

  1. 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. PMID:27531600

  2. Hidden genetic variation in the germline genome of Tetrahymena thermophila.

    PubMed

    Dimond, K L; Zufall, R A

    2016-06-01

    Genome architecture varies greatly among eukaryotes. This diversity may profoundly affect the origin and maintenance of genetic variation within a population. Ciliates are microbial eukaryotes with unusual genome features, such as the separation of germline and somatic genomes within a single cell and amitotic division. These features have previously been proposed to increase the rate of molecular evolution in these species. Here, we assessed the fitness effects of genetic variation in the two genomes of natural isolates of the ciliate Tetrahymena thermophila. We find more extensive genetic variation in fitness in the transcriptionally silent germline genome than in the expressed somatic genome. Surprisingly, this variation is not primarily deleterious, but has both beneficial and deleterious effects. We conclude that Tetrahymena genome architecture allows for the maintenance of genetic variation that would otherwise be eliminated by selection. We consider the effect of selection on the two genomes and the impacts of reproductive strategies and the mechanism of sex determination on the structure of this variation. PMID:26998689

  3. 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 ...

  4. 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

  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 architecture of regulatory variation in Arabidopsis thaliana.

    PubMed

    Zhang, Xu; Cal, Andrew J; Borevitz, Justin O

    2011-05-01

    Studying the genetic regulation of expression variation is a key method to dissect complex phenotypic traits. To examine the genetic architecture of regulatory variation in Arabidopsis thaliana, we performed genome-wide association (GWA) mapping of gene expression in an F(1) hybrid diversity panel. At a genome-wide false discovery rate (FDR) of 0.2, an associated single nucleotide polymorphism (SNP) explains >38% of trait variation. In comparison with SNPs that are distant from the genes to which they were associated, locally associated SNPs are preferentially found in regions with extended linkage disequilibrium (LD) and have distinct population frequencies of the derived alleles (where Arabidopsis lyrata has the ancestral allele), suggesting that different selective forces are acting. Locally associated SNPs tend to have additive inheritance, whereas distantly associated SNPs are primarily dominant. In contrast to results from mapping of expression quantitative trait loci (eQTL) in linkage studies, we observe extensive allelic heterogeneity for local regulatory loci in our diversity panel. By association mapping of allele-specific expression (ASE), we detect a significant enrichment for cis-acting variation in local regulatory variation. In addition to gene expression variation, association mapping of splicing variation reveals both local and distant genetic regulation for intron and exon level traits. Finally, we identify candidate genes for 59 diverse phenotypic traits that were mapped to eQTL. PMID:21467266

  7. Spatial patterns of variation due to natural selection in humans

    PubMed Central

    Novembre, John; Di Rienzo, Anna

    2013-01-01

    Empowered by technology and sampling efforts designed to facilitate genome-wide association mapping, human geneticists are now studying the geography of genetic variation with unprecedented detail. With high genomic coverage and geographic resolution, these studies are identifying loci with spatial signatures of selection, such as extreme levels of differentiation and correlations with environmental variables. Collectively, patterns at these loci are beginning to provide novel insights into the process of human adaptation. Here we review the challenges of these studies and emerging results, including how human population structure has influenced the response to novel selective pressures. PMID:19823195

  8. Genetic variation of St. Louis encephalitis virus

    PubMed Central

    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.

    2008-01-01

    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). PMID:18632961

  9. 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. PMID:24082819

  10. [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. PMID:15032097

  11. 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.

  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. 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. PMID:27053941

  14. Genetic Variation of Capsid Protein VP7 in Genotype G4 Human Rotavirus Strains: Simultaneous Emergence and Spread of Different Lineages in Argentina

    PubMed Central

    Bok, Karin; Matson, David O.; Gomez, Jorge A.

    2002-01-01

    Rotavirus is the most-common cause of severe diarrhea in young children. Complete rotavirus characterization includes determination of the antigenic type of the two outer capsid proteins, VP7 and VP4, designated G and P types, respectively. During a nationwide rotavirus surveillance study, genotype G4 frequency increased during the second year. To evaluate further the mechanism of emergence and the relationship among G4 strains, the genetic diversity of VP7 capsid protein in these samples was studied in detail. Overall nucleotide sequence divergence ranged from less than 0.1 to 19.5%, a higher divergence than that observed for other rotavirus G types (0.1 to 9%). Sequences were classified into two major lineages (designated I and II) based on their nucleotide distances. The most heterogeneous lineage was further subdivided into four sublineages (designated Ia to Id). Most Argentine sequences were of sublineages Ib and Ic, which were confirmed to be independent sequence clusters by parsimony analysis. This study describes different lineages and sublineages within G4 strains and shows that Argentine strains are distantly related to reference strain ST3. The appearance of at least two G4 genotype (sub)lineages during 1998 demonstrates that the increased frequency of these strains was due to the synchronized emergence of different groups of strains. PMID:12037057

  15. Most genetic risk for autism resides with common variation.

    PubMed

    Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J; Bodea, Corneliu A; Goldberg, Arthur P; Lee, Ann B; Mahajan, Milind; Manaa, Dina; Pawitan, Yudi; Reichert, Jennifer; Ripke, Stephan; Sandin, Sven; Sklar, Pamela; Svantesson, Oscar; Reichenberg, Abraham; Hultman, Christina M; Devlin, Bernie; Roeder, Kathryn; Buxbaum, Joseph D

    2014-08-01

    A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation. PMID:25038753

  16. 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. PMID

  17. 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

  18. 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

  19. 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

  20. 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. PMID:16396353

  1. 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...

  2. GENETIC VARIATION IN CARIBOU AND REINDEER (RANGIFER TARANDUS)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic variation at seven microsatellite DNA loci was quantified in 19 herds of caribou and reindeer (Rangifer tarandus) from North America, Scandinavia, and Russia. There is an average of 2.0 to 6.6 alleles per locus and observed individual heterozygosity of 0.33-0.50 in most herds. A herd on Sv...

  3. Genetic variation in testis size and testicular development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Breed differences in sperm production have been described in a number of studies with these differences reflecting variation in testicular size (Ford et al., 2006; Smital, 2008). Within a given breed or genetic line of boars, sperm production increases as testicular size increases. Furthermore, the...

  4. Genetic variation in resistance to infection and inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genes determine functions of the neuroendocrine and immunological systems that affect an animal’s ability to cope with stress, resulting in resistance or susceptibility to infection and inflammation. In this study, genetic variation in responses to lipopolysaccharide (LPS) challenge were examined i...

  5. Impact of restricted marital practices on genetic variation in an endogamous Gujarati group

    PubMed Central

    Pemberton, Trevor J.; Li, Fang-Yuan; Hanson, Erin K.; Mehta, Niyati U.; Choi, Sunju; Ballantyne, Jack; Belmont, John W.; Rosenberg, Noah A.; Tyler-Smith, Chris; Patel, Pragna I.

    2012-01-01

    Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as social classes that are defined by endogamous groups known as castes. Within a caste, there exist endogamous groups known as gols (marriage circles), each of which comprises a small number of exogamous gotra (lineages). Thus, while consanguinity is strictly avoided and some randomness in mate selection occurs within the gol, gene flow is limited with populations outside the gol. Gujarati Patels practice this form of “exogamic endogamy.” We have analyzed genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. Population structure analysis of 1,200 autosomal loci offers support for the existence of distinctive multilocus genotypes in the CGP with respect to both non-Gujaratis and other Gujaratis, and indicates that CGP individuals are genetically very similar. Analysis of Y-chromosomal and mitochondrial haplotypes provides support for both patrilocal and patrilineal practices within the gol, and a low-level of female gene flow into the gol. Our study illustrates how the practice of gol endogamy has introduced fine-scale genetic structure into the population of India, and contributes more generally to an understanding of the way in which marriage practices affect patterns of genetic variation. PMID:22729696

  6. Genetic variation, predator–prey interactions and food web structure

    PubMed Central

    Moya-Laraño, Jordi

    2011-01-01

    Food webs are networks of species that feed on each other. The role that within-population phenotypic and genetic variation plays in food web structure is largely unknown. Here, I show via simulation how variation in two key traits, growth rates and phenology, by influencing the variability of body sizes present through time, can potentially affect several structural parameters in the direction of enhancing food web persistence: increased connectance, decreased interaction strengths, increased variation among interaction strengths and increased degree of omnivory. I discuss other relevant traits whose variation could affect the structure of food webs, such as morphological and additional life-history traits, as well as animal personalities. Furthermore, trait variation could also contribute to the stability of food web modules through metacommunity dynamics. I propose future research to help establish a link between within-population variation and food web structure. If appropriately established, such a link could have important consequences for biological conservation, as it would imply that preserving (functional) genetic variation within populations could ensure the preservation of entire communities. PMID:21444316

  7. Most genetic risk for autism resides with common variation

    PubMed Central

    Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J.; Bodea, Corneliu A.; Goldberg, Arthur P.; Lee, Ann B.; Mahajan, Milind; Manaa, Dina; Pawitan, Yudi; Reichert, Jennifer; Ripke, Stephan; Sandin, Sven; Sklar, Pamela; Svantesson, Oscar; Reichenberg, Abraham; Hultman, Christina M.; Devlin, Bernie

    2014-01-01

    A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (henceforth autism) the nature of its allelic spectrum is uncertain. Individual risk genes have been identified from rare variation, especially de novo mutations1–8. From this evidence one might conclude that rare variation dominates its allelic spectrum, yet recent studies show that common variation, individually of small effect, has substantial impact en masse9,10. At issue is how much of an impact relative to rare variation. Using a unique epidemiological sample from Sweden, novel methods that distinguish total narrow-sense heritability from that due to common variation, and by synthesizing results from other studies, we reach several conclusions about autism’s genetic architecture: its narrow-sense heritability is ≈54% and most traces to common variation; rare de novo mutations contribute substantially to individuals’ liability; still their contribution to variance in liability, 2.6%, is modest compared to heritable variation. PMID:25038753

  8. The Genetics of Blood Pressure and Hypertension: the role of rare variation

    PubMed Central

    Doris, Peter A.

    2013-01-01

    Summary The role of heredity in influencing blood pressure and risk of hypertension is well recognized. However, progress in identifying specific genetic variation that contributes to heritability is very limited. This is in spite of completion of the human genome sequence, the development of extraordinary amounts of information about genome sequence variation and the investigation of blood pressure inheritance in linkage analysis, candidate gene studies and, most recently genome-wide association studies. This paper considers the progress of this research and the obstacles that have been encountered. This work has made clear that the genetic architecture of blood pressure regulation in the population is not likely to be shaped by commonly occurring genetic variation in a discrete set of blood pressure-influencing genes. Rather heritability may be accounted for by rare variation that has its biggest impact within pedigrees rather than on the population at large. Rare variants in a wide range of genes are likely to be the focus of high blood pressure genetics for the next several years and the emerging strategies that can be applied to uncover this genetic variation and the problems that must confronted are considered. PMID:21129164

  9. Diversity of human copy number variation and multicopy genes.

    PubMed

    Sudmant, Peter H; Kitzman, Jacob O; Antonacci, Francesca; Alkan, Can; Malig, Maika; Tsalenko, Anya; Sampas, Nick; Bruhn, Laurakay; Shendure, Jay; Eichler, Evan E

    2010-10-29

    Copy number variants affect both disease and normal phenotypic variation, but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read mapping depth for 159 human genomes, we demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kilobase pairs, ranging from 0 to 48 copies. We identified 4.1 million "singly unique nucleotide" positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversion in the human species. Our approach makes ~1000 genes accessible to genetic studies of disease association. PMID:21030649

  10. Genetic integration of molar cusp size variation in baboons.

    PubMed

    Koh, Christina; Bates, Elizabeth; Broughton, Elizabeth; Do, Nicholas T; Fletcher, Zachary; Mahaney, Michael C; Hlusko, Leslea J

    2010-06-01

    Many studies of primate diversity and evolution rely on dental morphology for insight into diet, behavior, and phylogenetic relationships. Consequently, variation in molar cusp size has increasingly become a phenotype of interest. In 2007 we published a quantitative genetic analysis of mandibular molar cusp size variation in baboons. Those results provided more questions than answers, as the pattern of genetic integration did not fit predictions from odontogenesis. To follow up, we expanded our study to include data from the maxillary molar cusps. Here we report on these later analyses, as well as inter-arch comparisons with the mandibular data. We analyzed variation in two-dimensional maxillary molar cusp size using data collected from a captive pedigreed breeding colony of baboons, Papio hamadryas, housed at the Southwest National Primate Research Center. These analyses show that variation in maxillary molar cusp size is heritable and sexually dimorphic. We also estimated additive genetic correlations between cusps on the same crown, homologous cusps along the tooth row, and maxillary and mandibular cusps. The pattern for maxillary molars yields genetic correlations of one between the paracone-metacone and protocone-hypocone. Bivariate analyses of cuspal homologues on adjacent teeth yield correlations that are high or not significantly different from one. Between dental arcades, the nonoccluding cusps consistently yield high genetic correlations, especially the metaconid-paracone and metaconid-metacone. This pattern of genetic correlation does not immediately accord with the pattern of development and/or calcification, however these results do follow predictions that can be made from the evolutionary history of the tribosphenic molar. PMID:20034010

  11. Genetic integration of molar cusp size variation in baboons

    PubMed Central

    Koh, Christina; Bates, Elizabeth; Broughton, Elizabeth; Do, Nicholas T.; Fletcher, Zachary; Mahaney, Michael C.; Hlusko, Leslea J.

    2010-01-01

    Many studies of primate diversity and evolution rely on dental morphology for insight into diet, behavior, and phylogenetic relationships. Consequently, variation in molar cusp size has increasingly become a phenotype of interest. In 2007 we published a quantitative genetic analysis of mandibular molar cusp size variation in baboons. Those results provided more questions than answers, as the pattern of genetic integration did not fit predictions from odontogenesis. To follow up, we expanded our study to include data from the maxillary molar cusps. Here we report on these later analyses, as well as inter-arch comparisons with the mandibular data. We analyzed variation in two-dimensional maxillary molar cusp size using data collected from a captive pedigreed breeding colony of baboons, Papio hamadryas, housed at the Southwest National Primate Research Center. These analyses show that variation in maxillary molar cusp size is heritable and sexually dimorphic. We also estimated additive genetic correlations between cusps on the same crown, homologous cusps along the tooth row, and maxillary and mandibular cusps. The pattern for maxillary molars yields genetic correlations of one between the paracone-metacone and protocone-hypocone. Bivariate analyses of cuspal homologues on adjacent teeth yield correlations that are high or not significantly different from one. Between dental arcades, the non-occluding cusps consistently yield high genetic correlations, especially the metaconid-paracone and metaconid-metacone. This pattern of genetic correlation does not immediately accord with the pattern of development and/or calcification, however these results do follow predictions that can be made from the evolutionary history of the tribosphenic molar. PMID:20034010

  12. Mouse genetic and phenotypic resources for human genetics

    PubMed Central

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

    2012-01-01

    The use of model organisms to provide information on gene function has proved to be a powerful approach to our understanding of both human disease and fundamental mammalian biology. Large-scale community projects using mice, based on forward and reverse genetics, and now the pan-genomic phenotyping efforts of the International Mouse Phenotyping Consortium (IMPC), are generating resources on an unprecedented scale which will be extremely valuable to human genetics and medicine. We discuss the nature and availability of data, mice and ES cells from these large-scale programmes, the use of these resources to help prioritise and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease. PMID:22422677

  13. Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain.

    PubMed

    Lan, Martin J; Ogden, R Todd; Huang, Yung-yu; Oquendo, Maria A; Sullivan, Gregory M; Miller, Jeffrey; Milak, Matthew; Mann, J John; Parsey, Ramin V

    2014-07-01

    Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT(1A)) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT(1A) receptor ligand, [(11)C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT(1A) receptor binding potential (BP(F), proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT(1A) receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BP(F) than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=-0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT(1A) receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT(1A) receptors in mood disorders. PMID:24607934

  14. Genetic variation and spread pattern of invasive Conyza sumatrensis around China’s Three Gorges Dam

    NASA Astrophysics Data System (ADS)

    Ren, Ming-Xun; Li, Xiao-Qiong; Ding, Jian-Qing

    2010-11-01

    Genetic diversity and structure within and between 17 populations of invasive Conyza sumatrensis (Asteraceae) around the world's biggest hydroelectric dam (Three Gorges Dam (TGD) on the Yangtze River in China) and nearby localities were surveyed using inter-simple sequence repeat (ISSR) markers to determine the spread pattern of this invader in TGD and nearby regions. A total of 434 individuals were analysed, for which 15 ISSR primers amplified 81 bands, with 54 (66.7%) being polymorphic. The percentage of polymorphic loci within a population ranged from 31% to 58%, Nei's gene diversity was 0.385 ± 0.056, and mean Shannon's Index was 0.5815 ± 0.0833, indicating a high genetic variation in this self-fertile plant. Mass seed production and multiple introductions associated with dam construction and local development were thought to be responsible for the high level of genetic variation. Analysis of Molecular Variance revealed 36.5% of genetic variation residing within populations, 35.0% among populations within regions, and 28.5% among the three regions: TGD, upper reaches of TGD, and lower reaches of TGD. Most populations were genetically related to their nearest neighbors, while gene flow (mainly via seed movement) across TGD existed. Long-distance dispersal of seeds and pollen such as by water current, wind and human transportation could explain the low level of geographic structure of genetic variation. The highest genetic variation was found in a population in TGD, and most populations from TGD showed closer genetic relationship to the lower reaches population, which indicated that C. sumatrensis at TGD has likely experienced multiple introductions mainly from lower reaches, which is near the area of primary introduction (southern China) of C. sumatrensis.

  15. Genetic variability in human immunodeficiency viruses.

    PubMed

    Alizon, M; Montagnier, L

    1987-01-01

    The genetic polymorphism of the human immunodeficiency virus (HIV) has been established. In addition to the nucleic acid variations responsible for the restriction map polymorphism, isolates of HIV differ significantly at the protein level, especially in the envelope, in terms of amino acid substitutions and reciprocal insertions-deletions. In this investigation, molecular cloning and nucleotide sequencing of the genomes of 2 HIV isolates obtained from patients in Zaire were carried out. The 1st isolate was recovered in 1983 from a 24-year-old woman with acquired immunodeficiency syndrome (AIDS); the 2nd was isolated in 1985 from a 7-year-old boy with AIDS-related complex (ARC). The genetic organization of these isolates was identical to that found in other HIV isolates from the US and Europe, particularly in terms of the conservation of the central region located between the pol and env genes composed of a series of overlapping open reading frames. There were, however, substantial differences in the primary structure of the viral proteins, with env being more variable than the gag and pol genes. Alignment of the envelopes revealed hypervariable domains with a great number of mutations and reciprocal insertions and deletions. Overall, this analysis suggests that the African and American HIV infections have a common origin given their identical genetic organization. The sequence variability reflects a divergent evolutionary process, and the fact that the 2 Zairian isolates were more divergent than American isolates studied by others indicates a longer evolution of HIV in Africa. An essential research goal is to identify the HIV envelope domains responsible for the virus-cellular surface antigen interaction since an immune response against these epitopes could elicit neutralizing antibodies for use in a vaccine. PMID:3439717

  16. 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

  17. Genetic and Environmental Contributions to Variation in Baboon Cranial Morphology

    PubMed Central

    Roseman, Charles C.; Willmore, Katherine E.; Rogers, Jeffrey; Hildebolt, Charles; Sadler, Brooke E.; Richtsmeier, Joan T.; Cheverud, James M.

    2011-01-01

    The development, function, and integration of morphological characteristics are all hypothesized to influence the utility of traits for phylogenetic reconstruction by affecting the way in which morphological characteristics evolve. We use a baboon model to test the hypotheses about phenotypic and quantitative genetic variation of traits in the cranium that bear on a phenotype’s propensity to evolve. We test the hypotheses that: 1) individual traits in different functionally and developmentally defined regions of the cranium are differentially environmentally, genetically, and phenotypically variable; 2) genetic covariance with other traits constrains traits in one region of the cranium more than those in others; 3) and regions of the cranium subject to different levels of mechanical strain differ in the magnitude of variation in individual traits. We find that the levels of environmental and genetic variation in individual traits are randomly distributed across regions of the cranium rather than being structured by developmental origin or degree of exposure to strain. Individual traits in the cranial vault tend to be more constrained by covariance with other traits than those in other regions. Traits in regions subject to high degrees of strain during mastication are not any more variable at any level than other traits. If these results are generalizable to other populations, they indicate that there is no reason to suppose that individual traits from any one part of the cranium are intrinsically less useful for reconstructing patterns of evolution than those from any other part. PMID:20623673

  18. Genetic variation and shared biological susceptibility underlying comorbidity in neuropsychiatry.

    PubMed

    Palomo, Tomas; Kostrzewa, Richard M; Beninger, Richard J; Archer, Trevor

    2007-07-01

    Genetic factors underlying alcoholism, substance abuse, antisocial and violent behaviour, psychosis, schizophrenia and psychopathy are emerging to implicate dopaminergic and cannabinoid, but also monoaminergic and glutamatergic systems through the maze of promoter genes and polymorphisms. Candidate gene association studies suggest the involvement of a range of genes in different disorders of CNS structure and function. Indices of comorbidity both complicate the array of gene-involvement and provide a substrate of hazardous interactivity. The putative role of the serotonin transporter gene in affective-dissociative spectrum disorders presents both plausible genetic variation and complication of comorbidity The position of genetic variation is further complicated through ethnic, contextual and social factors that provide geometric progressions in the comordity already underlying diagnostic obstacles. The concept of shared biological susceptibility to two or more disorder conditions of comorbidity seems a recurring observation, e.g., bipolar disorder with alcoholism or schizophrenia with alcohol/substance abuse or diabetes with schizopsychotic disorder. Several lines of evidence seem to suggest that the factors influencing variation in one set of symptoms and those affecting one or more disorders are observed to a marked extent which ought to facilitate the search for susceptibility genes in comorbid brain disorders. Identification of regional genetic factors is awaited for a more compelling outline that ought eventually to lead to greater efficacy of symptom-disorder arrangements and an augmentation of current pharmacological treatment therapies. PMID:17513198

  19. 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, M.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.

  20. A genetic basis for the variation in the vulnerability of cancer to DNA damage

    PubMed Central

    Yard, Brian D.; Adams, Drew J.; Chie, Eui Kyu; Tamayo, Pablo; Battaglia, Jessica S.; Gopal, Priyanka; Rogacki, Kevin; Pearson, Bradley E.; Phillips, James; Raymond, Daniel P.; Pennell, Nathan A.; Almeida, Francisco; Cheah, Jaime H.; Clemons, Paul A.; Shamji, Alykhan; Peacock, Craig D.; Schreiber, Stuart L.; Hammerman, Peter S.; Abazeed, Mohamed E.

    2016-01-01

    Radiotherapy is not currently informed by the genetic composition of an individual patient's tumour. To identify genetic features regulating survival after DNA damage, here we conduct large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 533 genetically annotated human tumour cell lines. We show that sensitivity to radiation is characterized by significant variation across and within lineages. We combine results from our platform with genomic features to identify parameters that predict radiation sensitivity. We identify somatic copy number alterations, gene mutations and the basal expression of individual genes and gene sets that correlate with the radiation survival, revealing new insights into the genetic basis of tumour cellular response to DNA damage. These results demonstrate the diversity of tumour cellular response to ionizing radiation and establish multiple lines of evidence that new genetic features regulating cellular response after DNA damage can be identified. PMID:27109210

  1. A genetic basis for the variation in the vulnerability of cancer to DNA damage.

    PubMed

    Yard, Brian D; Adams, Drew J; Chie, Eui Kyu; Tamayo, Pablo; Battaglia, Jessica S; Gopal, Priyanka; Rogacki, Kevin; Pearson, Bradley E; Phillips, James; Raymond, Daniel P; Pennell, Nathan A; Almeida, Francisco; Cheah, Jaime H; Clemons, Paul A; Shamji, Alykhan; Peacock, Craig D; Schreiber, Stuart L; Hammerman, Peter S; Abazeed, Mohamed E

    2016-01-01

    Radiotherapy is not currently informed by the genetic composition of an individual patient's tumour. To identify genetic features regulating survival after DNA damage, here we conduct large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 533 genetically annotated human tumour cell lines. We show that sensitivity to radiation is characterized by significant variation across and within lineages. We combine results from our platform with genomic features to identify parameters that predict radiation sensitivity. We identify somatic copy number alterations, gene mutations and the basal expression of individual genes and gene sets that correlate with the radiation survival, revealing new insights into the genetic basis of tumour cellular response to DNA damage. These results demonstrate the diversity of tumour cellular response to ionizing radiation and establish multiple lines of evidence that new genetic features regulating cellular response after DNA damage can be identified. PMID:27109210

  2. 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

  3. Genetic variation in biomass traits among 20 diverse rice varieties.

    PubMed

    Jahn, Courtney E; Mckay, John K; Mauleon, Ramil; Stephens, Janice; McNally, Kenneth L; Bush, Daniel R; Leung, Hei; Leach, Jan E

    2011-01-01

    Biofuels provide a promising route of producing energy while reducing reliance on petroleum. Developing sustainable liquid fuel production from cellulosic feedstock is a major challenge and will require significant breeding efforts to maximize plant biomass production. Our approach to elucidating genes and genetic pathways that can be targeted for improving biomass production is to exploit the combination of genomic tools and genetic diversity in rice (Oryza sativa). In this study, we analyzed a diverse set of 20 recently resequenced rice varieties for variation in biomass traits at several different developmental stages. The traits included plant size and architecture, aboveground biomass, and underlying physiological processes. We found significant genetic variation among the 20 lines in all morphological and physiological traits. Although heritability estimates were significant for all traits, heritabilities were higher in traits relating to plant size and architecture than for physiological traits. Trait variation was largely explained by variety and breeding history (advanced versus landrace) but not by varietal groupings (indica, japonica, and aus). In the context of cellulosic biofuels development, cell wall composition varied significantly among varieties. Surprisingly, photosynthetic rates among the varieties were inversely correlated with biomass accumulation. Examining these data in an evolutionary context reveals that rice varieties have achieved high biomass production via independent developmental and physiological pathways, suggesting that there are multiple targets for biomass improvement. Future efforts to identify loci and networks underlying this functional variation will facilitate the improvement of biomass traits in other grasses being developed as energy crops. PMID:21062890

  4. Genetically-Based Olfactory Signatures Persist Despite Dietary Variation

    PubMed Central

    Kwak, Jae; Willse, Alan; Matsumura, Koichi; Curran Opiekun, Maryanne; Yi, Weiguang; Preti, George; Yamazaki, Kunio; Beauchamp, Gary K.

    2008-01-01

    Individual mice have a unique odor, or odortype, that facilitates individual recognition. Odortypes, like other phenotypes, can be influenced by genetic and environmental variation. The genetic influence derives in part from genes of the major histocompatibility complex (MHC). A major environmental influence is diet, which could obscure the genetic contribution to odortype. Because odortype stability is a prerequisite for individual recognition under normal behavioral conditions, we investigated whether MHC-determined urinary odortypes of inbred mice can be identified in the face of large diet-induced variation. Mice trained to discriminate urines from panels of mice that differed both in diet and MHC type found the diet odor more salient in generalization trials. Nevertheless, when mice were trained to discriminate mice with only MHC differences (but on the same diet), they recognized the MHC difference when tested with urines from mice on a different diet. This indicates that MHC odor profiles remain despite large dietary variation. Chemical analyses of urinary volatile organic compounds (VOCs) extracted by solid phase microextraction (SPME) and analyzed by gas chromatography/mass spectrometry (GC/MS) are consistent with this inference. Although diet influenced VOC variation more than MHC, with algorithmic training (supervised classification) MHC types could be accurately discriminated across different diets. Thus, although there are clear diet effects on urinary volatile profiles, they do not obscure MHC effects. PMID:18974891

  5. Genetic variation in the endangered Southwestern Willow Flycatcher

    USGS Publications Warehouse

    Busch, Joseph; Miller, Mark P.; Paxton, E.H.; Sogge, M.K.; Keim, Paul

    2000-01-01

    The Southwestern Willow Flycatcher(Empidonax trailii extimus) is an endangered Neotropical migrant that breeds in isolated remnants of dense riparian habitat in the southwestern United States. We estimated genetic variation at 20 breedings sites of the Southwestern Willow Flycatcher(290 individuals) using 38 amplified fragment length polymorphisms(AFLPs). Our results suggest that considerable genetic diversity exists within the subspecies and within local breeding sites. Statistical analyses of genetic variation revealed only slight, although significant, differentiation among breeding sites( Mantel's r = 0.0705, P < 0.0005; 0 = 0.0816, 95% CI = 0.0608 to 0.1034; a??sr = 0.0458, P < 0.001). UPGMA cluster analysis of the AFLP markers indicates that extensive gene flow has occurred among breeding sites. No one site stood out as being genetically unique or isolated. Therefore the small level of genetic structure that we detected may not be biologically significant. Ongoing field studies are consistent with this conclusion. Of the banded birds that were resighted or recaptured in Arizona during the 1996 to 1998 breeding seasons, one-third moved between breeding sites and two-thirds were philopatric. Low differentiation maybe the result of historically high rangewide diversity followed by recent geographic isolation of breeding sites, although observational data indicate that gene flow is a current phenomenon. Our data suggest that breeding groups of E. t. extimus act as a metapopulation.

  6. Ecological genetics of range size variation in Boechera spp. (Brassicaceae).

    PubMed

    Lovell, John T; McKay, John K

    2015-11-01

    Many taxonomic groups contain both rare and widespread species, which indicates that range size can evolve quickly. Many studies have compared molecular genetic diversity, plasticity, or phenotypic traits between rare and widespread species; however, a suite of genetic attributes that unites rare species remains elusive. Here, using two rare and two widespread Boechera (Brassicaceae) species, we conduct a simultaneous comparison of quantitative trait diversity, genetic diversity, and population structure among species with highly divergent range sizes. Consistent with previous studies, we do not find strong associations between range size and within-population genetic diversity. In contrast, we find that both the degree of phenotypic plasticity and quantitative trait structure (Q ST) were positively correlated with range size. We also found higher F ST: Q ST ratios in rare species, indicative of either a greater response to stabilizing selection or a lack of additive genetic variation. While widespread species occupy more ecological and climactic space and have diverged at both traits and markers, rare species display constrained levels of population differentiation and phenotypic plasticity. Combined, our results provide evidence for a specialization-generalization trade-off across three orders of magnitude of range size variation in the ecological model genus, Boechera. PMID:26640674

  7. 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. PMID:25134695

  8. Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission.

    PubMed Central

    Beard, C. B.; Carter, J. L.; Keely, S. P.; Huang, L.; Pieniazek, N. J.; Moura, I. N.; Roberts, J. M.; Hightower, A. W.; Bens, M. S.; Freeman, A. R.; Lee, S.; Stringer, J. R.; Duchin, J. S.; del Rio, C.; Rimland, D.; Baughman, R. P.; Levy, D. A.; Dietz, V. J.; Simon, P.; Navin, T. R.

    2000-01-01

    To study transmission patterns of Pneumocystis carinii pneumonia (PCP) in persons with AIDS, we evaluated P. carinii isolates from patients in five U.S. cities for variation at two independent genetic loci, the mitochondrial large subunit rRNA and dihydropteroate synthase. Fourteen unique multilocus genotypes were observed in 191 isolates that were examined at both loci. Mixed infections, accounting for 17.8% of cases, were associated with primary PCP. Genotype frequency distribution patterns varied by patients' place of diagnosis but not by place of birth. Genetic variation at the two loci suggests three probable characteristics of transmission: that most cases of PCP do not result from infections acquired early in life, that infections are actively acquired from a relatively common source (humans or the environment), and that humans, while not necessarily involved in direct infection of other humans, are nevertheless important in the transmission cycle of P. carinii f. sp. hominis. PMID:10827116

  9. Mixture distributions in human genetics research.

    PubMed

    Schork, N J; Allison, D B; Thiel, B

    1996-06-01

    The use of mixture distributions in genetics research dates back to at least the late 1800s when Karl Pearson applied them in an analysis of crab morphometry. Pearson's use of normal mixture distributions to model the mixing of different species of crab (or 'families' of crab as he referred to them) within a defined geographic area motivated further use of mixture distributions in genetics research settings, and ultimately led to their development and recognition as intuitive modelling devices for the effects of underlying genes on quantitative phenotypic (i.e. trait) expression. In addition, mixture distributions are now used routinely to model or accommodate the genetic heterogeneity thought to underlie many human diseases. Specific applications of mixture distribution models in contemporary human genetics research are, in fact, too numerous to count. Despite this long, consistent and arguably illustrious history of use, little mention of mixture distributions in genetics research is made in many recent reviews on mixture models. This review attempts to rectify this by providing insight into the role that mixture distributions play in contemporary human genetics research. Tables providing examples from the literature that describe applications of mixture models in human genetics research are offered as a way of acquainting the interested reader with relevant studies. In addition, some of the more problematic aspects of the use of mixture models in genetics research are outlined and addressed. PMID:8817796

  10. 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

  11. 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

  12. Genetic variation in tsetse flies and implications for trypanosomiasis.

    PubMed

    Gooding, R H

    1992-03-01

    The role of tsetse flies in the transmission of trypanosomes has been known for nearly 100 years, their economic and public health impact justifying much of the research. About 20 years ago, no genetic variants of tsetses were known but the discovery of six visible mutants and the application o f protein electrophoretic techniques have changed the situation. During the intervening years many techniques have been developed to study the biology of the approximately 30 known species and subspecies of Glossina. Here, Ron Gooding summarizes recent developments in the estimation o f genetic variation in tsetse populations and speculates on the implications of this variation to population structure, vectorial capacity and disease control strategies. PMID:15463582

  13. 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

  14. 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

  15. Genetic variation in the vulnerable and endemic Monkey Puzzle tree, detected using RAPDs.

    PubMed

    Bekessy, Sarah A; Allnutt, T R; Premoli, A C; Lara, A; Ennos, R A; Burgman, M A; Cortes, M; Newton, A C

    2002-04-01

    Araucaria araucana (Monkey Puzzle), a southern South American tree species of exceptional cultural and economic importance, is of conservation concern owing to extensive historical clearance and current human pressures. Random amplified polymorphic DNA (RAPD) markers were used to characterise genetic heterogeneity within and among 13 populations of this species from throughout its natural range. Extensive genetic variability was detected and partitioned by analysis of molecular variance, with the majority of variation existing within populations (87.2%), but significant differentiation was recorded among populations (12.8%). Estimates of Shannon's genetic diversity and percent polymorphism were relatively high for all populations and provide no evidence for a major reduction in genetic diversity from historical events, such as glaciation. All pairwise genetic distance values derived from analysis of molecular variance (Phi(ST)) were significant when individual pairs of populations were compared. Although populations are geographically divided into Chilean Coastal, Chilean Andes and Argentinean regions, this grouping explained only 1.77% of the total variation. Within Andean groups there was evidence of a trend of genetic distance with increasing latitude, and clustering of populations across the Andes, suggesting postglacial migration routes from multiple refugia. Implications of these results for the conservation and use of the genetic resource of this species are discussed. PMID:11920130

  16. Comparing G: multivariate analysis of genetic variation in multiple populations.

    PubMed

    Aguirre, J D; Hine, E; McGuigan, K; Blows, M W

    2014-01-01

    The additive genetic variance-covariance matrix (G) summarizes the multivariate genetic relationships among a set of traits. The geometry of G describes the distribution of multivariate genetic variance, and generates genetic constraints that bias the direction of evolution. Determining if and how the multivariate genetic variance evolves has been limited by a number of analytical challenges in comparing G-matrices. Current methods for the comparison of G typically share several drawbacks: metrics that lack a direct relationship to evolutionary theory, the inability to be applied in conjunction with complex experimental designs, difficulties with determining statistical confidence in inferred differences and an inherently pair-wise focus. Here, we present a cohesive and general analytical framework for the comparative analysis of G that addresses these issues, and that incorporates and extends current methods with a strong geometrical basis. We describe the application of random skewers, common subspace analysis, the 4th-order genetic covariance tensor and the decomposition of the multivariate breeders equation, all within a Bayesian framework. We illustrate these methods using data from an artificial selection experiment on eight traits in Drosophila serrata, where a multi-generational pedigree was available to estimate G in each of six populations. One method, the tensor, elegantly captures all of the variation in genetic variance among populations, and allows the identification of the trait combinations that differ most in genetic variance. The tensor approach is likely to be the most generally applicable method to the comparison of G-matrices from any sampling or experimental design. PMID:23486079

  17. The effect of epistasis on sexually antagonistic genetic variation

    PubMed Central

    Arnqvist, Göran; Vellnow, Nikolas; Rowe, Locke

    2014-01-01

    There is increasing evidence of segregating sexually antagonistic (SA) genetic variation for fitness in laboratory and wild populations, yet the conditions for the maintenance of such variation can be restrictive. Epistatic interactions between genes can contribute to the maintenance of genetic variance in fitness and we suggest that epistasis between SA genes should be pervasive. Here, we explore its effect on SA genetic variation in fitness using a two locus model with negative epistasis. Our results demonstrate that epistasis often increases the parameter space showing polymorphism for SA loci. This is because selection in one locus is affected by allele frequencies at the other, which can act to balance net selection in males and females. Increased linkage between SA loci had more marginal effects. We also show that under some conditions, large portions of the parameter space evolve to a state where male benefit alleles are fixed at one locus and female benefit alleles at the other. This novel effect of epistasis on SA loci, which we term the ‘equity effect’, may have important effects on population differentiation and may contribute to speciation. More generally, these results support the suggestion that epistasis contributes to population divergence. PMID:24870040

  18. Implications of the apportionment of human genetic diversity for the apportionment of human phenotypic diversity

    PubMed Central

    Edge, Michael D.; Rosenberg, Noah A.

    2015-01-01

    Researchers in many fields have considered the meaning of two results about genetic variation for concepts of “race.” First, at most genetic loci, apportionments of human genetic diversity find that worldwide populations are genetically similar. Second, when multiple genetic loci are examined, it is possible to distinguish people with ancestry from different geographical regions. These two results raise an important question about human phenotypic diversity: To what extent do populations typically differ on phenotypes determined by multiple genetic loci? It might be expected that such phenotypes follow the pattern of similarity observed at individual loci. Alternatively, because they have a multilocus genetic architecture, they might follow the pattern of greater differentiation suggested by multilocus ancestry inference. To address the question, we extend a well-known classification model of Edwards (2003) by adding a selectively neutral quantitative trait. Using the extended model, we show, in line with previous work in quantitative genetics, that regardless of how many genetic loci influence the trait, one neutral trait is approximately as informative about ancestry as a single genetic locus. The results support the relevance of single-locus genetic-diversity partitioning for predictions about phenotypic diversity. PMID:25677859

  19. 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...

  20. Different differences: The use of ‘genetic ancestry’ versus race in biomedical human genetic research

    PubMed Central

    Fujimura, Joan H.; Rajagopalan, Ramya

    2011-01-01

    This article presents findings from our ethnographic research on biomedical scientists’ studies of human genetic variation and common complex disease. We examine the socio-material work involved in genome-wide association studies (GWAS) and discuss whether, how, and when notions of race and ethnicity are or are not used. We analyze how researchers produce simultaneously different kinds of populations and population differences. Although many geneticists use race in their analyses, we find some who have invented a statistical genetics method and associated software that they use specifically to avoid using categories of race in their genetics analysis. Their method allows them to operationalize their concept of ‘genetic ancestry’ without resorting to notions of race and ethnicity. We focus on the construction and implementation of the software’s algorithms, and discuss the consequences and implications of the software technology for debates and policies around the use of race in genetics research. We also demonstrate that the production and use of their method involves a dynamic and fluid assemblage of actors in various disciplines responding to disciplinary and sociopolitical contexts and concerns. This assemblage also includes particular discourses on human history and geography as they become entangled with research on genetic markers and disease. We introduce the concept of ‘genome geography’, to analyze how some researchers studying human genetic variation ‘locate’ stretches of DNA in different places and times. The concept of genetic ancestry and the practice of genome geography rely on old discourses, but they also incorporate new technologies, infrastructures, and political and scientific commitments. Some of these new technologies provide opportunities to change some of our institutional and cultural forms and frames around notions of difference and similarity. Neverthless, we also highlight the slipperiness of genome geography and the

  1. 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

  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. PMID:24926019

  3. 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

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

    PubMed

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

    1988-11-01

    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

  5. 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,…

  6. 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

  7. 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

  8. Genetic variation in personality traits explains genetic overlap between borderline personality features and substance use disorders

    PubMed Central

    Few, Lauren R.; Grant, Julia D; Trull, Timothy J.; Statham, Dixie J.; Martin, Nicholas G.; Lynskey, Michael T.; Agrawal, Arpana

    2014-01-01

    Aims To examine the genetic overlap between borderline personality features (BPF) and substance use disorders (SUDs) and the extent to which variation in personality traits contributes to this covariance. Design Genetic structural equation modelling was used to partition the variance in and covariance between personality traits, BPF, and SUDs into additive genetic, shared, and individual-specific environmental factors. Setting All participants were registered with the Australian Twin Registry. Participants A total of 3,127 Australian adult twins participated in the study. Measurements Diagnoses of DSM-IV alcohol and cannabis abuse/dependence (AAD; CAD), and nicotine dependence (ND) were derived via computer-assisted telephone interview. BPF and five-factor model personality traits were derived via self-report questionnaires. Findings Genetic factors were responsible for 49% (95%CI: 42%–55%) of the variance in BPF, 38–42% (95%CI range: 32%–49%) for personality traits and 47% (95%CI: 17%–77%), 54% (95%CI: 43%–64%), and 78% (67%–86%) for ND, AAD and CAD, respectively. Genetic and individual-specific environmental correlations between BPF and SUDs ranged from .33–.56 (95%CI range: .19–.74) and .19–.32 (95%CI range: .06–.43), respectively. Overall, there was substantial support for genetic influences that were specific to AAD, ND and CAD (31%–69%). Finally, genetic variation in personality traits was responsible for 11% (Extraversion for CAD) to 59% (Neuroticism for AAD) of the correlation between BPF and SUDs. Conclusions Both genetic and individual-specific environmental factors contribute to comorbidity between borderline personality features and substance use disorders. A substantial proportion of this comorbidity can be attributed to variation in normal personality traits, particularly Neuroticism. PMID:25041562

  9. Perspectives on the use of landscape genetics to detect genetic adaptive variation in the field.

    PubMed

    Manel, Stéphanie; Joost, Stéphane; Epperson, Bryan K; Holderegger, Rolf; Storfer, Andrew; Rosenberg, Michael S; Scribner, Kim T; Bonin, Aurélie; Fortin, Marie-Josée

    2010-09-01

    Understanding the genetic basis of species adaptation in the context of global change poses one of the greatest challenges of this century. Although we have begun to understand the molecular basis of adaptation in those species for which whole genome sequences are available, the molecular basis of adaptation is still poorly understood for most non-model species. In this paper, we outline major challenges and future research directions for correlating environmental factors with molecular markers to identify adaptive genetic variation, and point to research gaps in the application of landscape genetics to real-world problems arising from global change, such as the ability of organisms to adapt over rapid time scales. High throughput sequencing generates vast quantities of molecular data to address the challenge of studying adaptive genetic variation in non-model species. Here, we suggest that improvements in the sampling design should consider spatial dependence among sampled individuals. Then, we describe available statistical approaches for integrating spatial dependence into landscape analyses of adaptive genetic variation. PMID:20723056

  10. Seasonal variation in human reproduction: environmental factors.

    PubMed

    Bronson, F H

    1995-06-01

    Almost all human populations exhibit seasonal variation in births, owing mostly to seasonal variation in the frequency of conception. This review focuses on the degree to which environmental factors like nutrition, temperature and photoperiod contribute to these seasonal patterns by acting directly on the reproductive axis. The reproductive strategy of humans is basically that of the apes: Humans have the capacity to reproduce continuously, albeit slowly, unless inhibited by environmental influences. Two, and perhaps three, environmental factors probably act routinely as seasonal inhibitors in some human populations. First, it seems likely that ovulation is regulated seasonally in populations experiencing seasonal variation in food availability. More specifically, it seems likely that inadequate food intake or the increased energy expenditure required to obtain food, or both, can delay menarche, suppress the frequency of ovulation in the nonlactating adult, and prolong lactational amenorrhea in these populations on a seasonal basis. This action is most easily seen in tropical subsistence societies where food availability often varies greatly owing to seasonal variation in rainfall; hence births in these populations often correlate with rainfall. Second, it seems likely that seasonally high temperatures suppress spermatogenesis enough to influence the incidence of fertilization in hotter latitudes, but possibly only in males wearing clothing that diminishes scrotal cooling. Since most of our knowledge about this phenomenon comes from temperate latitudes, the sensitivity of spermatogenesis in both human and nonhuman primates to heat in the tropics needs further study. It is quite possible that high temperatures suppress ovulation and early embryo survival seasonally in some of these same populations. Since we know less than desired about the effect of heat stress on ovulation and early pregnancy in nonhuman mammals, and nothing at all about it in humans or any of the

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

    USGS Publications Warehouse

    Cronin, M.; Renecker, L.; Pierson, B. 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.

  12. Ancient genetic variation in one of the world's rarest seabirds.

    PubMed

    Lawrence, H A; Scofield, R P; Crockett, D E; Millar, C D; Lambert, D M

    2008-12-01

    The Chatham Island Taiko (Tchaik, Pterodroma magentae) is one of the world's rarest seabirds. In the past there were millions of breeding pairs of Taiko and it was the most abundant burrowing petrel on Chatham Island. The present population consists of just 120-150 birds, including only 8-15 breeding pairs. Surprisingly high genetic variation was revealed by DNA sequencing of almost every known adult Taiko (N=90). Given the massive population decline, genetic variation may have been even larger in the past. Therefore, we investigated past genetic diversity by sequencing regions of the mitochondrial cytochrome b gene in 44 ancient Taiko bones. We identified a total of 12 haplotypes in Taiko. Eight haplotypes were revealed in the ancient DNA: four were unique to the bones and four corresponded to those found in the modern Taiko population. Surprisingly, despite the critically endangered status of the Taiko, no significant reduction in mitochondrial DNA haplotype diversity was observed between ancient samples (N=44) and modern adult Taiko (N=90). The modern population may have however lost four haplotypes present in the ancient populations. PMID:19018271

  13. Variation and signatures of selection on the human face.

    PubMed

    Guo, Jing; Tan, Jingze; Yang, Yajun; Zhou, Hang; Hu, Sile; Hashan, Agu; Bahaxar, Nurmamat; Xu, Shuhua; Weaver, Timothy D; Jin, Li; Stoneking, Mark; Tang, Kun

    2014-10-01

    There has been much debate about why humans throughout the world differ in facial form. Previous studies of human skull morphology found levels of among-population differentiation that were comparable to those of neutral genetic markers, suggesting that genetic drift (neutral processes) played an important role in influencing facial differentiation. However, variation in soft-tissue morphology has not been studied in detail. In this study, we analyzed high-resolution 3D images of soft-tissue facial form in four Eurasian populations: Han Chinese, Tibetans, Uyghur and Europeans. A novel method was used to establish a high-density alignment across all of the faces, allowing facial diversity to be examined at an unprecedented resolution. These data exhibit signatures of population structure and history. However, among-population differentiation was higher for soft-tissue facial form than for genome-wide genetic loci, and high-resolution analyses reveal that the nose, brow area and cheekbones exhibit particularly strong signals of differentiation (Qst estimates: 0.3-0.8) between Europeans and Han Chinese. Our results suggest that local adaptation and/or sexual selection have been important in shaping human soft-tissue facial morphology. PMID:25186351

  14. 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

  15. 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

  16. Genetic variation and population structure in native Americans.

    PubMed

    Wang, Sijia; Lewis, Cecil M; Jakobsson, Mattias; 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

    2007-11-01

    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

  17. Human genetic variability and HIV treatment response.

    PubMed

    Haas, David W

    2006-07-01

    Access to potent antiretroviral medications greatly reduces morbidity and mortality due to HIV/AIDS, but drug toxicity limits treatment success in many individuals. The field of pharmacogenomics strives to understand the influence of human genetic variants in response to medications. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and hsp70-hom genotypes, and among CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system symptoms. Pharmacogenomics also holds great promise to suggest novel targets for drug development. The discovery that a naturally occurring, nonfunctional variant of the HIV receptor gene CCR5 protected against HIV infection encouraged the development of CCR5 antagonists. Through continued translational and applied research, pharmacogenomics will ultimately benefit persons living with HIV worldwide by identifying new therapeutic targets and through individualized drug prescribing that is informed by human genetic testing. PMID:16608660

  18. 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.

  19. 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. PMID:23915002

  20. Genetic variation of mini- and microsatellites and a clonal structure in Enterocytozoon bieneusi population in foxes and raccoon dogs and population differentiation of the parasite between fur animals and humans.

    PubMed

    Li, Wei; Wan, Qiang; Yu, Qinlei; Yang, Yuqi; Tao, Wei; Jiang, Yanxue; Xiao, Lihua

    2016-07-01

    Enterocytozoon bieneusi is an obligate intracellular protozoan parasite that infects a wide range of mammal hosts and birds. Previous genotypic surveys were limited to measure the polymorphisms at the ribosomal internal transcribed spacer (ITS) that evolved slowly. Data on population structure are available only on E. bieneusi isolates from primates. This study explored the genotypic and phylogenetic characteristics of four mini- and microsatellites and performed a population genetic analysis in 39 E. bieneusi isolates of potentially zoonotic ITS genotype D from farmed foxes and raccoon dogs in China. Sequence polymorphisms facilitated determination of six, two, four, and five genotypes at markers MS1, MS3, MS4, and MS7, respectively. Patterns of phylogeny revealed different levels of diversity within and among the genetic markers. Clear genotypic and phylogenetic divergences between E. bieneusi isolates of ITS genotype D from fur animals and humans were observed at individual markers. Complete linkage disequilibrium and very limited recombination in subsequent population genetic analysis supported a clonal structure for E. bieneusi population from fur animals (FID). Phylogenetic analysis, genetic network, and measures of F ST and gene flow demonstrated population differentiation of FID from two known human E. bieneusi populations HID (with a clonal structure) and HIA (with an epidemic structure). The data indicated an ideal resolving power of MLST compared to the previously widely used ITS genotyping and confirmed the clonal nature and population differentiation of E. bieneusi in various hosts. PMID:27095568

  1. 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

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

    PubMed

    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

    2016-09-01

    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

  3. Genetic variation for total fitness in Drosophila melanogaster.

    PubMed Central

    Fowler, K; Semple, C; Barton, N H; Partridge, L

    1997-01-01

    We measured the heterozygous effects on net fitness of a sample of 12 wild-type third chromosomes in D. melanogaster. Effects on fitness were assessed by competing the wild-type chromosomes against balancer chromosomes, to prevent the production of recombinants. The measurements were carried out in the population cage environment in which the life history had been evolving, in an undisturbed population with overlapping generations, and replicated measurements were made on each chromosome to control for confounding effects such as mutation accumulation. We found significant variation among the wild type chromosomes in their additive genetic effect on net fitness. The system provides an opportunity to obtain an accurate estimate of the distribution of heterozygous effects on net fitness, the contribution of different fitness components including male mating success, and the role of intra-chromosomal epistasis in fitness variation. PMID:9061969

  4. 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

  5. Evolutionary perspectives on human height variation.

    PubMed

    Stulp, Gert; Barrett, Louise

    2016-02-01

    Human height is a highly variable trait, both within and between populations, has a high heritability, and influences the manner in which people behave and are treated in society. Although we know much about human height, this information has rarely been brought together in a comprehensive, systematic fashion. Here, we present a synthetic review of the literature on human height from an explicit evolutionary perspective, addressing its phylogenetic history, development, and environmental and genetic influences on growth and stature. In addition to presenting evidence to suggest the past action of natural selection on human height, we also assess the evidence that natural and sexual selection continues to act on height in contemporary populations. Although there is clear evidence to suggest that selection acts on height, mainly through life-history processes but perhaps also directly, it is also apparent that methodological factors reduce the confidence with which such inferences can be drawn, and there remain surprising gaps in our knowledge. The inability to draw firm conclusions about the adaptiveness of such a highly visible and easily measured trait suggests we should show an appropriate degree of caution when dealing with other human traits in evolutionary perspective. PMID:25530478

  6. 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

  7. 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

  8. 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. PMID:26811909

  9. 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

  10. 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. PMID:25122193