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Sample records for common genetic mechanism

  1. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    PubMed Central

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  2. Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms

    PubMed Central

    Davydov, Dmitry M.; Zhdanov, Renad I.; Dvoenosov, Vladimir G.; Kravtsova, Olga A.; Voronina, Elena N.; Filipenko, Maxim L.

    2015-01-01

    A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits. PMID:26024428

  3. Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms.

    PubMed

    Davydov, Dmitry M; Zhdanov, Renad I; Dvoenosov, Vladimir G; Kravtsova, Olga A; Voronina, Elena N; Filipenko, Maxim L

    2015-01-01

    A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits. PMID:26024428

  4. Mechanisms of population genetic heterogeneity among molting common mergansers on Kodiak Island, Alaska: implications for assessments of migratory connectivity

    USGS Publications Warehouse

    Pearce, John M.; Zwiefelhofer, Denny; Maryanski, Nate

    2009-01-01

    Quantifying population genetic heterogeneity within nonbreeding aggregations can inform our understanding of patterns of site fidelity, migratory connectivity, and gene flow between breeding and nonbreeding areas. However, characterizing mechanisms that contribute to heterogeneity, such as migration and dispersal, is required before site fidelity and migratory connectivity can be assessed accurately. We studied nonbreeding groups of Common Mergansers (Mergus merganser) molting on Kodiak Island, Alaska, from 2005 to 2007, using banding data to assess rates of recapture, mitochondrial (mt) DNA to determine natal area, and nuclear microsatellite genotypes to assess dispersal. Using baseline information from differentiated mtDNA haplogroups across North America, we were able to assign individuals to natal regions and document population genetic heterogeneity within and among molting groups. Band-recovery and DNA data suggest that both migration from and dispersal among natal areas contribute to admixed groups of males molting on Kodiak Island. A lack of differentiation in the Common Merganser's nuclear, bi-parentally inherited DNA, observed across North America, implies that dispersal can mislead genetic assessments of migratory connectivity and assignments of nonbreeding individuals to breeding areas. Thus multiple and independent data types are required to account for such behaviors before accurate assessments of migratory connectivity can be made.

  5. Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms

    PubMed Central

    Bell, Jordana T.; Bhasin, Shalender; Eriksson, Joel; Eriksson, Anna; Ernst, Florian; Ferrucci, Luigi; Frayling, Timothy M.; Glass, Daniel; Grundberg, Elin; Haring, Robin; Hedman, Åsa K.; Hofman, Albert; Kiel, Douglas P.; Kroemer, Heyo K.; Liu, Yongmei; Lunetta, Kathryn L.; Maggio, Marcello; Lorentzon, Mattias; Mangino, Massimo; Melzer, David; Miljkovic, Iva; Nica, Alexandra; Penninx, Brenda W. J. H.; Vasan, Ramachandran S.; Rivadeneira, Fernando; Small, Kerrin S.; Soranzo, Nicole; Uitterlinden, André G.; Völzke, Henry; Wilson, Scott G.; Xi, Li; Zhuang, Wei Vivian; Harris, Tamara B.; Murabito, Joanne M.; Ohlsson, Claes; Murray, Anna; de Jong, Frank H.; Spector, Tim D.; Wallaschofski, Henri

    2011-01-01

    Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS. PMID:21533175

  6. Genetic Etiology of the Common Liability to Drug Dependence: Evidence of Common and Specific Mechanisms for DSM-IV Dependence Symptoms

    PubMed Central

    Palmer, Rohan H. C.; Button, Tanya M.; Rhee, Soo H.; Corley, Robin P.; Young, Susan E.; Stallings, Michael C.; Hopfer, Christian J.; Hewitt, John K.

    2012-01-01

    Background We investigated the etiological nature of comorbid alcohol, tobacco, and cannabis DSM-IV dependence symptoms in late adolescence and young adulthood while accounting for gender differences in the magnitude of genetic and environmental influences. Methods Univariate and multivariate twin modeling was used to determine the heritability of each substance and the etiology of multiple drug problems in a sample of 2484 registrants of the Center for Antisocial Drug Dependence who provided data at the second wave of an ongoing longitudinal study. We report on mean and prevalence levels of whole-life DSM-IV dependence symptoms that were assessed with the Composite International Diagnostic Interview-Substance Abuse Module. Biometrical analyses were limited to age-adjusted DSM-IV dependence symptom counts from a subset of twins that reported using alcohol, tobacco, or cannabis in their lifetime. Results Male and female alcohol, tobacco, and cannabis DSM-IV symptoms are indicators of a heritable unidimensional latent continuous trait. Additive genetic factors explain more than 60% of the common liability to drug dependence. A larger proportion of the variation in each substance is attributable to substance-specific genetic and environmental factors. Conclusions These data suggest that both common and substance-specific genetic and environmental factors contribute to individual differences in the levels of DSM-IV alcohol, tobacco, and cannabis dependence symptoms. PMID:22243758

  7. Common genetic and epigenetic syndromes.

    PubMed

    Adams, Darius J; Clark, David A

    2015-04-01

    Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes. PMID:25836705

  8. Genetic divergence of common bean cultivars.

    PubMed

    Veloso, J S; Silva, W; Pinheiro, L R; Dos Santos, J B; Fonseca, N S; Euzebio, M P

    2015-01-01

    The aim of this study was to evaluate genetic divergence in the 'Carioca' (beige with brown stripes) common bean cultivar used by different institutions and in 16 other common bean cultivars used in the Rede Cooperativa de Pesquisa de Feijão (Cooperative Network of Common Bean Research), by using simple sequence repeats associated with agronomic traits that are highly distributed in the common bean genome. We evaluated 22 polymorphic loci using bulks containing DNA from 30 plants. There was genetic divergence among the Carioca cultivar provided by the institutions. Nevertheless, there was lower divergence among them than among the other cultivars. The cultivar used by Instituto Agronômico do Paraná was the most divergent in relation to the Carioca samples. The least divergence was observed among the samples used by Universidade Federal de Lavras and by Embrapa Arroz e Feijão. Of all the cultivars, 'CNFP 10104' and 'BRSMG Realce' showed the greatest dissimilarity. The cultivars were separated in two groups of greatest similarity using the Structure software. Genetic variation among cultivars was greater than the variation within or between the groups formed. This fact, together with the high estimate of heterozygosity observed and the genetic divergence of the samples of the Carioca cultivar in relation to the original provided by Instituto Agronômico de Campinas, indicates a mixture of cultivars. The high divergence among cultivars provides potential for the utilization of this genetic variability in plant breeding. PMID:26400359

  9. Genetic control of inflorescence in common bean.

    PubMed

    Guilherme, S R; Ramalho, M A P; de F B Abreu, A; Pereira, L A

    2014-01-01

    The number of pods per common bean plant is a primary component of grain yield, which depends on the number of flowers produced and on the flower set. Thus, a larger number of flowers per plant would increase yield. Lines with inflorescences that had a large number of flowers compared to common bean plants now under cultivation were identified. We analyzed the genetic control of this trait and its association with grain yield. The cultivar BRSMG Talismã was crossed with 2 lines, L.59583 and L.59692, which have a large number of flowers. The F1, F2, and F3 generations were obtained. These generations were assessed together with the parents in a randomized block experimental design with 2 replications. The traits assessed included length of inflorescence, number of pods per inflorescence, number of pods per plant, number of grains per plant, 100-grain weight, and grain yield per plant. Mean genetic components and variance were estimated. The traits length of inflorescence and number of pods per inflorescence exhibited genetic control with predominance that showed an additive effect. In the 2 crosses, genetic control of grain yield and of its primary components showed that the allelic interaction of dominance was high. The wide variability in the traits assessed may be used to increase yield of the common bean plant by increasing the number of flowers on the plant. PMID:25501247

  10. Is there more than one way to skin a newt? Convergent toxin resistance in snakes is not due to a common genetic mechanism.

    PubMed

    Feldman, C R; Durso, A M; Hanifin, C T; Pfrender, M E; Ducey, P K; Stokes, A N; Barnett, K E; Brodie, E D; Brodie, E D

    2016-01-01

    Convergent evolution of tetrodotoxin (TTX) resistance, at both the phenotypic and genetic levels, characterizes coevolutionary arms races between amphibians and their snake predators around the world, and reveals remarkable predictability in the process of adaptation. Here we examine the repeatability of the evolution of TTX resistance in an undescribed predator-prey relationship between TTX-bearing Eastern Newts (Notophthalmus viridescens) and Eastern Hog-nosed Snakes (Heterodon platirhinos). We found that that local newts contain levels of TTX dangerous enough to dissuade most predators, and that Eastern Hog-nosed Snakes within newt range are highly resistant to TTX. In fact, these populations of Eastern Hog-nosed Snakes are so resistant to TTX that the potential for current reciprocal selection might be limited. Unlike all other cases of TTX resistance in vertebrates, H. platirhinos lacks the adaptive amino acid substitutions in the skeletal muscle sodium channel that reduce TTX binding, suggesting that physiological resistance in Eastern Hog-nosed Snakes is conferred by an alternate genetic mechanism. Thus, phenotypic convergence in this case is not due to parallel molecular evolution, indicating that there may be more than one way for this adaptation to arise, even among closely related species. PMID:26374236

  11. Is there a Common Genetic Basis for Autoimmune Diseases?

    PubMed Central

    Anaya, Juan-Manuel; Gómez, LuisMiguel; Castiblanco, John

    2006-01-01

    Autoimmune diseases (ADs) represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the “common genetic origin” theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sjögren's (pSS) syndrome or type 1 diabetes mellitus (T1D). A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22) influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy) and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies. PMID:17162361

  12. Epigenetic Mechanisms in Commonly Occurring Cancers

    PubMed Central

    2012-01-01

    Cancer is a collection of very complex diseases that share many traits while differing in many ways as well. This makes a universal cure difficult to attain, and it highlights the importance of understanding each type of cancer at a molecular level. Although many strides have been made in identifying the genetic causes for some cancers, we now understand that simple changes in the primary DNA sequence cannot explain the many steps that are necessary to turn a normal cell into a rouge cancer cell. In recent years, some research has shifted to focusing on detailing epigenetic contributions to the development and progression of cancer. These changes occur apart from primary genomic sequences and include DNA methylation, histone modifications, and miRNA expression. Since these epigenetic modifications are reversible, drugs targeting epigenetic changes are becoming more common in clinical settings. Daily discoveries elucidating these complex epigenetic processes are leading to advances in the field of cancer research. These advances, however, come at a rapid and often overwhelming pace. This review specifically summarizes the main epigenetic mechanisms currently documented in solid tumors common in the United States and Europe. PMID:22519822

  13. Genetic High-Cholesterol Condition More Common Than Thought

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_157755.html Genetic High-Cholesterol Condition More Common Than Thought Researchers ... the United States, she said. Rates of the genetic disorder vary based on racial/ethnic background, but ...

  14. Common Gene Variants Account for Most Genetic Risk for Autism

    MedlinePlus

    ... 20, 2014 Common gene variants account for most genetic risk for autism Roles of heritability, mutations, environment ... ASD) was traced to inherited variations in the genetic code shared by many people. These and other ( ...

  15. Genetic Determinants of Osteoporosis: Common Bases to Cardiovascular Diseases?

    PubMed Central

    Marini, Francesca; Brandi, Maria Luisa

    2010-01-01

    Osteoporosis is the most common and serious age-related skeletal disorder, characterized by a low bone mass and bone microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to spontaneous fractures, and it represents a major worldwide health care problem with important implications for health care costs, morbidity and mortality. Today is well accepted that osteoporosis is a multifactorial disorder caused by the interaction between environment and genes that singularly exert modest effects on bone mass and other aspects of bone strength and fracture risk. The individuation of genetic factors responsible for osteoporosis predisposition and development is fundamental for the disease prevention and for the setting of novel therapies, before fracture occurrence. In the last decades the interest of the Scientific Community has been concentrated in the understanding the genetic bases of this disease but with controversial and/or inconclusive results. This review tries to summarize data on the most representative osteoporosis candidate genes. Moreover, since recently osteoporosis and cardiovascular diseases have shown to share common physiopathological mechanisms, this review also provides information on the current understanding of osteoporosis and cardiovascular diseases common genetic bases. PMID:20948561

  16. Genetic mechanisms of apomixis.

    PubMed Central

    Spielman, Melissa; Vinkenoog, Rinke; Scott, Rod J

    2003-01-01

    The introduction of apomixis to crops would allow desirable genotypes to be propagated while preventing undesirable gene flow, but so far there has been little success in transferring this trait from a natural apomict to another species. One explanation is the sensitivity of endosperm to changes in relative maternal and paternal contribution owing to parental imprinting, an epigenetic system of transcriptional regulation by which some genes are expressed from only the maternally or paternally contributed allele. In sexual species, endosperm typically requires a ratio of two maternal genomes to one paternal genome for normal development, but this ratio is often altered in apomicts, suggesting that the imprinting system is altered as well. We present evidence that modification of DNA methylation is one mechanism by which the imprinting system could be altered to allow endosperm development in apomicts. Another feature of natural apomixis is the modification of the normal fertilization programme. Sexual reproduction uses both sperm from each pollen grain, but pseudogamous apomicts, which require a sexual endosperm to support the asexual embryo, often use just one. We present evidence that multiple fertilization of the central cell is possible in Arabidopsis thaliana, suggesting that pseudogamous apomicts may also need to acquire a mechanism for preventing more than one sperm from contributing to the endosperm. We conclude that strategies to transfer apomixis to crop species should take account of endosperm development and particularly its sensitivity to parental imprinting, as well as the mechanism of fertilization. PMID:12831475

  17. Common genetic variants influence human subcortical brain structures

    PubMed Central

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  18. Common genetic variants influence human subcortical brain structures.

    PubMed

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy

    2015-04-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  19. Genetics Home Reference: common variable immune deficiency

    MedlinePlus

    ... H, Lougaris V, Plebani A, Gertz EM, Schäffer AA, Hammarström L, Grimbacher B. Deleterious mutations in LRBA ... 2015 Jun 19. Review. Citation on PubMed Schäffer AA, Salzer U, Hammarström L, Grimbacher B. Deconstructing common ...

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

    PubMed

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

    2013-06-01

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

  1. Space Station Freedom common berthing mechanism

    NASA Technical Reports Server (NTRS)

    Illi, Erik

    1992-01-01

    The Common Berthing Mechanism (CBM) is a generic device used to join the pressurized elements of the Space Station Freedom (SSF) utilizing the Space Shuttle Orbiter Remote Manipulator System (SRMS) or the Space Station Remote Manipulator System (SSRMS). The two berthing halves, the active, and the passive, maintain a pressurized atmosphere to allow astronaut passage, as well as to provide a structural linkage between elements. The generic design of the CBM allows any Passive Berthing Mechanism to berth with any Active Berthing Mechanism, permitting a variety of pressurized module patterns to be built.

  2. A Review of Vascular Anomalies: Genetics and Common Syndromes

    PubMed Central

    Killion, Elizabeth; Mohan, Kriti; Lee, Edward I.

    2014-01-01

    Vascular tumors and malformations are unique in that affected cells exhibit disrupted angiogenesis. The current treatment options often yield suboptimal results. New insight into the genetics and molecular basis of vascular anomalies may pave the way for potential development of targeted therapy. The authors review the genetic and molecular basis of vascular anomalies and common associated syndromes. PMID:25045331

  3. Common themes in mechanisms of gene silencing.

    PubMed

    Moazed, D

    2001-09-01

    The assembly of DNA into regions of inaccessible chromatin, called silent chromatin, is involved in the regulation of gene expression and maintenance of chromosome stability in eukaryotes. Recent studies on Sir2-containing silencing complexes in budding yeast and HP1- and Swi6-containing silencing complexes in metazoans and fission yeast suggest a common mechanism for the assembly of these domains, which involves the physical coupling of histone modifying enzymes to histone binding proteins. PMID:11583612

  4. Worldwide genetic differentiation in the common fouling barnacle, Amphibalanus amphitrite.

    PubMed

    Chen, Hsi-Nien; Tsang, Ling Ming; Chong, Ving Ching; Chan, Benny K K

    2014-10-01

    Amphibalanus amphitrite is a common fouling barnacle distributed globally in tropical and subtropical waters. In the present study, the genetic (mitochondrial cytochrome oxidase subunit I) and morphological differentiation in A. amphitrite from 25 localities around the world were investigated. The results revealed three clades within A. amphitrite with a genetic divergence of ~ 4% among clades, whereas there were no diagnostic morphological differences among clades. Clade 1 is widely distributed in both temperate and tropical waters, whereas Clade 3 is currently restricted to the tropical region. The deep divergence among clades suggests historical isolation within A. amphitrite; thus, the present geographical overlaps are possibly a result of the combined effects of rising sea level and human-mediated dispersals. This study highlights the genetic differentiation that exists in a common, widely distributed fouling organism with great dispersal potential; future antifouling research should take into account the choice of lineages. PMID:25343722

  5. Evidence of Common Genetic Overlap Between Schizophrenia and Cognition

    PubMed Central

    Hubbard, Leon; Tansey, Katherine E.; Rai, Dheeraj; Jones, Peter; Ripke, Stephan; Chambert, Kimberly D.; Moran, Jennifer L.; McCarroll, Steven A.; Linden, David E. J.; Owen, Michael J.; O’Donovan, Michael C.; Walters, James T. R.; Zammit, Stanley

    2016-01-01

    Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophrenia en masse contribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n = 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n = 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P = .001) and lower full IQ (P = .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P = 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (r G = −.379, P = 6.62E-05) and full IQ (r G = −.202, P = 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis. PMID:26678674

  6. Evidence of Common Genetic Overlap Between Schizophrenia and Cognition.

    PubMed

    Hubbard, Leon; Tansey, Katherine E; Rai, Dheeraj; Jones, Peter; Ripke, Stephan; Chambert, Kimberly D; Moran, Jennifer L; McCarroll, Steven A; Linden, David E J; Owen, Michael J; O'Donovan, Michael C; Walters, James T R; Zammit, Stanley

    2016-05-01

    Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophreniaen massecontribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n= 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n= 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P= .001) and lower full IQ (P= .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P= 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (rG= -.379,P= 6.62E-05) and full IQ (rG= -.202,P= 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis. PMID:26678674

  7. Recent progress in the genetics of common obesity

    PubMed Central

    Loos, Ruth J F

    2009-01-01

    The genetic contribution to interindividual variation in common obesity has been estimated at 40–70%. Yet, despite a relatively high heritability, the search for obesity susceptibility genes has been an arduous task. This paper reviews recent progress made in the obesity genetics field with an emphasis on established obesity susceptibility loci identified through candidate gene as well as genome-wide studies. For the last 15 years, candidate gene and genome-wide linkage studies have been the two main genetic epidemiological approaches to identify genetic loci for common traits, yet progress has been slow and success limited. Only recently have candidate gene studies started to succeed; by means of large-scale studies and meta-analyses at least five variants in four candidate genes have been found to be robustly associated with obesity-related traits. Genome-wide linkage studies, however, have so far not been able to pinpoint genetic loci for common obesity. The genome-wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries for common disease, including obesity. Three waves of large-scale high-density genome-wide association studies have already discovered at least 15 previously unanticipated genetic loci incontrovertibly associated with body mass index and extreme obesity risk. Although the combined contribution of these loci to the variation in obesity risk at the population level is small and their predictive value is typically low, these recently discovered loci are set to improve fundamentally our insights into the pathophysiology of obesity. PMID:20002076

  8. Genetic diversity analysis of common beans based on molecular markers.

    PubMed

    Gill-Langarica, Homar R; Muruaga-Martínez, José S; Vargas-Vázquez, M L Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-10-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID:22215964

  9. Genetic diversity analysis of common beans based on molecular markers

    PubMed Central

    Gill-Langarica, Homar R.; Muruaga-Martínez, José S.; Vargas-Vázquez, M.L. Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-01-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID:22215964

  10. Progress and promise in understanding the genetic basis of common diseases.

    PubMed

    Price, Alkes L; Spencer, Chris C A; Donnelly, Peter

    2015-12-22

    Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that--even at large sample sizes--these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases. PMID:26702037

  11. Progress and promise in understanding the genetic basis of common diseases

    PubMed Central

    Price, Alkes L.; Spencer, Chris C. A.; Donnelly, Peter

    2015-01-01

    Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that—even at large sample sizes—these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases. PMID:26702037

  12. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    PubMed Central

    Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

  13. Common Genetic Influences Underlie Comorbidity of Migraine and Endometriosis

    PubMed Central

    Nyholt, Dale R.; Gillespie, Nathan G.; Merikangas, Kathleen R.; Treloar, Susan A.; Martin, Nicholas G.; Montgomery, Grant W.

    2009-01-01

    We examined the co-occurrence of migraine and endometriosis within the largest known collection of families containing multiple women with surgically confirmed endometriosis and in an independent sample of 815 monozygotic and 457 dizygotic female twin pairs. Within the endometriosis families, a significantly increased risk of migrainous headache was observed in women with endometriosis compared to women without endometriosis (odds ratio [OR] 1.57, 95% confidence interval [CI]: 1.12–2.21, P = 0.009). Bivariate heritability analyses indicated no evidence for common environmental factors influencing either migraine or endometriosis but significant genetic components for both traits, with heritability estimates of 69 and 49%, respectively. Importantly, a significant additive genetic correlation (rG = 0.27, 95% CI: 0.06–0.47) and bivariate heritability (h2 = 0.17, 95% CI: 0.08–0.27) was observed between migraine and endometriosis. Controlling for the personality trait neuroticism made little impact on this association. These results confirm the previously reported comorbidity between migraine and endometriosis and indicate common genetic influences completely explain their co-occurrence within individuals. Given pharmacological treatments for endometriosis typically target hormonal pathways and a number of findings provide support for a relationship between hormonal variations and migraine, hormone-related genes and pathways are highly plausible candidates for both migraine and endometriosis. Therefore, taking into account the status of both migraine and endometriosis may provide a novel opportunity to identify the genes underlying them. Finally, we propose that the analysis of such genetically correlated comorbid traits can increase power to detect genetic risk loci through the use of more specific, homogenous and heritable phenotypes. PMID:18636479

  14. 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

  15. Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.

    PubMed

    Hulbert, S W; Jiang, Y-H

    2016-05-01

    Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit-level analysis in genetically modified models with strong construct validity. PMID:26733386

  16. 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

  17. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

    PubMed Central

    Drummond, M. Bradley; Hawkins, Gregory A.; Yang, Jenny; Chen, Ting-huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R. Graham; Bleecker, Eugene R.; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H.; Comellas, Alejandro; Crapo, James D.; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A.; Couper, David J.; Doerschuk, Claire M.; Freeman, Christine M.; Gouskova, Natalia A.; Han, MeiLan K.; Hanania, Nicola A.; Hansel, Nadia N.; Hersh, Craig P.; Hoffman, Eric A.; Kaner, Robert J.; Kanner, Richard E.; Kleerup, Eric C.; Lutz, Sharon; Martinez, Fernando J.; Meyers, Deborah A.; Peters, Stephen P.; Regan, Elizabeth A.; Rennard, Stephen I.; Scholand, Mary Beth; Silverman, Edwin K.; Woodruff, Prescott G.; O’Neal, Wanda K.; Bowler, Russell P.

    2016-01-01

    conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group. PMID:27532455

  18. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

    PubMed

    Sun, Wei; Kechris, Katerina; Jacobson, Sean; Drummond, M Bradley; Hawkins, Gregory A; Yang, Jenny; Chen, Ting-Huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R Graham; Basta, Patricia V; Bleecker, Eugene R; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H; Comellas, Alejandro; Crapo, James D; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A; Couper, David J; Curtis, Jeffrey L; Doerschuk, Claire M; Freeman, Christine M; Gouskova, Natalia A; Han, MeiLan K; Hanania, Nicola A; Hansel, Nadia N; Hersh, Craig P; Hoffman, Eric A; Kaner, Robert J; Kanner, Richard E; Kleerup, Eric C; Lutz, Sharon; Martinez, Fernando J; Meyers, Deborah A; Peters, Stephen P; Regan, Elizabeth A; Rennard, Stephen I; Scholand, Mary Beth; Silverman, Edwin K; Woodruff, Prescott G; O'Neal, Wanda K; Bowler, Russell P

    2016-08-01

    conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group. PMID:27532455

  19. Common Mechanisms Regulate Flowering and Dormancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In 1960, Chouard hypothesized that there might be a connection between vernalization (facilitation of floral competence) and release from endodormancy. In 2003, we reiterated this hypothesis and suggested potential mechanisms involving chromatin remodeling. Since then, there have been several papers...

  20. Genetic and epigenetic mechanisms of NASH.

    PubMed

    Eslam, Mohammed; George, Jacob

    2016-05-01

    Along with the obesity epidemic, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased exponentially. The histological disease spectrum of NAFLD ranges from bland fatty liver (hepatic steatosis), to the concomitant presence of inflammation and ballooning which defines nonalcoholic steatohepatitis (NASH). The latter can progress in a subset to fibrosis, leading ultimately to cirrhosis and hepatocellular carcinoma. The past decade has seen tremendous advances in our understanding of the genetic and epigenetic bases of NAFLD, mainly through the application of high end technology platforms including genome-wide association studies (GWAS). These have helped to define common gene variants (minor allele frequency >5 %) that contribute to the NAFLD phenotype. Looking to the future, these discoveries are expected to lead to improved diagnostics, the personalization of medicine, and a better understanding of the pathophysiological underpinnings that drive the transition from NAFLD to steatohepatitis and fibrosis, leading to the identification of novel therapeutic targets. In this review, we summarize data on the current state of knowledge with regard to the genetic and epigenetic mechanisms for the development of NASH. PMID:26683320

  1. 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)

  2. Genetic basis of common diseases: the general theory of Mendelian recessive genetics.

    PubMed

    Hutchinson, Michael; Spanaki, Cleanthe; Lebedev, Sergey; Plaitakis, Andreas

    2005-01-01

    Common diseases tend to appear sporadically, i.e., they appear in an individual who has no first or second degree relatives with the disease. Yet diseases are often associated with a slight but definite increase in risk to the children of an affected individual. This weak pattern of inheritability cannot be explained by conventional interpretations of Mendelian genetics, and it is therefore commonly held that there is "incomplete penetrance" of a gene, or that there are polygenic, or multifactorial modes of inheritance. However, such arguments are heuristic and lack predictive power. Here, we explore the possibility that "incomplete penetrance" means the existence of a second, disease-related, gene. By examining in detail a specific common condition, Parkinson's disease (PD), we show that the sporadic form of the disease can be fully explained by a compact fully penetrant genotype involving an interaction between two, and only two, genes. In this model, therefore PD is fundamentally genetic. Our digenic model is complementary to Mendelian recessive genetics, but taken together with the latter forms a complete description for recessive genetics on one chromosome. It explains the slight increase in risk to the children if one parent has sporadic PD, and makes strict predictions where both parents coincidentally have sporadic PD. These predictions were verified in two large and carefully selected kindred, where the data also argue against other genetic models, including oligogenic and polygenic schemes. Since the inheritance patterns of sporadic PD are reminiscent of what is seen in many common diseases, it is plausible that similar genetic forms could apply to other diseases. Seen in this light, diseases wash in and out of every family, so that in a sense, over time every human family is equally at risk for most diseases. PMID:15922101

  3. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.

    PubMed

    Maffucci, Patrick; Filion, Charles A; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  4. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

    PubMed Central

    Maffucci, Patrick; Filion, Charles A.; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  5. Common Genetic Variants and Response to Atrial Fibrillation Ablation

    PubMed Central

    Shoemaker, M. Benjamin; Bollmann, Andreas; Lubitz, Steven A.; Ueberham, Laura; Saini, Harsimran; Montgomery, Jay; Edwards, Todd; Yoneda, Zachary; Sinner, Moritz F.; Arya, Arash; Sommer, Philipp; Delaney, Jessica; Goyal, Sandeep K.; Saavedra, Pablo; Kanagasundram, Arvindh; Whalen, S. Patrick; Roden, Dan M.; Hindricks, Gerhard; Ellis, Christopher R.; Ellinor, Patrick T.; Darbar, Dawood; Husser, Daniela

    2016-01-01

    Background Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation. Methods and Results Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio, 1.3 [95% confidence intervals, 1.1–1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence. Conclusions Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF. PMID:25684755

  6. Genetics of Common Antipsychotic-Induced Adverse Effects.

    PubMed

    MacNeil, Raymond R; Müller, Daniel J

    2016-07-01

    The effectiveness of antipsychotic drugs is limited due to accompanying adverse effects which can pose considerable health risks and lead to patient noncompliance. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual susceptibility to antipsychotic-induced adverse effects (AAEs), thereby improving clinical outcomes. We reviewed the literature on the PGx of common AAEs from 2010 to 2015, placing emphasis on findings that have been independently replicated and which have additionally been listed to be of interest by PGx expert panels. Gene-drug associations meeting these criteria primarily pertain to metabolic dysregulation, extrapyramidal symptoms (EPS), and tardive dyskinesia (TD). Regarding metabolic dysregulation, results have reaffirmed HTR2C as a strong candidate with potential clinical utility, while MC4R and OGFR1 gene loci have emerged as new and promising biomarkers for the prediction of weight gain. As for EPS and TD, additional evidence has accumulated in support of an association with CYP2D6 metabolizer status. Furthermore, HSPG2 and DPP6 have been identified as candidate genes with the potential to predict differential susceptibility to TD. Overall, considerable progress has been made within the field of psychiatric PGx, with inroads toward the development of clinical tools that can mitigate AAEs. Going forward, studies placing a greater emphasis on multilocus effects will need to be conducted. PMID:27606321

  7. Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish.

    PubMed

    Selwyn, Jason D; Hogan, J Derek; Downey-Wall, Alan M; Gurski, Lauren M; Portnoy, David S; Heath, Daniel D

    2016-01-01

    The phenomenon of chaotic genetic patchiness is a pattern commonly seen in marine organisms, particularly those with demersal adults and pelagic larvae. This pattern is usually associated with sweepstakes recruitment and variable reproductive success. Here we investigate the biological underpinnings of this pattern in a species of marine goby Coryphopterus personatus. We find that populations of this species show tell-tale signs of chaotic genetic patchiness including: small, but significant, differences in genetic structure over short distances; a non-equilibrium or "chaotic" pattern of differentiation among locations in space; and within locus, within population deviations from the expectations of Hardy-Weinberg equilibrium (HWE). We show that despite having a pelagic larval stage, and a wide distribution across Caribbean coral reefs, this species forms groups of highly related individuals at small spatial scales (<10 metres). These spatially clustered family groups cause the observed deviations from HWE and local population differentiation, a finding that is rarely demonstrated, but could be more common than previously thought. PMID:27119659

  8. Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish

    PubMed Central

    Hogan, J. Derek; Downey-Wall, Alan M.; Gurski, Lauren M.; Portnoy, David S.; Heath, Daniel D.

    2016-01-01

    The phenomenon of chaotic genetic patchiness is a pattern commonly seen in marine organisms, particularly those with demersal adults and pelagic larvae. This pattern is usually associated with sweepstakes recruitment and variable reproductive success. Here we investigate the biological underpinnings of this pattern in a species of marine goby Coryphopterus personatus. We find that populations of this species show tell-tale signs of chaotic genetic patchiness including: small, but significant, differences in genetic structure over short distances; a non-equilibrium or “chaotic” pattern of differentiation among locations in space; and within locus, within population deviations from the expectations of Hardy-Weinberg equilibrium (HWE). We show that despite having a pelagic larval stage, and a wide distribution across Caribbean coral reefs, this species forms groups of highly related individuals at small spatial scales (<10 metres). These spatially clustered family groups cause the observed deviations from HWE and local population differentiation, a finding that is rarely demonstrated, but could be more common than previously thought. PMID:27119659

  9. Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology

    PubMed Central

    Port, Russell G.; Gandal, Michael J.; Roberts, Timothy P. L.; Siegel, Steven J.; Carlson, Gregory C.

    2014-01-01

    Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD. PMID:25538564

  10. Molecular mechanisms of genetic adaptation to xenobiotic compounds.

    PubMed Central

    van der Meer, J R; de Vos, W M; Harayama, S; Zehnder, A J

    1992-01-01

    Microorganisms in the environment can often adapt to use xenobiotic chemicals as novel growth and energy substrates. Specialized enzyme systems and metabolic pathways for the degradation of man-made compounds such as chlorobiphenyls and chlorobenzenes have been found in microorganisms isolated from geographically separated areas of the world. The genetic characterization of an increasing number of aerobic pathways for degradation of (substituted) aromatic compounds in different bacteria has made it possible to compare the similarities in genetic organization and in sequence which exist between genes and proteins of these specialized catabolic routes and more common pathways. These data suggest that discrete modules containing clusters of genes have been combined in different ways in the various catabolic pathways. Sequence information further suggests divergence of catabolic genes coding for specialized enzymes in the degradation of xenobiotic chemicals. An important question will be to find whether these specialized enzymes evolved from more common isozymes only after the introduction of xenobiotic chemicals into the environment. Evidence is presented that a range of genetic mechanisms, such as gene transfer, mutational drift, and genetic recombination and transposition, can accelerate the evolution of catabolic pathways in bacteria. However, there is virtually no information concerning the rates at which these mechanisms are operating in bacteria living in nature and the response of such rates to the presence of potential (xenobiotic) substrates. Quantitative data on the genetic processes in the natural environment and on the effect of environmental parameters on the rate of evolution are needed. PMID:1480115

  11. NIH Scientists Map Genetic Changes That Drive Tumors in a Common Pediatric Soft-Tissue Cancer

    MedlinePlus

    ... Press Releases NCI Press Release NIH scientists map genetic changes that drive tumors in a common pediatric ... Office 301-496-6641 Scientists have mapped the genetic changes that drive tumors in rhabdomyosarcoma, a pediatric ...

  12. Race, Common Genetic Variation, and Therapeutic Response Disparities in Heart Failure

    PubMed Central

    Taylor, Mathew R.; Sun, Albert Y.; Davis, Gordon; Fiuzat, Mona; Liggett, Stephen B.; Bristow, Michael R.

    2015-01-01

    Because of its relatively recent evolution, Homo sapiens exhibits relatively little within-species genomic diversity. However, because of genome size, a proportionally small amount of variation creates ample opportunity for both rare mutations that may be disease-causative as well as more common genetic variation that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. These population effects extend to differences in the frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data on genetic variation between AA and EA populations. The data indicate that 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents, 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA vs. EA individuals, and 3) in many cases these differences likely play a role in observed racial differences in drug or device response. PMID:25443111

  13. Do common eiders nest in kin groups? Microgeographic genetic structure in a philopatric sea duck

    USGS Publications Warehouse

    Sonsthagen, S.A.; Talbot, S.L.; Lanctot, Richard B.; McCracken, K.G.

    2010-01-01

    We investigated local genetic associations among female Pacific common eiders (Somateria mollissima v-nigrum) nesting in a stochastic Arctic environment within two groups of barrier islands (Simpson Lagoon and Mikkelsen Bay) in the Beaufort Sea, Alaska. Nonrandom genetic associations were observed among nesting females using regional spatial autocorrelation analyses for distance classes up to 1000 m in Simpson Lagoon. Nearest-neighbour analyses identified clusters of genetically related females with positive lr values observed for 0-13% and 0-7% of the comparisons in Simpson Lagoon and Mikkelsen Bay, respectively, across years. These results indicate that a proportion of females are nesting in close proximity to more genetically related individuals, albeit at low frequency. Such kin groupings may form through active association between relatives or through natal philopatry and breeding site fidelity. Eiders nest in close association with driftwood, which is redistributed annually by seasonal storms. Yet, genetic associations were still observed. Microgeographic structure may thus be more attributable to kin association than natal philopatry and site fidelity. However, habitat availability may also influence the level of structure observed. Regional structure was present only within Simpson Lagoon and this island group includes at least three islands with sufficient driftwood for colonies, whereas only one island at Mikkelsen Bay has these features. A long-term demographic study is needed to understand more fully the mechanisms that lead to fine-scale genetic structure observed in common eiders breeding in the Beaufort Sea. ?? Published 2010. This article is a US Government work and is in the public domain in the USA.

  14. The genetics of insomnia--evidence for epigenetic mechanisms?

    PubMed

    Palagini, Laura; Biber, Knut; Riemann, Dieter

    2014-06-01

    Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic

  15. Mechanical design of a high field common coil magnet

    SciTech Connect

    Caspi, S.; Chow, K.; Dietderich, D.; Gourlay, S.; Gupta, R.; McInturff, A.; Millos, G.; Scanlan, R.

    1999-03-18

    A common coil design for high field 2-in-1 accelerator magnets has been previously presented as a 'conductor-friendly' option for high field magnets applicable for a Very Large Hadron Collider. This paper presents the mechanical design for a 14 tesla 2-in-1 dipole based on the common coil design approach. The magnet will use a high current density Nb{sub 3}Sn conductor. The design addresses mechanical issues particular to the common coil geometry: horizontal support against coil edges, vertical preload on coil faces, end loading and support, and coil stresses and strains. The magnet is the second in a series of racetrack coil magnets that will provide experimental verification of the common coil design approach.

  16. [Progress in the molecular genetic mechanism of gonadoblastoma].

    PubMed

    Lili, Yu; Wanru, Dong; Minghui, Chen; Xiangyang, Kong

    2015-11-01

    Gonadoblastoma (GB), a rare in situ germ cell tumor derived from sex cord and germ cells, is closely associated with gonadal dysgenesis. About 80% of GB individuals exhibit 46, XY female phenotype while the others are 45, XY and 46, XX with disorders of sex development. Moreover, 35% of GB can eventually develop into malignant tumors, such as seminoma and dysgerminoma tumors. The molecular genetic mechanism of GB remains to be fully uncovered due to phenotypic and genetic heterogeneity. Increasing studies show that the formation of GB is closely related to genes regulating sexual differentiation and determination (e.g., SRY, WT1, SOX9, Foxl2, TSPY, etc), and is affected by the interaction of genetic and epigenetic regulation. Here we describe the clinical and pathological features, diagnosis and treatment of GB, and also summarize the molecular genetic and epigenetic mechanisms underlying the gonadal abnormalities that lead to GB. We analyze and construct the common gene regulatory networks related to the development of GB, and describe some obstacles and deficiencies in current studies to provide innovative perspectives on further studying the pathological and molecular mechanisms of GB. PMID:26582524

  17. Genome-wide genetic investigation of serological measures of common infections.

    PubMed

    Rubicz, Rohina; Yolken, Robert; Drigalenko, Eugene; Carless, Melanie A; Dyer, Thomas D; Kent, Jack; Curran, Joanne E; Johnson, Matthew P; Cole, Shelley A; Fowler, Sharon P; Arya, Rector; Puppala, Sobha; Almasy, Laura; Moses, Eric K; Kraig, Ellen; Duggirala, Ravindranath; Blangero, John; Leach, Charles T; Göring, Harald H H

    2015-11-01

    Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from >1300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using ~1 million SNPs. Significant linkage (lod scores >3.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P=5.3 × 10(-8)). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels. PMID:25758998

  18. Common mechanism underlies repeated evolution of extreme pollution tolerance

    PubMed Central

    Whitehead, Andrew; Pilcher, Whitney; Champlin, Denise; Nacci, Diane

    2012-01-01

    Human alterations to the environment can exert strong evolutionary pressures, yet contemporary adaptation to human-mediated stressors is rarely documented in wildlife populations. A common-garden experimental design was coupled with comparative transcriptomics to discover evolved mechanisms enabling three populations of killifish resident in urban estuaries to survive normally lethal pollution exposure during development, and to test whether mechanisms are unique or common across populations. We show that killifish populations from these polluted sites have independently converged on a common adaptive mechanism, despite variation in contaminant profiles among sites. These populations are united by a similarly profound desensitization of aryl-hydrocarbon receptor-mediated transcriptional activation, which is associated with extreme tolerance to the lethal effects of toxic dioxin-like pollutants. The rapid, repeated, heritable and convergent nature of evolved tolerance suggests that ancestral killifish populations harboured genotypes that enabled adaptation to twentieth-century industrial pollutants. PMID:21733895

  19. Genetics and Common Disorders: Implications for Primary Care and Public Health Providers

    SciTech Connect

    McInerney, Joseph D.; Greendale, Karen; Peay, Holly L.

    2005-06-01

    We developed this program for primary care providers (PCPs) and public health professionals (PHPs) who are interested in increasing their understanding of the genetics of common chronic diseases and of the implications of genetics and genomics for their fields. The program differs from virtually all previous educational efforts in genetics for health professionals in that it focuses on the genetics of common chronic disease and on the broad principles that emerge when one views disease from the perspectives of variation and individuality, which are at the heart of thinking genetically. The CD-ROM introduces users to content that will improve their understanding of topics such as: • A framework for genetics and common disease; • Basic information on genetics, genomics, genetic medicine, and public health genetics, all in the context of common chronic disease; • The status of research on genetic contributions to specific common diseases, including a review of research methods; • Genetic/environmental interaction as the new “central dogma” of public health genetics; • The importance of taking and analyzing a family history; • The likely impact of potential gene discovery and genetic testing on genetic counseling and risk assessment and on the practices of PCPs and PHPs; • Stratification of populations into low-, moderate-, and high-risk categories; • The potential role of PCPs and PHPs in identifying high-risk individuals and families, in providing limited genetics services, and in referring to clinical genetics specialists; the potential for standard referral algorithms; • Implications of genetic insights for diagnosis and treatment; • Ethical, legal, and social issues that arise from genetic testing for common chronic diseases; and • Specific prevention strategies based on understanding of genetics and genetic/ environmental interactions. The interactive content – developed by experts in genetics, primary care, and public health – is

  20. Genetic mechanisms involved in the phenotype of Down syndrome.

    PubMed

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA sequencing and annotation of the long arm of chromosome 21 was a critical step towards understanding the genetics of the phenotype. However, annotation of the chromosome continues and the functions of many genes on chromosome 21 remain uncertain. Recent findings about the structure of the human genome and of chromosome 21, in particular, and studies on mechanisms of gene regulation indicate that various genetic mechanisms may be contributors to the phenotype of DS and to the variability of the phenotype. These include variability of gene expression, the activity of transcription factors both encoded on chromosome 21 and encoded elsewhere in the genome, copy number polymorphisms, the function of conserved nongenic regions, microRNA activities, RNA editing, and perhaps DNA methylation. In this manuscript, we describe current knowledge about these genetic complexities and their likely importance in the context of DS. We identify gaps in current knowledge and suggest priorities to fill these gaps. PMID:17910086

  1. Genetic animal models of dystonia: common features and diversities.

    PubMed

    Richter, Franziska; Richter, Angelika

    2014-10-01

    Animal models are pivotal for studies of pathogenesis and treatment of disorders of the central nervous system which in its complexity cannot yet be modeled in vitro or using computer simulations. The choice of a specific model to test novel therapeutic strategies for a human disease should be based on validity of the model for the approach: does the model reflect symptoms, pathogenesis and treatment response present in human patients? In the movement disorder dystonia, prior to the availability of genetically engineered mice, spontaneous mutants were chosen based on expression of dystonic features, including abnormal muscle contraction, movements and postures. Recent discovery of a number of genes and gene products involved in dystonia initiated research on pathogenesis of the disorder, and the creation of novel models based on gene mutations. Here we present a review of current models of dystonia, with a focus on genetic rodent models, which will likely be first choice in the future either for pathophysiological or for preclinical drug testing or both. In order to help selection of a model depending on expression of a specific feature of dystonia, this review is organized by symptoms and current knowledge of pathogenesis of dystonia. We conclude that albeit there is increasing need for research on pathogenesis of the disease and development of improved models, current models do replicate features of dystonia and are useful tools to develop urgently demanded treatment for this debilitating disorder. PMID:25034123

  2. [Genetic polymorphisms commonly influencing efficacy of diverse addictive substances].

    PubMed

    Nishizawa, Daisuke; Ikeda, Kazutaka

    2014-04-01

    Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. The authors have focused on G-protein-activated inwardly rectifying potassium (GIRK) channel subunits, GIRK2 and GIRK3, that are important molecules in opioid transmission, and found that the single-nucleotide polymorphisms (SNPs) within the GIRK2 and GIRK3 gene regions were significantly associated with postoperative requirements of analgesics including opioids in patients who underwent abdominal surgery and mRNA expression of these genes in postmortem specimens, one of which was also associated with vulnerability to methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate SNP, rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. The results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. These outcomes provide valuable information for the

  3. Genetic location of genes encoding enterobacterial common antigen.

    PubMed Central

    Meier, U; Mayer, H

    1985-01-01

    A new rff mutation (rff-726) of Escherichia coli is described which affects the biosynthesis of the enterobacterial common antigen. This mutation was detected in an rfe-defective strain. A Tn10 insertion near the rfe locus was isolated to facilitate further mapping. Both mutations rfe and rff were mapped by transduction with bacteriophage P1, giving the gene order ilv rfe rff uvrD metE. The F' factor F14 was able to complement both mutations rfe and rff, whereas the F' factor F16 could complement the rfe but not the rff mutation. The rff mutation did not affect the biosynthesis of N-acetyl-D-mannosaminuronic acid, as the previously described rff mutations in Salmonella typhimurium do (H. C. Lew, H. Nikaido, and P. H. Mäkelä, J. Bacteriol. 136:227-233, 1978), and also did not affect the biosynthesis of other enterobacterial common antigen components; however, the biosynthesis of the complete enterobacterial common antigen molecule was blocked. PMID:3894334

  4. Genetic prediction of common diseases. Still no help for the clinical diabetologist!

    PubMed Central

    Prudente, Sabrina; Dallapiccola, Bruno; Pellegrini, Fabio; Doria, Alessandro; Trischitta, Vincenzo

    2013-01-01

    Genome-wide association studies (GWAS) have identified several loci associated with many common, multifactorial diseases which have been recently used to market genetic testing directly to the consumers. We here addressed the clinical utility of such GWAS-derived genetic information in predicting type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in diabetic patients. In addition, the development of new statistical approaches, novel technologies of genome sequencing and ethical, legal and social aspects related to genetic testing have been also addressed. Available data clearly show that, similarly to what reported for most common diseases, genetic testing offered today by commercial companies cannot be used as predicting tools for T2DM and CAD, both in the general and in the diabetic population. Further studies taking into account the complex interaction between genes as well as between genetic and non genetic factors, including age, obesity and glycemic control which seem to modify genetic effects on the risk of T2DM and CAD, might mitigate such negative conclusions. Also, addressing the role of relatively rare variants by next-generation sequencing may help identify novel and strong genetic markers with an important role in genetic prediction. Finally, statistical tools concentrated on reclassifying patients might be a useful application of genetic information for predicting many common diseases. By now, prediction of such diseases, including those of interest for the clinical diabetologist, have to be pursued by using traditional clinical markers which perform well and are not costly. PMID:22819342

  5. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    PubMed Central

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-01-01

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins. PMID:26959016

  6. Genetics and pathological mechanisms of Usher syndrome.

    PubMed

    Yan, Denise; Liu, Xue Z

    2010-06-01

    Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder. PMID:20379205

  7. Kidney and eye diseases: common risk factors, etiological mechanisms, and pathways.

    PubMed

    Wong, Chee Wai; Wong, Tien Yin; Cheng, Ching-Yu; Sabanayagam, Charumathi

    2014-06-01

    Chronic kidney disease is an emerging health problem worldwide. The eye shares striking structural, developmental, and genetic pathways with the kidney, suggesting that kidney disease and ocular disease may be closely linked. A growing number of studies have found associations of chronic kidney disease with age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract. In addition, retinal microvascular parameters have been shown to be predictive of chronic kidney disease. Chronic kidney disease shares common vascular risk factors including diabetes, hypertension, smoking, and obesity, and pathogenetic mechanisms including inflammation, oxidative stress, endothelial dysfunction, and microvascular dysfunction, with ocular diseases supporting the 'Common Soil Hypothesis.' In this review, we present major epidemiological evidence for these associations and explore underlying pathogenic mechanisms and common risk factors for kidney and ocular disease. Understanding the link between kidney and ocular disease can lead to the development of new treatment and screening strategies for both diseases. PMID:24336029

  8. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases

    PubMed Central

    Wynn, Thomas A.

    2007-01-01

    Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies. PMID:17332879

  9. Common and Rare Genetic Variants Associated With Alzheimer's Disease.

    PubMed

    Marei, Hany E; Althani, Asmaa; Suhonen, Jaana; El Zowalaty, Mohamed E; Albanna, Mohammad A; Cenciarelli, Carlo; Wang, Tengfei; Caceci, Thomas

    2016-07-01

    Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets. J. Cell. Physiol. 231: 1432-1437, 2016. © 2015 Wiley Periodicals, Inc. PMID:26496533

  10. Cognitive impairments in psychotic disorders: common mechanisms and measurement

    PubMed Central

    Barch, Deanna M; Sheffield, Julia M

    2014-01-01

    Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a “generalized deficit”, in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM-5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders. PMID:25273286

  11. GATOR1 complex: the common genetic actor in focal epilepsies.

    PubMed

    Baldassari, Sara; Licchetta, Laura; Tinuper, Paolo; Bisulli, Francesca; Pippucci, Tommaso

    2016-08-01

    The mammalian or mechanistic target of rapamycin (mTOR) signalling pathway has multiple roles in regulating physiology of the whole body and, particularly, the brain. Deregulation of mTOR signalling has been associated to various neurological conditions, including epilepsy. Mutations in genes encoding components of Gap Activity TOward Rags 1 (GATOR1) (DEPDC5, NPRL2 and NPRL3), a complex involved in the inhibition of the mTOR complex 1 (mTORC1), have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), both lesional and non-lesional. The involvement of DEPDC5, NPRL2 and NRPL3 in about 10% of FEs is in contrast to the concept that specific seizure semiology points to the main involvement of a distinct brain area. The hypothesised pathogenic mechanism underlying epilepsy is the loss of the inhibitory function of GATOR1 towards mTORC1. The identification of the correct therapeutic strategy in patients with FE is challenging, especially in those with refractory epilepsy and/or malformations of cortical development (MCDs). In such cases, surgical excision of the epileptogenic zone is a curative option, although the long-term outcome is still undefined. The GATOR1/mTOR signalling represents a promising therapeutic target in FEs due to mutations in mTOR pathway genes, as in tuberous sclerosis complex, another MCD-associated epilepsy caused by mTOR signalling hyperactivation. PMID:27208208

  12. A Rapid Genetic Assay for the Identification of the Most Common Pocillopora damicornis Genetic Lineages on the Great Barrier Reef

    PubMed Central

    Torda, Gergely; Schmidt-Roach, Sebastian; Peplow, Lesa M.; Lundgren, Petra; van Oppen, Madeleine J. H.

    2013-01-01

    Pocillopora damicornis (Linnaeus, 1758; Scleractinia, Pocilloporidae) has recently been found to comprise at least five distinct genetic lineages in Eastern Australia, some of which likely represent cryptic species. Due to similar and plastic gross morphology of these lineages, field identification is often difficult. Here we present a quick, cost effective genetic assay as well as three novel microsatellite markers that distinguish the two most common lineages found on the Great Barrier Reef. The assay is based on PCR amplification of two regions within the mitochondrial putative control region, which show consistent and easily identifiable fragment size differences for the two genetic lineages after Alu1 restriction enzyme digestion of the amplicons. PMID:23505507

  13. Genome-Wide Association Studies: Progress in Identifying Genetic Biomarkers in Common, Complex Diseases

    PubMed Central

    Kingsmore, Stephen F.; Lindquist, Ingrid E.; Mudge, Joann; Beavis, William D.

    2007-01-01

    Novel, comprehensive approaches for biomarker discovery and validation are urgently needed. One particular area of methodologic need is for discovery of novel genetic biomarkers in complex diseases and traits. Here, we review recent successes in the use of genome wide association (GWA) approaches to identify genetic biomarkers in common human diseases and traits. Such studies are yielding initial insights into the allelic architecture of complex traits. In general, it appears that complex diseases are associated with many common polymorphisms, implying profound genetic heterogeneity between affected individuals. PMID:19662211

  14. Common mechanisms of human perceptual and motor learning

    PubMed Central

    Censor, Nitzan; Sagi, Dov; Cohen, Leonardo G.

    2016-01-01

    The adult mammalian brain has a remarkable capacity to learn in both the perceptual and motor domains through the formation and consolidation of memories. Such practice-enabled procedural learning results in perceptual and motor skill improvements. Here, we examine evidence supporting the notion that perceptual and motor learning in humans exhibit analogous properties, including similarities in temporal dynamics and the interactions between primary cortical and higher-order brain areas. These similarities may point to the existence of a common general mechanism for learning in humans. PMID:22903222

  15. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

    PubMed Central

    Bennett, Brian J.; Davis, Richard C.; Civelek, Mete; Orozco, Luz; Wu, Judy; Qi, Hannah; Pan, Calvin; Packard, René R. Sevag; Eskin, Eleazar; Yan, Mujing; Kirchgessner, Todd; Wang, Zeneng; Li, Xinmin; Gregory, Jill C.; Hazen, Stanley L.; Gargalovic, Peter S.; Lusis, Aldons J.

    2015-01-01

    Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression

  16. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.

    PubMed

    Bennett, Brian J; Davis, Richard C; Civelek, Mete; Orozco, Luz; Wu, Judy; Qi, Hannah; Pan, Calvin; Packard, René R Sevag; Eskin, Eleazar; Yan, Mujing; Kirchgessner, Todd; Wang, Zeneng; Li, Xinmin; Gregory, Jill C; Hazen, Stanley L; Gargalovic, Peter S; Lusis, Aldons J

    2015-12-01

    Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression

  17. PRELIMINARY ANALYSIS OF COMMON LOON GENETIC STRUCTURE IN NORTH AMERICA BASED ON FIVE MICROSATELLITE LOCI

    EPA Science Inventory

    This study seeks to determine fine-scale genetic structure of Common Loon breeding populations in order to link wintering birds with their breeding regions. Common Loons are large piscivorous birds that breed in lakes of northern North America and Iceland. Loons are highly phil...

  18. Intraspecific morphological and genetic variation of common species predicts ranges of threatened ones.

    PubMed

    Fuller, Trevon L; Thomassen, Henri A; Peralvo, Manuel; Buermann, Wolfgang; Milá, Borja; Kieswetter, Charles M; Jarrín-V, Pablo; Devitt, Susan E Cameron; Mason, Eliza; Schweizer, Rena M; Schlunegger, Jasmin; Chan, Janice; Wang, Ophelia; Schneider, Christopher J; Pollinger, John P; Saatchi, Sassan; Graham, Catherine H; Wayne, Robert K; Smith, Thomas B

    2013-06-01

    Predicting where threatened species occur is useful for making informed conservation decisions. However, because they are usually rare, surveying threatened species is often expensive and time intensive. Here, we show how regions where common species exhibit high genetic and morphological divergence among populations can be used to predict the occurrence of species of conservation concern. Intraspecific variation of common species of birds, bats and frogs from Ecuador were found to be a significantly better predictor for the occurrence of threatened species than suites of environmental variables or the occurrence of amphibians and birds. Fully 93 per cent of the threatened species analysed had their range adequately represented by the geographical distribution of the morphological and genetic variation found in seven common species. Both higher numbers of threatened species and greater genetic and morphological variation of common species occurred along elevation gradients. Higher levels of intraspecific divergence may be the result of disruptive selection and/or introgression along gradients. We suggest that collecting data on genetic and morphological variation in common species can be a cost effective tool for conservation planning, and that future biodiversity inventories include surveying genetic and morphological data of common species whenever feasible. PMID:23595273

  19. Intraspecific morphological and genetic variation of common species predicts ranges of threatened ones

    PubMed Central

    Fuller, Trevon L.; Thomassen, Henri A.; Peralvo, Manuel; Buermann, Wolfgang; Milá, Borja; Kieswetter, Charles M.; Jarrín-V, Pablo; Devitt, Susan E. Cameron; Mason, Eliza; Schweizer, Rena M.; Schlunegger, Jasmin; Chan, Janice; Wang, Ophelia; Schneider, Christopher J.; Pollinger, John P.; Saatchi, Sassan; Graham, Catherine H.; Wayne, Robert K.; Smith, Thomas B.

    2013-01-01

    Predicting where threatened species occur is useful for making informed conservation decisions. However, because they are usually rare, surveying threatened species is often expensive and time intensive. Here, we show how regions where common species exhibit high genetic and morphological divergence among populations can be used to predict the occurrence of species of conservation concern. Intraspecific variation of common species of birds, bats and frogs from Ecuador were found to be a significantly better predictor for the occurrence of threatened species than suites of environmental variables or the occurrence of amphibians and birds. Fully 93 per cent of the threatened species analysed had their range adequately represented by the geographical distribution of the morphological and genetic variation found in seven common species. Both higher numbers of threatened species and greater genetic and morphological variation of common species occurred along elevation gradients. Higher levels of intraspecific divergence may be the result of disruptive selection and/or introgression along gradients. We suggest that collecting data on genetic and morphological variation in common species can be a cost effective tool for conservation planning, and that future biodiversity inventories include surveying genetic and morphological data of common species whenever feasible. PMID:23595273

  20. Common mechanisms of pain and depression: are antidepressants also analgesics?

    PubMed Central

    Nekovarova, Tereza; Yamamotova, Anna; Vales, Karel; Stuchlik, Ales; Fricova, Jitka; Rokyta, Richard

    2014-01-01

    Neither pain, nor depression exist as independent phenomena per se, they are highly subjective inner states, formed by our brain and built on the bases of our experiences, cognition and emotions. Chronic pain is associated with changes in brain physiology and anatomy. It has been suggested that the neuronal activity underlying subjective perception of chronic pain may be divergent from the activity associated with acute pain. We will discuss the possible common pathophysiological mechanism of chronic pain and depression with respect to the default mode network of the brain, neuroplasticity and the effect of antidepressants on these two pathological conditions. The default mode network of the brain has an important role in the representation of introspective mental activities and therefore can be considered as a nodal point, common for both chronic pain and depression. Neuroplasticity which involves molecular, cellular and synaptic processes modifying connectivity between neurons and neuronal circuits can also be affected by pathological states such as chronic pain or depression. We suppose that pathogenesis of depression and chronic pain shares common negative neuroplastic changes in the central nervous system (CNS). The positive impact of antidepressants would result in a reduction of these pathological cellular/molecular processes and in the amelioration of symptoms, but it may also increase survival times and quality of life of patients with chronic cancer pain. PMID:24723864

  1. [Embryological and genetic mechanisms of cardiac great arteries malformations].

    PubMed

    Bonnet, Damien; Zaffran, Stéphane; Kelly, Robert; Bajolle, Fanny

    2009-01-01

    Developmental genetics of congenital heart diseases have evolved from analysis of embryonic hearts towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Ablation techniques, transgenic animal models and clonal analysis of the developing heart led to identification of different cardiac lineages and their respective roles. The mechanistic approach for great arteries anomalies has led to emerging concepts such as common embryological origin of anatomically different cardiac defects, phenotypic continuum of left heart obstructive defects, or developmental algorithms for cardiac isomerisms. Recent experiments that demonstrated the myocardial rotation of the outflow tract in mouse embryos led to a better understanding of the origin of transposition of the large arteries. This has also raised the hypothesis of a new group of congenital heart anomalies defined as laterality defects limited to a segment of the embryonic heart. These results confirm that genetic heterogeneity of congenital heart defects is related to the heterogeneity of the mechanisms that finally produce the same phenotype. PMID:19527629

  2. Drosophila Neurotrophins Reveal a Common Mechanism for Nervous System Formation

    PubMed Central

    McQuilton, Peter; Forero, Manuel G; Mizuguchi, Kenji; Sutcliffe, Ben; Gu, Chun-Jing; Fenton, Janine C; Hidalgo, Alicia

    2008-01-01

    Neurotrophic interactions occur in Drosophila, but to date, no neurotrophic factor had been found. Neurotrophins are the main vertebrate secreted signalling molecules that link nervous system structure and function: they regulate neuronal survival, targeting, synaptic plasticity, memory and cognition. We have identified a neurotrophic factor in flies, Drosophila Neurotrophin (DNT1), structurally related to all known neurotrophins and highly conserved in insects. By investigating with genetics the consequences of removing DNT1 or adding it in excess, we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. We show that Spätzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. Our findings imply that most likely a neurotrophin was present in the common ancestor of all bilateral organisms, giving rise to invertebrate and vertebrate neurotrophins through gene or whole-genome duplications. This work provides a missing link between aspects of neuronal function in flies and vertebrates, and it opens the opportunity to use Drosophila to investigate further aspects of neurotrophin function and to model related diseases. PMID:19018662

  3. Genetic diversity in cultivated carioca common beans based on molecular marker analysis

    PubMed Central

    Küpper Cardoso Perseguini, Juliana Morini; Chioratto, Alisson Fernando; Zucchi, Maria Imaculada; Colombo, Carlos Augusto; Carbonell, Sérgio Augusto Moraes; Costa Mondego, Jorge Mauricio; Gazaffi, Rodrigo; Franco Garcia, Antonio Augusto; de Campos, Tatiana; de Souza, Anete Pereira; Rubiano, Luciana Benchimol

    2011-01-01

    A wide array of molecular markers has been used to investigate the genetic diversity among common bean species. However, the best combination of markers for studying such diversity among common bean cultivars has yet to be determined. Few reports have examined the genetic diversity of the carioca bean, commercially one of the most important common beans in Brazil. In this study, we examined the usefulness of two molecular marker systems (simple sequence repeats – SSRs and amplified fragment length polymorphisms – AFLPs) for assessing the genetic diversity of carioca beans. The amount of information provided by Roger’s modified genetic distance was used to analyze SSR data and Jaccards similarity coefficient was used for AFLP data. Seventy SSRs were polymorphic and 20 AFLP primer combinations produced 635 polymorphic bands. Molecular analysis showed that carioca genotypes were quite diverse. AFLPs revealed greater genetic differentiation and variation within the carioca genotypes (Gst = 98% and Fst = 0.83, respectively) than SSRs and provided better resolution for clustering the carioca genotypes. SSRs and AFLPs were both suitable for assessing the genetic diversity of Brazilian carioca genotypes since the number of markers used in each system provided a low coefficient of variation. However, fingerprint profiles were generated faster with AFLPs, making them a better choice for assessing genetic diversity in the carioca germplasm. PMID:21637550

  4. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

    PubMed Central

    Kasperavičiūtė, Dalia; Catarino, Claudia B.; Heinzen, Erin L.; Depondt, Chantal; Cavalleri, Gianpiero L.; Caboclo, Luis O.; Tate, Sarah K.; Jamnadas-Khoda, Jenny; Chinthapalli, Krishna; Clayton, Lisa M.S.; Shianna, Kevin V.; Radtke, Rodney A.; Mikati, Mohamad A.; Gallentine, William B.; Husain, Aatif M.; Alhusaini, Saud; Leppert, David; Middleton, Lefkos T.; Gibson, Rachel A.; Johnson, Michael R.; Matthews, Paul M.; Hosford, David; Heuser, Kjell; Amos, Leslie; Ortega, Marcos; Zumsteg, Dominik; Wieser, Heinz-Gregor; Steinhoff, Bernhard J.; Krämer, Günter; Hansen, Jörg; Dorn, Thomas; Kantanen, Anne-Mari; Gjerstad, Leif; Peuralinna, Terhi; Hernandez, Dena G.; Eriksson, Kai J.; Kälviäinen, Reetta K.; Doherty, Colin P.; Wood, Nicholas W.; Pandolfo, Massimo; Duncan, John S.; Sander, Josemir W.; Delanty, Norman

    2010-01-01

    Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies. PMID:20522523

  5. Human CD1a-deficiency is Common and Genetically Regulated1

    PubMed Central

    Seshadri, Chetan; Shenoy, Meera; Wells, Richard D.; Hensley, Tiffany; Andersen-Nissen, Erica; McElrath, M. Juliana; Cheng, Tan-Yun; Moody, D. Branch; Hawn, Thomas R.

    2013-01-01

    CD1 proteins evolved to present diverse lipid antigens to T cells. In comparison to MHC proteins, CD1 proteins exhibit minimal allelic diversity as a result of non-synonymous single nucleotide polymorphisms (SNPs). However, it is unknown if common SNPs in gene regulatory regions affect CD1 expression and function. We report surprising diversity in patterns of inducible CD1a expression on human dendritic cells (DCs), spanning the full range from undetectable to high density, a finding not seen with other CD1 isoforms. CD1a-deficient DCs failed to present mycobacterial lipopeptide to T cells but had no defects in endocytosis, cytokine secretion, or expression of co-stimulatory molecules after LPS treatment. We identified a SNP in the 5’ untranslated region (rs366316) that was common and strongly associated with low CD1a surface expression and mRNA levels (p=0.03 and p=0.001, respectively). Using a CD1a promoter-luciferase system in combination with mutagenesis studies, we found that the polymorphic allele reduced luciferase expression by 44% compared to the wild-type variant (p<0.001). Genetic regulation of lipid antigen presentation by varying expression on human DCs provides a mechanism for achieving population level differences in immune responses despite limited structural variation in CD1a proteins. PMID:23858036

  6. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D

    2015-07-01

    Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review. PMID:25737209

  7. Admixture and the organization of genetic diversity in a butterfly species complex revealed through common and rare genetic variants.

    PubMed

    Gompert, Zachariah; Lucas, Lauren K; Buerkle, C Alex; Forister, Matthew L; Fordyce, James A; Nice, Chris C

    2014-09-01

    Detailed information about the geographic distribution of genetic and genomic variation is necessary to better understand the organization and structure of biological diversity. In particular, spatial isolation within species and hybridization between them can blur species boundaries and create evolutionary relationships that are inconsistent with a strictly bifurcating tree model. Here, we analyse genome-wide DNA sequence and genetic ancestry variation in Lycaeides butterflies to quantify the effects of admixture and spatial isolation on how biological diversity is organized in this group. We document geographically widespread and pervasive historical admixture, with more restricted recent hybridization. This includes evidence supporting previously known and unknown instances of admixture. The genome composition of admixed individuals varies much more among than within populations, and tree- and genetic ancestry-based analyses indicate that multiple distinct admixed lineages or populations exist. We find that most genetic variants in Lycaeides are rare (minor allele frequency <0.5%). Because the spatial and taxonomic distributions of alleles reflect demographic and selective processes since mutation, rare alleles, which are presumably younger than common alleles, were spatially and taxonomically restricted compared with common variants. Thus, we show patterns of genetic variation in this group are multifaceted, and we argue that this complexity challenges simplistic notions concerning the organization of biological diversity into discrete, easily delineated and hierarchically structured entities. PMID:24866941

  8. 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

  9. The genetic architecture of autism spectrum disorders (ASDs) and the potential importance of common regulatory genetic variants.

    PubMed

    Saffen, David

    2015-10-01

    Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disorders (ASDs), due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants (CNVs) are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic mutations. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identify many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identification will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance (AEI) of mRNA expression for identifying cis-acting regulatory variants that contribute to ASDs. PMID:26335735

  10. Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders.

    PubMed

    Johnson, Rebecca A; Mitchell, Gordon S

    2013-11-01

    In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: (1) increased (descending) central respiratory drive, (2) motor neuron plasticity, (3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and (4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: (1) respiratory motor neuron death, (2) de- or dysmyelination of cervical spinal pathways, and (3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to "fight" for adequate breathing in the face of mounting pathology. PMID:23727226

  11. Excessive TGFβ signaling is a common mechanism in Osteogenesis Imperfecta

    PubMed Central

    Grafe, Ingo; Yang, Tao; Alexander, Stefanie; Homan, Erica; Lietman, Caressa; Jiang, Ming Ming; Bertin, Terry; Munivez, Elda; Chen, Yuqing; Dawson, Brian; Ishikawa, Yoshihiro; Weis, Mary Ann; Sampath, T. Kuber; Ambrose, Catherine; Eyre, David; Bächinger, Hans Peter; Lee, Brendan

    2014-01-01

    Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations1. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms2. Here, we show that excessive transforming growth factor-beta (TGFβ) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) OI mouse models. In the skeleton, we find higher expression of TGFβ target genes, ratio of pSmad2/Smad2 protein, and in vivo Smad2 reporter activity. Anti-TGFβ treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI, and improves the lung abnormalities in Crtap−/− mice. Moreover, type I collagen of Crtap−/− mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGFβ activity3–4. Hence, altered TGFβ matrix-cell signaling is a primary mechanism in the pathogenesis of OI, and could be a promising target for the treatment of OI. PMID:24793237

  12. Population genetic structure in Atlantic and Pacific Ocean common murres (Uria aalge): Natural replicate tests of post-Pleistocene evolution

    USGS Publications Warehouse

    Morris-Pocock, J. A.; Taylor, S.A.; Birt, T.P.; Damus, M.; Piatt, J.F.; Warheit, K.I.; Friesen, V.L.

    2008-01-01

    Understanding the factors that influence population differentiation in temperate taxa can be difficult because the signatures of both historic and contemporary demographics are often reflected in population genetic patterns. Fortunately, analyses based on coalescent theory can help untangle the relative influence of these historic and contemporary factors. Common murres (Uria aalge) are vagile seabirds that breed in the boreal and low arctic waters of the Northern Hemisphere. Previous analyses revealed that Atlantic and Pacific populations are genetically distinct; however, less is known about population genetic structure within ocean basins. We employed the mitochondrial control region, four microsatellite loci and four intron loci to investigate population genetic structure throughout the range of common murres. As in previous studies, we found that Atlantic and Pacific populations diverged during the Pleistocene and do not currently exchange migrants. Therefore, Atlantic and Pacific murre populations can be used as natural replicates to test mechanisms of population differentiation. While we found little population genetic structure within the Pacific, we detected significant east-west structuring among Atlantic colonies. The degree that population genetic structure reflected contemporary population demographics also differed between ocean basins. Specifically, while the low levels of population differentiation in the Pacific are at least partially due to high levels of contemporary gene flow, the east-west structuring of populations within the Atlantic appears to be the result of historic fragmentation of populations rather than restricted contemporary gene flow. The contrasting results in the Atlantic and Pacific Oceans highlight the necessity of carefully considering multilocus nonequilibrium population genetic approaches when reconstructing the demographic history of temperate Northern Hemisphere taxa. ?? 2008 The Authors.

  13. Common genetic variants, acting additively, are a major source of risk for autism

    PubMed Central

    2012-01-01

    Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome

  14. Are Farm-Reared Quails for Game Restocking Really Common Quails (Coturnix coturnix)?: A Genetic Approach

    PubMed Central

    Sanchez-Donoso, Ines; Vilà, Carles; Puigcerver, Manel; Butkauskas, Dalius; Caballero de la Calle, José Ramón; Morales-Rodríguez, Pablo Antonio; Rodríguez-Teijeiro, José Domingo

    2012-01-01

    The common quail (Coturnix coturnix) is a popular game species for which restocking with farm-reared individuals is a common practice. In some areas, the number of released quails greatly surpasses the number of wild breeding common quail. However, common quail are difficult to raise in captivity and this casts suspicion about a possible hybrid origin of the farmed individuals from crosses with domestic Japanese quail (C. japonica). In this study we used a panel of autosomal microsatellite markers to characterize the genetic origin of quails reared for hunting purposes in game farms in Spain and of quails from an experimental game farm which was founded with hybrids that have been systematically backcrossed with wild common quails. The genotypes of these quail were compared to those of wild common quail and domestic strains of Japanese quail. Our results show that more than 85% of the game farm birds were not common quail but had domestic Japanese quail ancestry. In the experimental farm a larger proportion of individuals could not be clearly separated from pure common quails. We conclude that the majority of quail sold for restocking purposes were not common quail. Genetic monitoring of individuals raised for restocking is indispensable as the massive release of farm-reared hybrids could represent a severe threat for the long term survival of the native species. PMID:22701745

  15. Ancient Humans Influenced the Current Spatial Genetic Structure of Common Walnut Populations in Asia

    PubMed Central

    Pollegioni, Paola; Woeste, Keith E.; Chiocchini, Francesca; Del Lungo, Stefano; Olimpieri, Irene; Tortolano, Virginia; Clark, Jo; Hemery, Gabriel E.; Mapelli, Sergio; Malvolti, Maria Emilia

    2015-01-01

    Common walnut (Juglans regia L) is an economically important species cultivated worldwide for its wood and nuts. It is generally accepted that J. regia survived and grew spontaneously in almost completely isolated stands in its Asian native range after the Last Glacial Maximum. Despite its natural geographic isolation, J. regia evolved over many centuries under the influence of human management and exploitation. We evaluated the hypothesis that the current distribution of natural genetic resources of common walnut in Asia is, at least in part, the product of ancient anthropogenic dispersal, human cultural interactions, and afforestation. Genetic analysis combined with ethno-linguistic and historical data indicated that ancient trade routes such as the Persian Royal Road and Silk Road enabled long-distance dispersal of J. regia from Iran and Trans-Caucasus to Central Asia, and from Western to Eastern China. Ancient commerce also disrupted the local spatial genetic structure of autochthonous walnut populations between Tashkent and Samarkand (Central-Eastern Uzbekistan), where the northern and central routes of the Northern Silk Road converged. A significant association between ancient language phyla and the genetic structure of walnut populations is reported even after adjustment for geographic distances that could have affected both walnut gene flow and human commerce over the centuries. Beyond the economic importance of common walnut, our study delineates an alternative approach for understanding how the genetic resources of long-lived perennial tree species may be affected by the interaction of geography and human history. PMID:26332919

  16. Ancient Humans Influenced the Current Spatial Genetic Structure of Common Walnut Populations in Asia.

    PubMed

    Pollegioni, Paola; Woeste, Keith E; Chiocchini, Francesca; Del Lungo, Stefano; Olimpieri, Irene; Tortolano, Virginia; Clark, Jo; Hemery, Gabriel E; Mapelli, Sergio; Malvolti, Maria Emilia

    2015-01-01

    Common walnut (Juglans regia L) is an economically important species cultivated worldwide for its wood and nuts. It is generally accepted that J. regia survived and grew spontaneously in almost completely isolated stands in its Asian native range after the Last Glacial Maximum. Despite its natural geographic isolation, J. regia evolved over many centuries under the influence of human management and exploitation. We evaluated the hypothesis that the current distribution of natural genetic resources of common walnut in Asia is, at least in part, the product of ancient anthropogenic dispersal, human cultural interactions, and afforestation. Genetic analysis combined with ethno-linguistic and historical data indicated that ancient trade routes such as the Persian Royal Road and Silk Road enabled long-distance dispersal of J. regia from Iran and Trans-Caucasus to Central Asia, and from Western to Eastern China. Ancient commerce also disrupted the local spatial genetic structure of autochthonous walnut populations between Tashkent and Samarkand (Central-Eastern Uzbekistan), where the northern and central routes of the Northern Silk Road converged. A significant association between ancient language phyla and the genetic structure of walnut populations is reported even after adjustment for geographic distances that could have affected both walnut gene flow and human commerce over the centuries. Beyond the economic importance of common walnut, our study delineates an alternative approach for understanding how the genetic resources of long-lived perennial tree species may be affected by the interaction of geography and human history. PMID:26332919

  17. Identification of Genetic Differentiation between Waxy and Common Maize by SNP Genotyping

    PubMed Central

    Hao, Derong; Zhang, Zhenliang; Cheng, Yujing; Chen, Guoqing; Lu, Huhua; Mao, Yuxiang; Shi, Mingliang; Huang, Xiaolan; Zhou, Guangfei; Xue, Lin

    2015-01-01

    Waxy maize (Zea mays L. var. ceratina) is an important vegetable and economic crop that is thought to have originated from cultivated flint maize and most recently underwent divergence from common maize. In this study, a total of 110 waxy and 110 common maize inbred lines were genotyped with 3072 SNPs to evaluate the genetic diversity, population structure, and linkage disequilibrium decay as well as identify putative loci that are under positive selection. The results revealed abundant genetic diversity in the studied panel and that genetic diversity was much higher in common than in waxy maize germplasms. Principal coordinate analysis and neighbor-joining cluster analysis consistently classified the 220 accessions into two major groups and a mixed group with mixed ancestry. Subpopulation structure in both waxy and common maize sets were associated with the germplasm origin and corresponding heterotic groups. The LD decay distance (1500–2000 kb) in waxy maize was lower than that in common maize. Fourteen candidate loci were identified as under positive selection between waxy and common maize at the 99% confidence level. The information from this study can assist waxy maize breeders by enhancing parental line selection and breeding program design. PMID:26566240

  18. NAFLD and Increased Aortic Stiffness: Parallel or Common Physiopathological Mechanisms?

    PubMed Central

    Villela-Nogueira, Cristiane A.; Leite, Nathalie C.; Cardoso, Claudia R. L.; Salles, Gil F.

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide. Liver inflammation and fibrosis related to NAFLD contribute to disease progression and increasing liver-related mortality and morbidity. Increasing data suggest that NAFLD may be linked to atherosclerotic vascular disease independent of other established cardiovascular risk factors. Central arterial stiffness has been recognized as a measure of cumulative cardiovascular risk marker load, and the measure of carotid-femoral pulse wave velocity (cf-PWV) is regarded as the gold standard assessment of aortic stiffness. It has been shown that increased aortic stiffness predicts cardiovascular morbidity and mortality in several clinical settings, including type 2 diabetes mellitus, a well-known condition associated with advanced stages of NAFLD. Furthermore, recently-published studies reported a strong association between NAFLD and increased arterial stiffness, suggesting a possible link in the pathogenesis of atherosclerosis and NAFLD. We sought to review the published data on the associations between NAFLD and aortic stiffness, in order to better understand the interplay between these two conditions and identify possible common physiopathological mechanisms. PMID:27104526

  19. Common Genetic and Environmental Influences on Major Depressive Disorder and Conduct Disorder

    ERIC Educational Resources Information Center

    Subbarao, Anjali; Rhee, Soo Hyun; Young, Susan E.; Ehringer, Marissa A.; Corley, Robin P.; Hewitt, John K.

    2008-01-01

    The evidence for common genetic and environmental influences on conduct disorder (CD) and major depressive disorder (MDD) in adolescents was examined. A sample of 570 monozygotic twin pairs, 592 dizygotic twin pairs, and 426 non-twin siblings, aged 12-18 years, was recruited from the Colorado Twin Registry. For the past year data, there was a…

  20. Genetic diversity and selection of genotypes to enhance Zn and Fe content in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common bean (Phaseolus vulgaris L.) is an important source of dietary protein and minerals worldwide. Genes conditioning variability for mineral contents are not clearly understood. Our ultimate goal is to identify genes conditioning genetic variation for Zn and Fe content. To establish mapping popu...

  1. Genetic analysis and molecular mapping of crown rust resistance in common wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Barley crown rust, caused by Puccinia coronata var. hordei, primarily occurs on barley in the Great Plain regions of the United States. However, a few genotypes of common wheat were found to be susceptible to this pathogen among 750 wheat accessions evaluated. To investigate the genetics of crown ru...

  2. Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

    PubMed

    Lowery, Robert K; Uribe, Gabriel; Jimenez, Eric B; Weiss, Mark A; Herrera, Kristian J; Regueiro, Maria; Herrera, Rene J

    2013-11-01

    Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations. PMID:23872234

  3. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.

    PubMed

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-09-23

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. PMID:25201988

  4. From genetics to mechanism of disease liability.

    PubMed

    Rohrwasser, Andreas; Lott, Paul; Weiss, Robert B; Lalouel, Jean-Marc

    2008-01-01

    With each advance in genomic technology, new statistical methods have regularly emerged to test genetic hypotheses in complex inheritance, as evidenced throughout this book. Notwithstanding the approach used, the greatest challenge in the genetics of complex traits remains the identification of the gene(s) and the molecular variant(s) accounting for a genetic inference based on statistical testing. We take the example of quantitative trait locus (QTL) mapping for blood pressure (BP) and related phenotypes in rodents to review the current landscape. Traditional approaches to refined mapping are typically hampered by the small effect and the small proportion of the variance attached to individual QTLs. The alternative of functional screens in intact animals, whether by chemical mutagenesis or gene targeting, remains a daunting undertaking. Such limitations account for the slow progress to date of inferences from QTL to gene(s). We select a QTL for differential sodium sensitivity between two mouse inbred lines to propose an approach that can be used in relatively large genomic regions (1) by optimizing the selection of candidate genes and (2) by subjecting such genes to high-throughput functional screens. While this is still work in progress, we think it abundantly illustrates what is ahead of us in delineating genetic variation that underlie complex disease. PMID:18358337

  5. Genetic Characterization of Legionella pneumophila Isolated from a Common Watershed in Comunidad Valenciana, Spain

    PubMed Central

    Sánchez-Busó, Leonor; Coscollá, Mireia; Pinto-Carbó, Marta; Catalán, Vicente; González-Candelas, Fernando

    2013-01-01

    Legionella pneumophila infects humans to produce legionellosis and Pontiac fever only from environmental sources. In order to establish control measures and study the sources of outbreaks it is essential to know extent and distribution of strain variants of this bacterium in the environment. Sporadic and outbreak-related cases of legionellosis have been historically frequent in the Comunidad Valenciana region (CV, Spain), with a high prevalence in its Southeastern-most part (BV). Environmental investigations for the detection of Legionella pneumophila are performed in this area routinely. We present a population genetics study of 87 L. pneumophila strains isolated in 13 different localities of the BV area irrigated from the same watershed and compare them to a dataset of 46 strains isolated in different points of the whole CV. Our goal was to compare environmental genetic variation at two different geographic scales, at county and regional levels. Genetic diversity, recombination and population structure were analyzed with Sequence-Based Typing data and three intergenic regions. The results obtained reveal a low, but detectable, level of genetic differentiation between both datasets, mainly, but not only, attributed to the occurrence of unusual variants of the neuA locus present in the BV populations. This differentiation is still detectable when the 10 loci considered are analyzed independently, despite the relatively high incidence of the most common genetic variant in this species, sequence type 1 (ST-1). However, when the genetic data are considered without their associated geographic information, four major groups could be inferred at the genetic level which did not show any correlation with sampling locations. The overall results indicate that the population structure of these environmental samples results from the joint action of a global, widespread ST-1 along with genetic differentiation at shorter geographic distances, which in this case are related to

  6. Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

    PubMed

    Rittschof, Clare C; Bukhari, Syed Abbas; Sloofman, Laura G; Troy, Joseph M; Caetano-Anollés, Derek; Cash-Ahmed, Amy; Kent, Molly; Lu, Xiaochen; Sanogo, Yibayiri O; Weisner, Patricia A; Zhang, Huimin; Bell, Alison M; Ma, Jian; Sinha, Saurabh; Robinson, Gene E; Stubbs, Lisa

    2014-12-16

    Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa. PMID:25453090

  7. Teaching Evolutionary Mechanisms: Genetic Drift and M&M's.

    ERIC Educational Resources Information Center

    Staub, Nancy L.

    2002-01-01

    Describes a classroom activity that teaches the mechanism of genetic drift to undergraduates. Illustrates a number of concepts that are critical in developing evolution literacy by sampling M&M milk chocolate candies. (MM)

  8. Common Transcriptional Mechanisms for Visual Photoreceptor Cell Differentiation among Pancrustaceans

    PubMed Central

    Mahato, Simpla; Morita, Shinichi; Tucker, Abraham E.; Liang, Xulong; Jackowska, Magdalena; Friedrich, Markus; Shiga, Yasuhiro; Zelhof, Andrew C.

    2014-01-01

    A hallmark of visual rhabdomeric photoreceptors is the expression of a rhabdomeric opsin and uniquely associated phototransduction molecules, which are incorporated into a specialized expanded apical membrane, the rhabdomere. Given the extensive utilization of rhabdomeric photoreceptors in the eyes of protostomes, here we address whether a common transcriptional mechanism exists for the differentiation of rhabdomeric photoreceptors. In Drosophila, the transcription factors Pph13 and Orthodenticle (Otd) direct both aspects of differentiation: rhabdomeric opsin transcription and rhabdomere morphogenesis. We demonstrate that the orthologs of both proteins are expressed in the visual systems of the distantly related arthropod species Tribolium castaneum and Daphnia magna and that their functional roles are similar in these species. In particular, we establish that the Pph13 homologs have the ability to bind a subset of Rhodopsin core sequence I sites and that these sites are present in key phototransduction genes of both Tribolium and Daphnia. Furthermore, Pph13 and Otd orthologs are capable of executing deeply conserved functions of photoreceptor differentiation as evidenced by the ability to rescue their respective Drosophila mutant phenotypes. Pph13 homologs are equivalent in their ability to direct both rhabdomere morphogenesis and opsin expression within Drosophila, whereas Otd paralogs demonstrate differential abilities to regulate photoreceptor differentiation. Finally, loss-of-function analyses in Tribolium confirm the conserved requirement of Pph13 and Otd in regulating both rhabdomeric opsin transcription and rhabdomere morphogenesis. Taken together, our data identify components of a regulatory framework for rhabdomeric photoreceptor differentiation in Pancrustaceans, providing a foundation for defining ancestral regulatory modules of rhabdomeric photoreceptor differentiation. PMID:24991928

  9. Movement patterns and genetic diversity of wild and reintroduced common dormice, Muscardinus avellanarius.

    PubMed

    Naim, D M; Telfer, S; Tatman, S; Bird, S; Kemp, S J; Watts, P C

    2014-01-01

    Movement is an important life history trait that can have an impact on local adaptation, and other evolutionary phenomena. We used a combination of nestbox survey data and genetic techniques (genotyping at 10 microsatellite loci) to quantify patterns of movement in common dormice Muscardinus avellanarius at two distinct sites in the UK: 1) Bontuchel (a natural population) and 2) Wych (captive-bred individuals that were reintroduced to this site), over three consecutive years (2006-2008). Both methods revealed a consistent pattern of sex-biased movement (movements by adult males and females) in both populations that allowed isolation-by-distance genetic structure to develop within 1 km. The similarity of data from captive-bred and natural individuals indicated that ex situ programing has not significantly altered the natural movement behavior of common dormice; consequently, the two populations could be managed with the same conservation strategies. We also found that the reintroduced dormice in Wych maintained relatively high levels of genetic diversity. This first report of movement patterns in reintroduced and natural populations of M. avellanarius combining genetic and field-survey data highlights the role of genetic studies in the investigation of ecological behaviour and for conservation management. PMID:24446300

  10. Resolving Intralocus Sexual Conflict: Genetic Mechanisms and Time Frame

    PubMed Central

    Pischedda, Alison; Rice, William R.

    2010-01-01

    Intralocus sexual conflict occurs due to the expression of sexually antagonistic alleles: those that increase fitness when expressed in one sex but decrease fitness when expressed in the other sex. This genetic conflict is expected whenever the sexes are selected toward differing phenotypic optima for a trait that has a positive genetic correlation between the sexes. Here we synthesize recent developments in the areas of genomics, microarray analysis, and developmental and molecular genetics to establish feasible mechanisms by which the intersexual genetic correlation can be reduced, as well as the time course over which conflict resolution is expected to evolve. PMID:20421329

  11. Phenotype-Based Genetic Association Studies (PGAS)—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes

    PubMed Central

    Ehrenreich, Hannelore; Nave, Klaus-Armin

    2014-01-01

    Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro

  12. [Genetic Structure of Urban Population of the Common Hamster (Cricetus cricetus)].

    PubMed

    Feoktistova, N Yu; Meschersky, I G; Surov, A V; Bogomolov, P L; Tovpinetz, N N; Poplavskaya, N S

    2016-02-01

    Over the past half-century, the common hamster (Cricetus cricetus), along with range-wide decline of natural populations, has actively populated the cities. The study of the genetic structure of urban populations of common hamster may shed light on features of the habitation of this species in urban landscapes. This article is focused on the genetic structure of common hamster populations in Simferopol (Crimea), one of the largest known urban populations of this species. On the basis of the analysis of nucleotide sequences of the cytochrome b gene and mtDNA control region, and the allelic composition of ten microsatellite loci of nDNA, we revealed that, despite the fact that some individuals can move throughout the city at considerable distances, the entire population of the city is represented by separate demes confined to different areas. These demes are characterized by a high degree of the genetic isolation and reduced genetic diversity compared to that found for the city as a whole. PMID:27215037

  13. Improved prediction of complex diseases by common genetic markers: state of the art and further perspectives.

    PubMed

    Müller, Bent; Wilcke, Arndt; Boulesteix, Anne-Laure; Brauer, Jens; Passarge, Eberhard; Boltze, Johannes; Kirsten, Holger

    2016-03-01

    Reliable risk assessment of frequent, but treatable diseases and disorders has considerable clinical and socio-economic relevance. However, as these conditions usually originate from a complex interplay between genetic and environmental factors, precise prediction remains a considerable challenge. The current progress in genotyping technology has resulted in a substantial increase of knowledge regarding the genetic basis of such diseases and disorders. Consequently, common genetic risk variants are increasingly being included in epidemiological models to improve risk prediction. This work reviews recent high-quality publications targeting the prediction of common complex diseases. To be included in this review, articles had to report both, numerical measures of prediction performance based on traditional (non-genetic) risk factors, as well as measures of prediction performance when adding common genetic variants to the model. Systematic PubMed-based search finally identified 55 eligible studies. These studies were compared with respect to the chosen approach and methodology as well as results and clinical impact. Phenotypes analysed included tumours, diabetes mellitus, and cardiovascular diseases. All studies applied one or more statistical measures reporting on calibration, discrimination, or reclassification to quantify the benefit of including SNPs, but differed substantially regarding the methodological details that were reported. Several examples for improved risk assessments by considering disease-related SNPs were identified. Although the add-on benefit of including SNP genotyping data was mostly moderate, the strategy can be of clinical relevance and may, when being paralleled by an even deeper understanding of disease-related genetics, further explain the development of enhanced predictive and diagnostic strategies for complex diseases. PMID:26839113

  14. Genetic structure of the Common Eider in the western Aleutian Islands prior to fox eradication

    USGS Publications Warehouse

    Sonsthagen, Sarah A.; Talbot, Sandra L.; Wilson, Robert E.; Petersen, Margaret R.; Williams, Jeffrey C.; Byrd, G. Vernon; McCracken, Kevin G.

    2013-01-01

    Since the late 18th century bird populations residing in the Aleutian Archipelago have been greatly reduced by introduced arctic foxes (Alopex lagopus). We analyzed data from microsatellite, nuclear intron, and mitochondrial (mtDNA) loci to examine the spatial genetic structure, demography, and gene flow among four Aleutian Island populations of the Common Eider (Somateria mollissima) much reduced by introduced foxes. In mtDNA, we found high levels of genetic structure within and between island groups (ΦST = 0.643), but we found no population subdivision in microsatellites or nuclear introns. Differences in genetic structure between the mitochondrial and nuclear genomes are consistent with the Common Eider's breeding and winter biology, as females are highly philopatric and males disperse. Nevertheless, significant differences between islands in the mtDNA of males and marginal significance (P =0.07) in the Z-linked locus Smo 1 suggest that males may also have some level of fidelity to island groups. Severe reduction of populations by the fox, coupled with females' high philopatry, may have left the genetic signature of a bottleneck effect, resulting in the high levels of genetic differentiation observed in mtDNA (ΦST = 0.460–0.807) between islands only 440 km apart. Reestablishment of the Common Eider following the fox's eradication was likely through recruitment from within the islands and bolstered by dispersal from neighboring islands, as suggested by the lack of genetic structure and asymmetry in gene flow between Attu and the other Near Islands.

  15. More than one genotype: how common is intracolonial genetic variability in scleractinian corals?

    PubMed

    Schweinsberg, Maximilian; Weiss, Linda C; Striewski, Sebastian; Tollrian, Ralph; Lampert, Kathrin P

    2015-06-01

    In recent years, a few colonial marine invertebrates have shown intracolonial genetic variability, a previously unreported phenomenon. Intracolonial genetic variability describes the occurrence of more than a single genotype within an individual colony. This variability can be traced back to two underlying processes: chimerism and mosaicism. Chimerism is the fusion of two or more individuals, whereas mosaicism mostly derives from somatic cell mutations. Until now, it remained unclear to what degree the ecologically important group of hermatypic (reef building) corals might be affected. We investigate the occurrence of intracolonial genetic variability in five scleractinian corals: Acropora florida, Acropora hyacinthus, Acropora sarmentosa, Pocillopora species complex and Porites australiensis. The main focus was to test different genera for the phenomenon via microsatellite markers and to distinguish which underlying process caused the genetic heterogeneity. Our results show that intracolonial genetic variability was common (between 46.6% for A. sarmentosa and 23.8% for P. species complex) in all tested corals. The main process was mosaicism (69 cases of 222 tested colonies), but at least one chimera existed in every species. This suggests that intracolonial genetic variability is widespread in scleractinian corals and could challenge the view of a coral colony as an individual and therefore a unit of selection. However, it might also hold potential for colony survival under rapidly changing environmental conditions. PMID:25872099

  16. Citizens in the commons: blood and genetics in the making of the civic

    PubMed Central

    Reddy, Deepa S.

    2013-01-01

    This essay is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH/NHGRI-sponsored ethics study and sample collection initiative entitled ‘Indian and Hindu Perspectives on Genetic Variation Research.’ Taking a cue from my Indian interlocutors who largely support and readily respond to such initiatives on the grounds that they will undoubtedly serve ‘humanity’ and the common good, I explore notions of the commons that are created in the process of soliciting blood for genetic research. How does blood become the stuff of which a civic discourse is made? How do idealistic individual appeals to donate blood, ethics research protocols, open-source databases, debates on approaches to genetic research, patents and Intellectual Property regulations, markets and the nation-state itself variously engage, limit or further ideas of the common good? Moving much as my interlocutors do, between India and the United States, I explore the nature of the commons that is both imagined and pragmatically reckoned in both local and global diasporic contexts. PMID:24478538

  17. Citizens in the commons: blood and genetics in the making of the civic.

    PubMed

    Reddy, Deepa S

    2013-01-01

    This essay is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH/NHGRI-sponsored ethics study and sample collection initiative entitled 'Indian and Hindu Perspectives on Genetic Variation Research.' Taking a cue from my Indian interlocutors who largely support and readily respond to such initiatives on the grounds that they will undoubtedly serve 'humanity' and the common good, I explore notions of the commons that are created in the process of soliciting blood for genetic research. How does blood become the stuff of which a civic discourse is made? How do idealistic individual appeals to donate blood, ethics research protocols, open-source databases, debates on approaches to genetic research, patents and Intellectual Property regulations, markets and the nation-state itself variously engage, limit or further ideas of the common good? Moving much as my interlocutors do, between India and the United States, I explore the nature of the commons that is both imagined and pragmatically reckoned in both local and global diasporic contexts. PMID:24478538

  18. The Mosaic Theory Revisited: Common Molecular Mechanisms Coordinating Diverse Organ and Cellular Events in Hypertension

    PubMed Central

    Harrison, David G.

    2012-01-01

    Over 60 years ago, Dr. Irvine Page proposed the Mosaic Theory of hypertension, which states that many factors, including genetics, environment, adaptive, neural, mechanical and hormonal perturbations interdigitate to raise blood pressure. In the past two decades, it has become clear that common molecular and cellular events in various organs underlie many features of the Mosaic Theory. Two of these are the production of reactive oxygen species (ROS) and inflammation. These factors increase neuronal firing in specific brain centers, increase sympathetic outflow, alter vascular tone and morphology and promote sodium retention in the kidney. Moreover, factors such as genetics and environment contribute to oxidant generation and inflammation. Other common cellular signals, including calcium signaling and endoplasmic reticulum stress are similarly perturbed in different cells in hypertension and contribute to components of Dr. Page’s theory. Thus, Dr. Page’s Mosaic Theory formed a framework for future studies of molecular and cellular signals in the context of hypertension, and has greatly aided our understanding of this complex disease. PMID:23321405

  19. A common genetic basis to the origin of the leaf economics spectrum and metabolic scaling allometry.

    PubMed

    Vasseur, François; Violle, Cyrille; Enquist, Brian J; Granier, Christine; Vile, Denis

    2012-10-01

    Many facets of plant form and function are reflected in general cross-taxa scaling relationships. Metabolic scaling theory (MST) and the leaf economics spectrum (LES) have each proposed unifying frameworks and organisational principles to understand the origin of botanical diversity. Here, we test the evolutionary assumptions of MST and the LES using a cross of two genetic variants of Arabidopsis thaliana. We show that there is enough genetic variation to generate a large fraction of variation in the LES and MST scaling functions. The progeny sharing the parental, naturally occurring, allelic combinations at two pleiotropic genes exhibited the theorised optimum ¾ allometric scaling of growth rate and intermediate leaf economics. Our findings: (1) imply that a few pleiotropic genes underlie many plant functional traits and life histories; (2) unify MST and LES within a common genetic framework and (3) suggest that observed intermediate size and longevity in natural populations originate from stabilising selection to optimise physiological trade-offs. PMID:22856883

  20. Common Mechanism Underlies Repeated Evolution of Extreme Pollution Tolerance

    EPA Science Inventory

    Human alterations to the environment can exert strong evolutionary pressures, yet contemporary adaptation to human-mediated stressors is rarely documented in wild populations. A common-garden experimental design was coupled with comparative transcriptomics to discover evolved me...

  1. Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins

    PubMed Central

    Solomon, Terry; Smith, Erin N.; Matsui, Hiroko; Braekkan, Sigrid K.; Wilsgaard, Tom; Njølstad, Inger; Mathiesen, Ellisiv B.; Hansen, John-Bjarne

    2016-01-01

    Background— Genetic variation can be used to study causal relationships between biomarkers and diseases. Here, we identify new common and rare genetic variants associated with cardiovascular-related protein levels (protein quantitative trait loci [pQTLs]). We functionally annotate these pQTLs, predict and experimentally confirm a novel molecular interaction, and determine which pQTLs are associated with diseases and physiological phenotypes. Methods and Results— As part of a larger case–control study of venous thromboembolism, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Tromsø Study. Exonic genetic variation near each protein’s respective gene (cis) was identified using sequencing and arrays. Using single site and gene-based tests, we identified 27 genetic associations between pQTLs and the serum levels of 20 proteins: 14 associated with common variation in cis, of which 6 are novel (ie, not previously reported); 7 associations with rare variants in cis, of which 4 are novel; and 6 associations in trans. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein and with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro. Nine of the pQTLs have previously identified associations with 17 disease and physiological phenotypes. Conclusions— We have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes. PMID:27329291

  2. Microsatellite DNA marker analysis of genetic diversity in wild common carp (Cyprinus carpio L.) populations.

    PubMed

    Li, Dayu; Kang, Dahai; Yin, Qianqian; Sun, Xiaowen; Liang, Liqun

    2007-11-01

    Thirty microsatellite loci were used for analyzing six wild populations of common carp (Cyprinus carpio L.). Observed (H(o)) and expected (H(e)) heterozygosity values, polymorphic information content (PIC), and number of effective alleles (A(e)) were all detected. Genetic similarity index and genetic distance were computed based on the allele frequency. The Hardy-Weinberg Equilibrium was checked according to the test of chi2. Genetic differentiation and hierarchical partition of genetic diversity were evaluated by F(ST) and N(m). A clustering dendrogram was made based on the results of UPGMA methods using the PHYLIP software package (version 3.63). There were totally 8,136 fragments ranging from 125 bp to 414 bp in length. Three to thirteen alleles were amplified in 30 loci and 210 alleles in all six populations. The average number of alleles in each locus was seven. The result showed that 1) the level of genetic variability was moderate in the six populations. Polymorphic information contents of the six wild common carp populations were 0.44, 0.52, 0.53, 0.57, 0.63, and 0.64 respectively. Effective alleles were from 1.04 to 4.72, the average numbers in each population were 2.19, 2.60, 2.42, 2.43, 2.45, and 2.33. The average expected heterozygosity values were 0.50, 0.59, 0.56, 0.56, 0.57, and 0.54 respectively; 2) the highest genetic similarity index that came from the populations of BR and ZL was 0.8511 and the lowest index was 0.6688, and it came from the populations of BR and HN. There was a correlation between the clustering result and the geographical distribution. PMID:18037135

  3. Mechanisms of Non-Genetic Inheritance and Psychiatric Disorders

    PubMed Central

    Toth, Miklos

    2015-01-01

    Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles (DNA sequence). However, empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve genetic alleles, referred to as non-genetic inheritance. Information that is non-genetically transmitted across generations includes parental experience and exposure to certain environments, but also parental mutations and polymorphisms, because they can change the parental ‘intrinsic' environment. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. Non-genetic inheritance has been observed for multiple traits including overall development, cardiovascular risk and metabolic symptoms, but this review will focus on the inheritance of behavioral abnormalities pertinent to psychiatric disorders. Multigenerational non-genetic inheritance is often interpreted as the transmission of epigenetic marks, such as DNA methylation and chromatin modifications, via the gametes (transgenerational epigenetic inheritance). However, information can be carried across generations by a large number of bioactive substances, including hormones, cytokines, and even microorganisms, without the involvement of the gametes. We reason that this broader definition of non-genetic inheritance is more appropriate, especially in the context of psychiatric disorders, because of the well-recognized role of parental and early life environmental factors in later life psychopathology. Here we discuss the various forms of non-genetic inheritance in humans and animals, as well as rodent models of psychiatric conditions to illustrate possible mechanisms. PMID:24889369

  4. Identifying common genetic variants in blood pressure due to polygenic pleiotropy with associated phenotypes.

    PubMed

    Andreassen, Ole A; McEvoy, Linda K; Thompson, Wesley K; Wang, Yunpeng; Reppe, Sjur; Schork, Andrew J; Zuber, Verena; Barrett-Connor, Elizabeth; Gautvik, Kaare; Aukrust, Pål; Karlsen, Tom H; Djurovic, Srdjan; Desikan, Rahul S; Dale, Anders M

    2014-04-01

    Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional false discovery rate method, we systematically investigated genetic overlap between systolic blood pressure (SBP) and 12 comorbid traits and diseases. We found significant enrichment of single nucleotide polymorphisms associated with SBP as a function of their association with body mass index, low-density lipoprotein, waist/hip ratio, schizophrenia, bone mineral density, type 1 diabetes mellitus, and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high-density lipoproteins, type 2 diabetes mellitus, rheumatoid arthritis, and height). Applying the conditional false discovery rate method to the enriched phenotypes, we identified 62 loci associated with SBP (false discovery rate <0.01), including 42 novel loci. The observed polygenic overlap between SBP and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors but also reflect an etiologic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in SBP. PMID:24396023

  5. Identifying common genetic variants in blood pressure due to polygenic pleiotropy with associated phenotypes

    PubMed Central

    Andreassen, Ole A.; McEvoy, Linda K.; Thompson, Wesley K.; Wang, Yunpeng; Reppe, Sjur; Schork, Andrew J.; Zuber, Verena; Barrett-Connor, Elizabeth; Gautvik, Kaare; Aukrust, Pål; Karlsen, Tom H.; Djurovic, Srdjan; Desikan, Rahul S.; Dale, Anders M.

    2014-01-01

    Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional False Discovery Rate method, we systematically investigated genetic overlap between systolic blood pressure and 12 co-morbid traits and diseases. We found significant ‘enrichment’ of single nucleotide polymorphisms associated with systolic blood pressure as a function of their association with body mass index, low density lipoprotein, waist hip ratio, schizophrenia, bone mineral density, type 1 diabetes and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high density lipoproteins, type 2 diabetes, rheumatoid arthritis, and height). Applying the conditional False Discovery Rate method to the enriched phenotypes, we identified 62 loci associated with systolic blood pressure (False Discovery Rate < 0.01), including 42 novel loci. The observed polygenic overlap between systolic blood pressure and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors, but also reflect an etiological relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in systolic blood pressure. PMID:24396023

  6. A current genetic and epigenetic view on human aging mechanisms.

    PubMed

    Ostojić, Sala; Pereza, Nina; Kapović, Miljenko

    2009-06-01

    The process of aging is one of the most complex and intriguing biological phenomenons. Aging is a genetically regulated process in which the organism's maximum lifespan potential is pre-determined, while the rate of aging is influenced by environmental factors and lifestyle. Considering the complexity of mechanisms involved in the regulation of aging process, up to this date there isn't a major, unifying theory which could explain them. As genetic/epigenetic and environmental factors both inevitably influence the aging process, here we present a review on the genetic and epigenetic regulation of the most important molecular and cellular mechanisms involved in the process of aging. Based on the studies on oxidative stress, metabolism, genome stability, epigenetic modifications and cellular senescence in animal models and humans, we give an overview of key genetic and molecular pathways related to aging. As most of genetic manipulations which influence the aging process also affect reproduction, we discuss aging in humans as a post-reproductive genetically determined process. After the age of reproductive success, aging continously progresses which clinically coincides with the onset of most chronic diseases, cancers and dementions. As evolution shapes the genomes for reproductive success and not for post-reproductive survival, aging could be defined as a protective mechanism which ensures the preservation and progress of species through the modification, trasmission and improvement of genetic material. PMID:19662799

  7. Sensitization to Common and Uncommon Pets or Other Furry Animals: Which May Be Common Mechanisms?

    PubMed Central

    Liccardi, G; Triggiani, M; Piccolo, A; Salzillo, A; Parente, R; Manzi, F; Vatrella, A

    2016-01-01

    Exposure to animal allergens constitutes a relevant risk factor for the development of allergic sensitization. Moreover, an increasing number of people become owners of less common animals. In this article we summarize aspects related to sensitization to cat/dog which may be applied also to uncommon pets or other furry animals. The data discussed here suggest that several different factors may induce allergic sensitization to furry animals with or without previous contact. Allergic sensitization without animal exposure is a relevant risk for patients because they are not aware about the possibility that even severe respiratory symptoms may develop after an occasional animal contact. This aspect should be taken into account by susceptible individuals before acquiring pets or beginning a contact for working/leisure activity with a common as well as uncommon animal. As a consequence, skin prick test and/or evaluation of specific IgE antibodies (by classic ImmunoCAP or micro-array technique ImmunoCAP ISAC) also to less common (“new”) mammalian allergens could be recommended in individuals already sensitized to common pets to identify the occurrence of allergic sensitization and consequently to avoid future exposures to uncommon animal allergens. PMID:27326390

  8. Sensitization to Common and Uncommon Pets or Other Furry Animals: Which May Be Common Mechanisms?

    PubMed

    Liccardi, G; Triggiani, M; Piccolo, A; Salzillo, A; Parente, R; Manzi, F; Vatrella, A

    2016-05-01

    Exposure to animal allergens constitutes a relevant risk factor for the development of allergic sensitization. Moreover, an increasing number of people become owners of less common animals. In this article we summarize aspects related to sensitization to cat/dog which may be applied also to uncommon pets or other furry animals. The data discussed here suggest that several different factors may induce allergic sensitization to furry animals with or without previous contact. Allergic sensitization without animal exposure is a relevant risk for patients because they are not aware about the possibility that even severe respiratory symptoms may develop after an occasional animal contact. This aspect should be taken into account by susceptible individuals before acquiring pets or beginning a contact for working/leisure activity with a common as well as uncommon animal. As a consequence, skin prick test and/or evaluation of specific IgE antibodies (by classic ImmunoCAP or micro-array technique ImmunoCAP ISAC) also to less common ("new") mammalian allergens could be recommended in individuals already sensitized to common pets to identify the occurrence of allergic sensitization and consequently to avoid future exposures to uncommon animal allergens. PMID:27326390

  9. Examining the role of common genetic variants on alcohol, tobacco, cannabis, and illicit drug dependence

    PubMed Central

    Palmer, RHC; Brick, L; Nugent, NR; Bidwell, LC; McGeary, JE; Knopik, VS; Keller, MC

    2014-01-01

    Background and Aims Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures. Participants 2596 unrelated subjects from the “Study of Addiction: Genetics and Environment” provided information on alcohol, tobacco, cocaine, cannabis, and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e., 1+ DSM-IV symptoms), and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used). Findings Univariate and bivariate Genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h2SNP (CI)=0.36 (0.11-0.62) and 0.33(0.07-0.58), respectively; PU = 0.25 (-0.01-0.51)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems (rSNP; rDD-PU = 0.92 (0.76-1.00), rDD-DV = 0.97 (0.87-1.00), and rPU-DV = 0.96 (0.82-1.00)). Conclusion At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems. PMID:25424661

  10. Multicollinearity in spatial genetics: separating the wheat from the chaff using commonality analyses.

    PubMed

    Prunier, J G; Colyn, M; Legendre, X; Nimon, K F; Flamand, M C

    2015-01-01

    Direct gradient analyses in spatial genetics provide unique opportunities to describe the inherent complexity of genetic variation in wildlife species and are the object of many methodological developments. However, multicollinearity among explanatory variables is a systemic issue in multivariate regression analyses and is likely to cause serious difficulties in properly interpreting results of direct gradient analyses, with the risk of erroneous conclusions, misdirected research and inefficient or counterproductive conservation measures. Using simulated data sets along with linear and logistic regressions on distance matrices, we illustrate how commonality analysis (CA), a detailed variance-partitioning procedure that was recently introduced in the field of ecology, can be used to deal with nonindependence among spatial predictors. By decomposing model fit indices into unique and common (or shared) variance components, CA allows identifying the location and magnitude of multicollinearity, revealing spurious correlations and thus thoroughly improving the interpretation of multivariate regressions. Despite a few inherent limitations, especially in the case of resistance model optimization, this review highlights the great potential of CA to account for complex multicollinearity patterns in spatial genetics and identifies future applications and lines of research. We strongly urge spatial geneticists to systematically investigate commonalities when performing direct gradient analyses. PMID:25495950

  11. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    PubMed Central

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-01-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person’s genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  12. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-03-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  13. Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia.

    PubMed

    Martin, Andrew K; Robinson, G; Reutens, D; Mowry, B

    2015-09-30

    Schizophrenia is a clinically heterogeneous disorder associated with broad deficits across cognitive domains. As large genomewide association studies uncover the genetic architecture of schizophrenia, the relationship between common genetic variants and clinical and cognitive characteristics will form part of an integrative approach to understanding genetic effects on the clinical phenotype. In the current study, association between common genetic risk variants and clinical and cognitive variables was investigated. Common risk variants were associated with positive symptoms and decision-making ability from the Cambridge Gambling Task with trends in other domains. PMID:26070766

  14. The Genetics of Common Variation affecting Platelet Development, Function and Pharmaceutical Targeting

    PubMed Central

    Johnson, Andrew D.

    2011-01-01

    Summary Common variant effects on human platelet function and response to anti-platelet treatment have traditionally been studied using candidate gene approaches involving a limited number of variants and genes. These studies have often been undertaken in clinically defined cohorts. More recently, studies have applied genome-wide scans in larger population samples than prior candidate studies, in some cases scanning relatively healthy individuals. These studies demonstrate synergy with some prior candidate gene findings (e.g., GP6, ADRA2A) but also uncover novel loci involved in platelet function. Here, I summarise findings on common genetic variation influencing platelet development, function and therapeutics. Taken together, candidate gene and genome-wide studies begin to account for common variation in platelet function and provide information that may ultimately be useful in pharmacogenetic applications in the clinic. More than 50 loci have been identified with consistent associations with platelet phenotypes in ≥2 populations. Several variants are under further study in clinical trials relating to anti-platelet therapies. In order to have useful clinical applications, variants must have large effects on a modifiable outcome. Regardless of clinical applications, studies of common genetic influences, even of small effect, offer additional insights into platelet biology including the importance of intracellular signalling and novel receptors. Understanding of common platelet-related genetics remains behind parallel fields (e.g., lipids, blood pressure) due to challenges in phenotype ascertainment. Further work is necessary to discover and characterise loci for platelet function, and to assess whether these loci contribute to disease aetiologies or response to therapeutics. PMID:21781261

  15. Hyperinsulinaemic Hypoglycaemia: Genetic Mechanisms, Diagnosis and Management

    PubMed Central

    Mohamed, Zainaba; Arya, Ved Bhushan; Hussain, Khalid

    2012-01-01

    Hyperinsulinaemic hypoglycaemia (HH) is characterized by unregulated insulin secretion from pancreatic β-cells. Untreated hypoglycaemia in infants can lead to seizures, developmental delay, and subsequent permanent brain injury. Early identification and meticulous managementof these patients is vital to prevent neurological insult. Mutations in eight different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A and UCP2) have been identified to date in patients with congenital forms of hyperinsulinism (CHI). The most severe forms of CHI are due to mutations in ABCC8 and KCJN11, which encode the two components of pancreatic β-cell ATP-sensitive potassium channel. Recent advancement in understanding the genetic aetiology, histological characterisation into focal and diffuse variety combined with improved imaging (such as fluorine 18 L-3, 4-dihydroxyphenylalanine positron emission tomography 18F-DOPA-PET scanning) and laparoscopic surgical techniques have greatly improved management. In adults, HH can be due to an insulinoma, pancreatogenous hypoglycaemic syndrome, post gastric-bypass surgery for morbid obesity as well as to mutations in insulin receptor gene. This review provides an overview of the molecular basis of CHI and outlines the clinical presentation, diagnostic criteria, and management of these patients. Conflict of interest:None declared. PMID:23032149

  16. [Genetic background in common forms of obesity - from studies on identical twins to candidate genes of obesity].

    PubMed

    Bendlová, Běla; Lukášová, Petra; Vaňková, Markéta; Vejražková, Daniela; Bradnová, Olga; Včelák, Josef; Stanická, Soňa; Zamrazilová, Hana; Aldhoon-Hainerová, Irena; Dušátková, Lenka; Kunešová, Marie; Hainer, Vojtěch

    2014-01-01

    Common obesity is a result of interaction between genes and environmental/lifestyle factors, with heritability estimates 40-70%. Not only the susceptibility to obesity but also the success of weight management depends on the genetic background of each individual. This paper summarizes the up-to-date knowledge on genetic causes of common obesities. Introduction of genome-wide association studies (GWAS) led to an identification of a total of 32 variants associated with obesity/BMI and 14 with body fat distribution. Further, a great progress in revealing the mechanisms regulating the energy balance was also noted. However, the proportion of explained variance for BMI is still low, suggesting other mechanisms such as gene-gene and gene-environment interactions, rare gene variants, copy number variants polymorphisms, or epigenetic modifications and microRNAs regulating gene transcription. In summary, we present results of our studies on obesity risk variants in Czech adults, children and adolescents including those evaluating the influence of selected gene variants on the outcomes of weight management. PMID:25199545

  17. A common biological mechanism in cancer and Alzheimer’s disease?

    PubMed Central

    Behrens, Maria I; Lendon, Corinne; Roe, Catherine M.

    2009-01-01

    Cancer and Alzheimer’s disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Aβ) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to “repair and live”- or “die” could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer. PMID:19519301

  18. Serial and Free Recall: Common Effects and Common Mechanisms? A Reply to Murdock (2008)

    ERIC Educational Resources Information Center

    Brown, Gordon D. A.; Chater, Nick; Neath, Ian

    2008-01-01

    Reply to comments on an article "Issues With the SIMPLE Model: Comment on Brown, Neath, and Chater" (2007) by Bennet Murdock on the current authors' original article "A temporal ratio model of memory" by Brown, Neath, and Chater. Does a single mechanism underpin serial and free recall? B. Murdock (2008) argued against the claim, embodied in the…

  19. Genetic mechanisms in the intergenerational transmission of health.

    PubMed

    Thompson, Owen

    2014-05-01

    This paper uses a sample of adoptees to study the genetic mechanisms underlying intergenerational associations in chronic health conditions. I begin by estimating baseline intergenerational models with a sample of approximately 125,000 parent-child pairs, and find that children with a parent who has a specific chronic health condition are at least 100% more likely to have the same condition themselves. To assess the role of genetic mechanisms in generating these strong correlations, I estimate models using a sample of approximately 2400 adoptees, and find that genetic transmission accounts for only 20-30% of the baseline associations. As falsification tests, I repeat this exercise using health measures with externally established levels of genetic determination (height and chicken pox), and the results suggest that comparisons of biological and adopted children are a valid method of isolating genetic effects in this sample. Finally, to corroborate these adoptee-based estimates, I examine health correlations among monozygotic twins, which provide an upper bound estimate of genetic influences, and find a similarly modest role for genetic transmission. I conclude that intergenerational health transmission is an important hindrance to overall socioeconomic mobility, but that the majority of transmission occurs through environmental factors or gene-environment interactions, leaving scope for interventions to effectively mitigate health persistence. PMID:24674912

  20. Genetic analysis of chromosomal loci affecting the content of insoluble glutenin in common wheat.

    PubMed

    Jin, Huaibing; Wang, Zhaojun; Li, Da; Wu, Peipei; Dong, Zhengying; Rong, Chaowu; Liu, Xin; Qin, Huanju; Li, Huili; Wang, Daowen; Zhang, Kunpu

    2015-09-20

    In common wheat, insoluble glutenin (IG) is an important fraction of flour glutenin macropolymers, and insoluble glutenin content (IGC) is positively associated with key end-use quality parameters. Here, we present a genetic analysis of the chromosomal loci affecting IGC with the data collected from 90 common wheat varieties cultivated in four environments. Statistical analysis showed that IGC was controlled mainly genetically and influenced by the environment. Among the major genetic components known to affect end-use quality, 1BL/1RS translocation had a significantly negative effect on IGC across all four environments. As to the different alleles of Glu-A1, -B1 and -D1 loci, Glu-A1a, Glu-B1b and Glu-D1d exhibited relatively strong positive effects on IGC in all environments. To identify new loci affecting IGC, association mapping with 1355 DArT markers was conducted. A total of 133 markers were found associated with IGC in two or more environments (P < 0.05), ten of which consistently affected IGC in all four environments. The phenotypic variance explained by the ten markers varied from 4.66% to 8.03%, and their elite alleles performed significantly better than the inferior counterparts in enhancing IGC. Among the ten markers, wPt-3743 and wPt-733835 reflected the action of Glu-D1, and wPt-664972 probably indicated the effect of Glu-A1. The other seven markers, forming three clusters on 2AL, 3BL or 7BL chromosome arms, represented newly identified genetic determinants of IGC. Our work provided novel insights into the genetic control of IGC, which may facilitate wheat end-use quality improvement through molecular breeding in the future. PMID:26408094

  1. Genetic evidence for female host-specific races of the common cuckoo.

    PubMed

    Gibbs, H L; Sorenson, M D; Marchetti, K; Brooke, M D; Davies, N B; Nakamura, H

    2000-09-14

    The common cuckoo Cuculus canorus is divided into host-specific races (gentes). Females of each race lay a distinctive egg type that tends to match the host's eggs, for instance, brown and spotted for meadow pipit hosts or plain blue for redstart hosts. The puzzle is how these gentes remain distinct. Here, we provide genetic evidence that gentes are restricted to female lineages, with cross mating by males maintaining the common cuckoo genetically as one species. We show that there is differentiation between gentes in maternally inherited mitochondrial DNA, but not in microsatellite loci of nuclear DNA. This supports recent behavioural evidence that female, but not male, common cuckoos specialize on a particular host, and is consistent with the possibility that genes affecting cuckoo egg type are located on the female-specific W sex chromosome. Our results also support the ideas that common cuckoos often switched hosts during evolution, and that some gentes may have multiple, independent origins, due to colonization by separate ancestral lineages. PMID:11001055

  2. Genetic Mechanisms Involved in the Phenotype of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2007-01-01

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

  3. Assessing Genetic Structure in Common but Ecologically Distinct Carnivores: The Stone Marten and Red Fox

    PubMed Central

    Basto, Mafalda P.; Santos-Reis, Margarida; Simões, Luciana; Grilo, Clara; Cardoso, Luís; Cortes, Helder; Bruford, Michael W.; Fernandes, Carlos

    2016-01-01

    The identification of populations and spatial genetic patterns is important for ecological and conservation research, and spatially explicit individual-based methods have been recognised as powerful tools in this context. Mammalian carnivores are intrinsically vulnerable to habitat fragmentation but not much is known about the genetic consequences of fragmentation in common species. Stone martens (Martes foina) and red foxes (Vulpes vulpes) share a widespread Palearctic distribution and are considered habitat generalists, but in the Iberian Peninsula stone martens tend to occur in higher quality habitats. We compared their genetic structure in Portugal to see if they are consistent with their differences in ecological plasticity, and also to illustrate an approach to explicitly delineate the spatial boundaries of consistently identified genetic units. We analysed microsatellite data using spatial Bayesian clustering methods (implemented in the software BAPS, GENELAND and TESS), a progressive partitioning approach and a multivariate technique (Spatial Principal Components Analysis-sPCA). Three consensus Bayesian clusters were identified for the stone marten. No consensus was achieved for the red fox, but one cluster was the most probable clustering solution. Progressive partitioning and sPCA suggested additional clusters in the stone marten but they were not consistent among methods and were geographically incoherent. The contrasting results between the two species are consistent with the literature reporting stricter ecological requirements of the stone marten in the Iberian Peninsula. The observed genetic structure in the stone marten may have been influenced by landscape features, particularly rivers, and fragmentation. We suggest that an approach based on a consensus clustering solution of multiple different algorithms may provide an objective and effective means to delineate potential boundaries of inferred subpopulations. sPCA and progressive partitioning

  4. Assessing Genetic Structure in Common but Ecologically Distinct Carnivores: The Stone Marten and Red Fox.

    PubMed

    Basto, Mafalda P; Santos-Reis, Margarida; Simões, Luciana; Grilo, Clara; Cardoso, Luís; Cortes, Helder; Bruford, Michael W; Fernandes, Carlos

    2016-01-01

    The identification of populations and spatial genetic patterns is important for ecological and conservation research, and spatially explicit individual-based methods have been recognised as powerful tools in this context. Mammalian carnivores are intrinsically vulnerable to habitat fragmentation but not much is known about the genetic consequences of fragmentation in common species. Stone martens (Martes foina) and red foxes (Vulpes vulpes) share a widespread Palearctic distribution and are considered habitat generalists, but in the Iberian Peninsula stone martens tend to occur in higher quality habitats. We compared their genetic structure in Portugal to see if they are consistent with their differences in ecological plasticity, and also to illustrate an approach to explicitly delineate the spatial boundaries of consistently identified genetic units. We analysed microsatellite data using spatial Bayesian clustering methods (implemented in the software BAPS, GENELAND and TESS), a progressive partitioning approach and a multivariate technique (Spatial Principal Components Analysis-sPCA). Three consensus Bayesian clusters were identified for the stone marten. No consensus was achieved for the red fox, but one cluster was the most probable clustering solution. Progressive partitioning and sPCA suggested additional clusters in the stone marten but they were not consistent among methods and were geographically incoherent. The contrasting results between the two species are consistent with the literature reporting stricter ecological requirements of the stone marten in the Iberian Peninsula. The observed genetic structure in the stone marten may have been influenced by landscape features, particularly rivers, and fragmentation. We suggest that an approach based on a consensus clustering solution of multiple different algorithms may provide an objective and effective means to delineate potential boundaries of inferred subpopulations. sPCA and progressive partitioning

  5. Pleiotropy among Common Genetic Loci Identified for Cardiometabolic Disorders and C-Reactive Protein

    PubMed Central

    Ligthart, Symen; de Vries, Paul S.; Uitterlinden, André G.; Hofman, Albert; Franco, Oscar H.; Chasman, Daniel I.; Dehghan, Abbas

    2015-01-01

    Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes. PMID:25768928

  6. Comparative Transcriptome Analysis Reveals the Genetic Basis of Skin Color Variation in Common Carp

    PubMed Central

    Jiang, Yanliang; Zhang, Songhao; Xu, Jian; Feng, Jianxin; Mahboob, Shahid; Al-Ghanim, Khalid A.; Sun, Xiaowen; Xu, Peng

    2014-01-01

    Background The common carp is an important aquaculture species that is widely distributed across the world. During the long history of carp domestication, numerous carp strains with diverse skin colors have been established. Skin color is used as a visual criterion to determine the market value of carp. However, the genetic basis of common carp skin color has not been extensively studied. Methodology/Principal Findings In this study, we performed Illumina sequencing on two common carp strains: the reddish Xingguo red carp and the brownish-black Yellow River carp. A total of 435,348,868 reads were generated, resulting in 198,781 assembled contigs that were used as reference sequences. Comparisons of skin transcriptome files revealed 2,012 unigenes with significantly different expression in the two common carp strains, including 874 genes that were up-regulated in Xingguo red carp and 1,138 genes that were up-regulated in Yellow River carp. The expression patterns of 20 randomly selected differentially expressed genes were validated using quantitative RT-PCR. Gene pathway analysis of the differentially expressed genes indicated that melanin biosynthesis, along with the Wnt and MAPK signaling pathways, is highly likely to affect the skin pigmentation process. Several key genes involved in the skin pigmentation process, including TYRP1, SILV, ASIP and xCT, showed significant differences in their expression patterns between the two strains. Conclusions In this study, we conducted a comparative transcriptome analysis of Xingguo red carp and Yellow River carp skins, and we detected key genes involved in the common carp skin pigmentation process. We propose that common carp skin pigmentation depends upon at least three pathways. Understanding fish skin color genetics will facilitate future molecular selection of the fish skin colors with high market values. PMID:25255374

  7. No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis

    PubMed Central

    Goris, An; van Setten, Jessica; Diekstra, Frank; Ripke, Stephan; Patsopoulos, Nikolaos A.; Sawcer, Stephen J.; van Es, Michael; Andersen, Peter M.; Melki, Judith; Meininger, Vincent; Hardiman, Orla; Landers, John E.; Brown, Robert H.; Shatunov, Aleksey; Leigh, Nigel; Al-Chalabi, Ammar; Shaw, Christopher E.; Traynor, Bryan J.; Chiò, Adriano; Restagno, Gabriella; Mora, Gabriele; Ophoff, Roel A.; Oksenberg, Jorge R.; Van Damme, Philip; Compston, Alastair; Robberecht, Wim; Dubois, Bénédicte; van den Berg, Leonard H.; De Jager, Philip L.; Veldink, Jan H.; de Bakker, Paul I.W.

    2014-01-01

    Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS. PMID:24234648

  8. Common mechanisms activate plant guard receptors and TLR4

    PubMed Central

    Kagan, Jonathan C.

    2014-01-01

    In metazoans, the innate immune system uses Pattern Recognition Receptors to detect conserved microbial products, whereas in plants Guard Receptors detect virulence factors or activities encoded by pathogens. In a recent study, Williams and colleagues report that plant Guard receptors can be activated by a mechanism remarkably similar to that of mammalian Toll-like Receptor 4. PMID:25224694

  9. Nitrogen fixation: key genetic regulatory mechanisms.

    PubMed

    Martinez-Argudo, I; Little, R; Shearer, N; Johnson, P; Dixon, R

    2005-02-01

    The necessity to respond to the level of fixed nitrogen and external oxygen concentrations and to provide sufficient energy for nitrogen fixation imposes common regulatory principles amongst diazotrophs. The NifL-NifA system in Azotobacter vinelandii integrates the signals of redox, fixed-nitrogen and carbon status to regulate nif transcription. Multidomain signalling interactions between NifL and NifA are modulated by redox changes, ligand binding and interaction with the signal-transduction protein GlnK. Under adverse redox conditions (excess oxygen) or when fixed nitrogen is in excess, NifL forms a complex with NifA in which transcriptional activation is prevented. Oxidized NifL forms a binary complex with NifA to inhibit NifA activity. When fixed nitrogen is in excess, the non-covalently modified form of GlnK interacts with NifL to promote the formation of a GlnK-NifL-NifA ternary complex. When the cell re-encounters favourable conditions for nitrogen fixation, it is necessary to deactivate the signals to ensure that the NifL-NifA complex is dissociated so that NifA is free to activate transcription. This is achieved through interactions with 2-oxoglutarate, a key metabolic signal of the carbon status, which binds to the N-terminal GAF (cGMP-specific and stimulated phosphodiesterases, Anabaena adenylate cyclases and Escherichia coli FhlA) domain of NifA. PMID:15667291

  10. A common genetic influence on human intensity ratings of sugars and high-potency sweeteners.

    PubMed

    Hwang, Liang-Dar; Zhu, Gu; Breslin, Paul A S; Reed, Danielle R; Martin, Nicholas G; Wright, Margaret J

    2015-08-01

    The perception of sweetness varies among individuals but the sources of this variation are not fully understood. Here, in a sample of 1,901 adolescent and young adults (53.8% female; 243 MZ and 452 DZ twin pairs, 511 unpaired individuals; mean age 16.2±2.8, range 12–26 years), we studied the variation in the perception of sweetness intensity of two monosaccharides and two high-potency sweeteners: glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame. Perceived intensity for all sweeteners decreased with age (2–5% per year) and increased with the history of otitis media (6–9%). Males rated aspartame slightly stronger than females (7%). We found similar heritabilities for sugars (glucose: h2=0.31, fructose: h2=0.34) and high-potency sweeteners (NHDC: h2=0.31, aspartame: h2=0.30); all were in the modest range. Multivariate modeling showed that a common genetic factor accounted for >75% of the genetic variance in the four sweeteners, suggesting that individual differences in perceived sweet intensity, which are partly due to genetic factors, may be attributed to a single set of genes. This study provided evidence of the shared genetic pathways between the perception of sugars and high-potency sweeteners. PMID:26181574

  11. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    PubMed Central

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  12. The Oncolytic Poxvirus JX-594 Selectively Replicates in and Destroys Cancer Cells Driven by Genetic Pathways Commonly Activated in Cancers

    PubMed Central

    Parato, Kelley A; Breitbach, Caroline J; Le Boeuf, Fabrice; Wang, Jiahu; Storbeck, Chris; Ilkow, Carolina; Diallo, Jean-Simon; Falls, Theresa; Burns, Joseph; Garcia, Vanessa; Kanji, Femina; Evgin, Laura; Hu, Kang; Paradis, Francois; Knowles, Shane; Hwang, Tae-Ho; Vanderhyden, Barbara C; Auer, Rebecca; Kirn, David H; Bell, John C

    2012-01-01

    Oncolytic viruses are generally designed to be cancer selective on the basis of a single genetic mutation. JX-594 is a thymidine kinase (TK) gene-inactivated oncolytic vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and lac-Z transgenes that is designed to destroy cancer cells through replication-dependent cell lysis and stimulation of antitumoral immunity. JX-594 has demonstrated a favorable safety profile and reproducible tumor necrosis in a variety of solid cancer types in clinical trials. However, the mechanism(s) responsible for its cancer-selectivity have not yet been well described. We analyzed the replication of JX-594 in three model systems: primary normal and cancer cells, surgical explants, and murine tumor models. JX-594 replication, transgene expression, and cytopathic effects were highly cancer-selective, and broad spectrum activity was demonstrated. JX-594 cancer-selectivity was multi-mechanistic; replication was activated by epidermal growth factor receptor (EGFR)/Ras pathway signaling, cellular TK levels, and cancer cell resistance to type-I interferons (IFNs). These findings confirm a large therapeutic index for JX-594 that is driven by common genetic abnormalities in human solid tumors. This appears to be the first description of multiple selectivity mechanisms, both inherent and engineered, for an oncolytic virus. These findings have implications for oncolytic viruses in general, and suggest that their cancer targeting is a complex and multifactorial process. PMID:22186794

  13. Genetics of common forms of heart failure: challenges and potential solutions

    PubMed Central

    Rau, Christoph D.; Lusis, Aldons J.; Wang, Yibin

    2015-01-01

    Purpose of review In contrast to many other human diseases, the use of genome-wide association studies (GWAS) to identify genes for heart failure (HF) has had limited success. We will discuss the underlying challenges as well as potential new approaches to understanding the genetics of common forms of HF. Recent findings Recent research using intermediate phenotypes, more detailed and quantitative stratification of HF symptoms, founder populations and novel animal models has begun to allow researchers to make headway toward explaining the genetics underlying HF using GWAS techniques. Summary By expanding analyses of HF to improved clinical traits, additional HF classifications and innovative model systems, the intractability of human HF GWAS should be ameliorated significantly. PMID:25768955

  14. Common Brain Mechanisms of Chronic Pain and Addiction.

    PubMed

    Elman, Igor; Borsook, David

    2016-01-01

    While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients. PMID:26748087

  15. Genetic variability for iron and zinc content in common bean lines and interaction with water availability.

    PubMed

    Pereira, H S; Del Peloso, M J; Bassinello, P Z; Guimarães, C M; Melo, L C; Faria, L C

    2014-01-01

    The common bean is an important source of iron and zinc in humans. Increases in the contents of these minerals can combat mineral deficiencies, but these contents are influenced by environmental conditions. Thus, the objectives of this study were to investigate the interaction between common bean lines and water availability on iron and zinc contents (CFe and CZn, respectively), identify superior lines with stable CFe and CZn, and test for a genetic relationship between CFe and CZn. Six crop trials were performed using a randomized block design with three replications. The trials were performed during the winter sowing period for three different combinations of year and site in Brazil. For each combination, 53 lines were evaluated across two parallel trials; one trial was irrigated according to the crop requirements, and the other trial operated under a water deficit. Interaction was detected between lines and environments, and between lines and water availability for CFe and CZn. However, some lines exhibited high CFe and CZn in both conditions. Lines G 6492 and G 6490 exhibited high mean values, stability, and adaptability for both minerals. Other lines exhibited high CFe (Xamego) or CZn (Bambuí and Iapar 65). A moderate genetic correlation (0.62) between CFe and CZn was detected. Water availability during the common bean cycle had an effect on CFe and CZn; however, lines with high CFe and CZn in different conditions of water availability and environment were detected. PMID:25177957

  16. A Common Mechanism Underlying Food Choice and Social Decisions.

    PubMed

    Krajbich, Ian; Hare, Todd; Bartling, Björn; Morishima, Yosuke; Fehr, Ernst

    2015-10-01

    People make numerous decisions every day including perceptual decisions such as walking through a crowd, decisions over primary rewards such as what to eat, and social decisions that require balancing own and others' benefits. The unifying principles behind choices in various domains are, however, still not well understood. Mathematical models that describe choice behavior in specific contexts have provided important insights into the computations that may underlie decision making in the brain. However, a critical and largely unanswered question is whether these models generalize from one choice context to another. Here we show that a model adapted from the perceptual decision-making domain and estimated on choices over food rewards accurately predicts choices and reaction times in four independent sets of subjects making social decisions. The robustness of the model across domains provides behavioral evidence for a common decision-making process in perceptual, primary reward, and social decision making. PMID:26460812

  17. A Common Mechanism Underlying Food Choice and Social Decisions

    PubMed Central

    Krajbich, Ian; Hare, Todd; Bartling, Björn; Morishima, Yosuke; Fehr, Ernst

    2015-01-01

    People make numerous decisions every day including perceptual decisions such as walking through a crowd, decisions over primary rewards such as what to eat, and social decisions that require balancing own and others’ benefits. The unifying principles behind choices in various domains are, however, still not well understood. Mathematical models that describe choice behavior in specific contexts have provided important insights into the computations that may underlie decision making in the brain. However, a critical and largely unanswered question is whether these models generalize from one choice context to another. Here we show that a model adapted from the perceptual decision-making domain and estimated on choices over food rewards accurately predicts choices and reaction times in four independent sets of subjects making social decisions. The robustness of the model across domains provides behavioral evidence for a common decision-making process in perceptual, primary reward, and social decision making. PMID:26460812

  18. Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

    PubMed Central

    Bakken, Trygve E.; Roddey, J. Cooper; Djurovic, Srdjan; Akshoomoff, Natacha; Amaral, David G.; Bloss, Cinnamon S.; Casey, B. J.; Chang, Linda; Ernst, Thomas M.; Gruen, Jeffrey R.; Jernigan, Terry L.; Kaufmann, Walter E.; Kenet, Tal; Kennedy, David N.; Kuperman, Joshua M.; Murray, Sarah S.; Sowell, Elizabeth R.; Rimol, Lars M.; Mattingsdal, Morten; Melle, Ingrid; Agartz, Ingrid; Andreassen, Ole A.; Schork, Nicholas J.; Dale, Anders M.

    2012-01-01

    Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (Pcombined = 3.2 × 10−8). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10−9) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5′ UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception. PMID:22343285

  19. PERIODIC LATERALIZED EPILEPTIFORM DISCHARGES AND AFTERDISCHARGES: COMMON DYNAMIC MECHANISMS

    PubMed Central

    Kalamangalam, Giridhar P; Slater, Jeremy D

    2015-01-01

    Objective No neurophysiological hypothesis currently exist addressing how and why periodic lateralized epileptiform discharges (PLEDs) arise in certain types of brain disease. Based on spectral analysis of clinical scalp EEG traces, we formulated a general mechanism for the emergence of PLEDs. Methods We retrospectively analyzed spectra of PLED time-series and control EEG segments from the opposite hemisphere in 25 hospitalized neurological patients. The observations led to the development of a phenomenological model for PLED emergence. Results Similar to that observed in our previous work (Kalamangalam et al. 2014) with afterdischarges, an analytic relationship is found between the spectrum of the baseline EEG and the PLED EEG, characterized by ‘condensation’ of the main baseline spectral cluster, with variable inclusion of higher harmonics of the condensate. Significance PLEDs may arise by synchronization of pre-existing local field potentials, through a variable combination of enhancement of excitatory neurotransmission and inactivation of inhibitory neurotransmission provoked by the PLED-associated disease process. Higher harmonics in the PLED spectrum may arise by recurrent feedback, possibly from entrained single units. Significance A mechanism is suggested for PLED emergence in certain diseased brain states, and the association of PLEDs with EEG seizures. The framework is a spatially extended version of that which we proposed underlies afterdischarge, and analogous to the cooperative behavior seen in a variety of natural multi-oscillator systems. PMID:25710632

  20. Evaluation of Mechanical Losses in Piezoelectric Plates using Genetic algorithm

    NASA Astrophysics Data System (ADS)

    Arnold, F. J.; Gonçalves, M. S.; Massaro, F. R.; Martins, P. S.

    Numerical methods are used for the characterization of piezoelectric ceramics. A procedure based on genetic algorithm is applied to find the physical coefficients and mechanical losses. The coefficients are estimated from a minimum scoring of cost function. Electric impedances are calculated from Mason's model including mechanical losses constant and dependent on frequency as a linear function. The results show that the electric impedance percentage error in the investigated interval of frequencies decreases when mechanical losses depending on frequency are inserted in the model. A more accurate characterization of the piezoelectric ceramics mechanical losses should be considered as frequency dependent.

  1. Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss – A Common Hereditary Deafness

    PubMed Central

    Wingard, Jeffrey C.; Zhao, Hong-Bo

    2015-01-01

    Hearing loss due to mutations in the connexin gene family, which encodes gap junctional proteins, is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2) mutations are responsible for ~50% of non-syndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. However, there is no apparent, demonstrable relationship between specific changes in connexin (channel) functions and the phenotypes of mutation-induced hearing loss. Moreover, new experiments further demonstrate that the hypothesized K+-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Cx30 (GJB6), Cx29 (GJC3), Cx31 (GJB3), and Cx43 (GJA1) mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation-induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes remain unclear. Also, little is known about specific mutation-induced pathological changes in vivo and little information is available for humans. Such further studies are urgently required. PMID:26074771

  2. Memory, reasoning, and categorization: parallels and common mechanisms

    PubMed Central

    Hayes, Brett K.; Heit, Evan; Rotello, Caren M.

    2014-01-01

    Traditionally, memory, reasoning, and categorization have been treated as separate components of human cognition. We challenge this distinction, arguing that there is broad scope for crossover between the methods and theories developed for each task. The links between memory and reasoning are illustrated in a review of two lines of research. The first takes theoretical ideas (two-process accounts) and methodological tools (signal detection analysis, receiver operating characteristic curves) from memory research and applies them to important issues in reasoning research: relations between induction and deduction, and the belief bias effect. The second line of research introduces a task in which subjects make either memory or reasoning judgments for the same set of stimuli. Other than broader generalization for reasoning than memory, the results were similar for the two tasks, across a variety of experimental stimuli and manipulations. It was possible to simultaneously explain performance on both tasks within a single cognitive architecture, based on exemplar-based comparisons of similarity. The final sections explore evidence for empirical and processing links between inductive reasoning and categorization and between categorization and recognition. An important implication is that progress in all three of these fields will be expedited by further investigation of the many commonalities between these tasks. PMID:24987380

  3. 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.

  4. Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases

    PubMed Central

    Mostowy, Joanna; Montén, Caroline; Gudjonsdottir, Audur H.; Arnell, Henrik; Browaldh, Lars; Nilsson, Staffan; Agardh, Daniel

    2016-01-01

    Background and Objectives Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. Material and Methods Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6–17.8) and from 154 disease controls at a median (range) age 11.4.years (1.4–18.3). Results A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. Conclusion Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases. PMID:27483138

  5. Common Mechanisms Underlying Epileptogenesis and the Comorbidities of Epilepsy.

    PubMed

    Mazarati, Andrey; Sankar, Raman

    2016-01-01

    The importance of comorbidities in determining the quality of life of individuals with epilepsy and their families has received increasing attention in the past decade. Along with it has come a recognition that in some individuals, certain comorbidities may have preexisted, and may have contributed to their developing epilepsy. Many mechanisms are capable of interconnecting different dysfunctions that manifest as distinct disorders, often diagnosed and managed by different specialists. We review the human data from the perspective of epidemiology as well as insights gathered from neurodiagnostic and endocrine studies. Animal studies are reviewed to refine our mechanistic understanding of the connections, because they permit the narrowing of variables, which is not possible when studying humans. PMID:27371669

  6. An Overview of Genetic Mechanisms in the Bacterial Cell.

    ERIC Educational Resources Information Center

    Metcalfe, Judith; Baumberg, Simon

    1988-01-01

    Outlines the genetic elements found in the bacterial cell which play a role in recombining DNA sequences. Provides a core structure to which the mechanisms occurring in and between bacterial cells can be related. Discusses the practicalities of recombinant DNA techniques. (Author/CW)

  7. Mixed reproductive strategies of the Common moorhen on a microscale as revealed by genetic data.

    PubMed

    Loyau, Adeline; Schmeller, Dirk S

    2012-01-01

    External factors shaping reproductive strategies within a population are still poorly understood. How individuals use space and where they decide to build a nest may influence reproductive strategies, as individuals that are close in space may more frequently interact socially. Here, we investigated a population (n=58 from 15 nests) of the Common moorhen in the Loir river (Western France) using microsatellite data (54 alleles). We found a surprisingly low level of genetic monogamy, a low relatedness among offspring in some nests and a low relatedness between the social parents and the offspring. Nest heterozygosity was highest close to the geographic center of the population. The mating strategies of the Common moorhen were highly variable, despite the social monogamy of the species, and were, to some extent, influenced by the microspatial structure. We discuss how our results contribute to the understanding of parent-offspring and offspring-offspring relationships. PMID:23199635

  8. Inheritance of seed α-amylase inhibitor in the common bean and genetic relationship to arcelin.

    PubMed

    Suzuki, K; Ishimoto, M; Iwanaga, M; Kikuchi, F; Kitamura, K

    1995-05-01

    The inheritance of seed α-amylase inhibitor in the common bean and the genetic relationships among the variants and six arcelin variants in the common bean were investigated by crossing between accessions containing different αAI and arcelin variants. All seed proteins in parental, F1 and F2 seeds from the crosses were examined by Western-blot analysis. All F1 seeds gave combined αAI banding patterns from parents on the blotting membranes. The segregation of F2 seeds for αAI variants indicated that the polypeptides of αAI variants were inherited as single co-dominant units. Moreover, αAI and arcelin behaved as a single block in crosses, indicating a close linkage relationship between the genes controlling these proteins. PMID:24172916

  9. The Relationship Between the Genetic and Environmental Influences on Common Internalizing Psychiatric Disorders and Mental Well-Being

    PubMed Central

    Myers, John M.; Maes, Hermine H.; Keyes, Corey L. M.

    2011-01-01

    To determine the relationship between the genetic and environmental risk factors for common internalizing psychopathology (IP) and mental well-being (MWB), we examined detailed measures of emotional, social and psychological well-being, and a history of major depression (MD), generalized anxiety disorder (GAD) and panic attacks in the last year, in 1,386 twins from same-sex pairs from the MIDUS national USA sample assessed in 1995 and then again in 2005. Statistical analyses were performed with the Mx program. In the 1995 data, the best fit model contained one substantially heritable common factor for MD, GAD and panic attacks, and one strongly heritable common factor for the three well-being measures. Genetic and environmental risk factors for IP accounted for, respectively, 50 and 5%, of the genetic and environmental influences on MWB. We then constructed, using 1995 and 2005 data, two common factors that reflected temporally stable influences on (i) MD and GAD, and (ii) on emotional and psychological well-being. Genetic and environmental risk factors for the stable liability to IP accounted for 41 and 29% of the stable genetic and environmental influences, respectively, on MWB. This study suggests that genetic risk factors for IP make up 41–50% of the genetic influences on MWB. The overlap of environmental risk factors is more modest. Although low levels of IP on average reflect a high genetic propensity for MWB, other independent genetic influences play an important role in producing good mental health. PMID:21451959

  10. Innovation and problem solving: a review of common mechanisms.

    PubMed

    Griffin, Andrea S; Guez, David

    2014-11-01

    Behavioural innovations have become central to our thinking about how animals adjust to changing environments. It is now well established that animals vary in their ability to innovate, but understanding why remains a challenge. This is because innovations are rare, so studying innovation requires alternative experimental assays that create opportunities for animals to express their ability to invent new behaviours, or use pre-existing ones in new contexts. Problem solving of extractive foraging tasks has been put forward as a suitable experimental assay. We review the rapidly expanding literature on problem solving of extractive foraging tasks in order to better understand to what extent the processes underpinning problem solving, and the factors influencing problem solving, are in line with those predicted, and found, to underpin and influence innovation in the wild. Our aim is to determine whether problem solving can be used as an experimental proxy of innovation. We find that in most respects, problem solving is determined by the same underpinning mechanisms, and is influenced by the same factors, as those predicted to underpin, and to influence, innovation. We conclude that problem solving is a valid experimental assay for studying innovation, propose a conceptual model of problem solving in which motor diversity plays a more central role than has been considered to date, and provide recommendations for future research using problem solving to investigate innovation. This article is part of a Special Issue entitled: Cognition in the wild. PMID:25245306

  11. Common Neural Mechanisms Underlying Reversal Learning by Reward and Punishment

    PubMed Central

    Xue, Gui; Xue, Feng; Droutman, Vita; Lu, Zhong-Lin; Bechara, Antoine; Read, Stephen

    2013-01-01

    Impairments in flexible goal-directed decisions, often examined by reversal learning, are associated with behavioral abnormalities characterized by impulsiveness and disinhibition. Although the lateral orbital frontal cortex (OFC) has been consistently implicated in reversal learning, it is still unclear whether this region is involved in negative feedback processing, behavioral control, or both, and whether reward and punishment might have different effects on lateral OFC involvement. Using a relatively large sample (N = 47), and a categorical learning task with either monetary reward or moderate electric shock as feedback, we found overlapping activations in the right lateral OFC (and adjacent insula) for reward and punishment reversal learning when comparing correct reversal trials with correct acquisition trials, whereas we found overlapping activations in the right dorsolateral prefrontal cortex (DLPFC) when negative feedback signaled contingency change. The right lateral OFC and DLPFC also showed greater sensitivity to punishment than did their left homologues, indicating an asymmetry in how punishment is processed. We propose that the right lateral OFC and anterior insula are important for transforming affective feedback to behavioral adjustment, whereas the right DLPFC is involved in higher level attention control. These results provide insight into the neural mechanisms of reversal learning and behavioral flexibility, which can be leveraged to understand risky behaviors among vulnerable populations. PMID:24349211

  12. The mGA1.0: A common LISP implementation of a messy genetic algorithm

    NASA Technical Reports Server (NTRS)

    Goldberg, David E.; Kerzic, Travis

    1990-01-01

    Genetic algorithms (GAs) are finding increased application in difficult search, optimization, and machine learning problems in science and engineering. Increasing demands are being placed on algorithm performance, and the remaining challenges of genetic algorithm theory and practice are becoming increasingly unavoidable. Perhaps the most difficult of these challenges is the so-called linkage problem. Messy GAs were created to overcome the linkage problem of simple genetic algorithms by combining variable-length strings, gene expression, messy operators, and a nonhomogeneous phasing of evolutionary processing. Results on a number of difficult deceptive test functions are encouraging with the mGA always finding global optima in a polynomial number of function evaluations. Theoretical and empirical studies are continuing, and a first version of a messy GA is ready for testing by others. A Common LISP implementation called mGA1.0 is documented and related to the basic principles and operators developed by Goldberg et. al. (1989, 1990). Although the code was prepared with care, it is not a general-purpose code, only a research version. Important data structures and global variations are described. Thereafter brief function descriptions are given, and sample input data are presented together with sample program output. A source listing with comments is also included.

  13. Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits.

    PubMed

    Ulirsch, Jacob C; Nandakumar, Satish K; Wang, Li; Giani, Felix C; Zhang, Xiaolan; Rogov, Peter; Melnikov, Alexandre; McDonel, Patrick; Do, Ron; Mikkelsen, Tarjei S; Sankaran, Vijay G

    2016-06-01

    Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164. Functional follow-up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type-specific transcriptional regulatory pathways. PMID:27259154

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

    PubMed Central

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

    2015-01-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings. PMID:26051359

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

    NASA Astrophysics Data System (ADS)

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

    2015-06-01

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

  16. The role of common genetic variation in educational attainment and income: evidence from the National Child Development Study

    PubMed Central

    Davies, Neil M.; Hemani, Gibran; Timpson, Nic J.; Windmeijer, Frank; Davey Smith, George

    2015-01-01

    We investigated the role of common genetic variation in educational attainment and household income. We used data from 5,458 participants of the National Child Development Study to estimate: 1) the associations of rs9320913, rs11584700 and rs4851266 and socioeconomic position and educational phenotypes; and 2) the univariate chip-heritability of each phenotype, and the genetic correlation between each phenotype and educational attainment at age 16. The three SNPs were associated with most measures of educational attainment. Common genetic variation contributed to 6 of 14 socioeconomic background phenotypes, and 17 of 29 educational phenotypes. We found evidence of genetic correlations between educational attainment at age 16 and 4 of 14 social background and 8 of 28 educational phenotypes. This suggests common genetic variation contributes both to differences in educational attainment and its relationship with other phenotypes. However, we remain cautious that cryptic population structure, assortative mating, and dynastic effects may influence these associations. PMID:26561353

  17. Genetic potential of common bean progenies selected for crude fiber content obtained through different breeding methods.

    PubMed

    Júnior, V A P; Melo, P G S; Pereira, H S; Bassinello, P Z; Melo, L C

    2015-01-01

    Gastrointestinal health is of great importance due to the increasing consumption of functional foods, especially those concern-ing diets rich in fiber content. The common bean has been valorized as a nutritious food due to its appreciable fiber content and the fact that it is consumed in many countries. The current study aimed to evaluate and compare the genetic potential of common bean progenies of the carioca group, developed through different breeding methods, for crude fiber content. The progenies originated through hybridization of two advanced strains, CNFC 7812 and CNFC 7829, up to the F7 generation using three breeding methods: bulk-population, bulk within F2 families, and single seed descent. Fifteen F8 progenies were evaluated in each method, as well as two check cultivars and both parents, us-ing a 7 x 7 simple lattice design, with experimental plots comprised of two 4-m long rows. Field trials were conducted in eleven environments encompassing four Brazilian states and three different sowing times during 2009 and 2010. Estimates of genetic parameters indicate differences among the breeding methods, which seem to be related to the different processes for sampling the advanced progenies inherent to each method, given that the trait in question is not subject to natural selection. Variability amongst progenies occurred within the three breeding methods and there was also a significant effect of environment on the progeny for all methods. Progenies developed by bulk-population attained the highest estimates of genetic parameters, had less interaction with the environment, and greater variability. PMID:26125775

  18. Development of taxon-specific sequences of common wheat for the detection of genetically modified wheat.

    PubMed

    Iida, Mayu; Yamashiro, Satomi; Yamakawa, Hirohito; Hayakawa, Katsuyuki; Kuribara, Hideo; Kodama, Takashi; Furui, Satoshi; Akiyama, Hiroshi; Maitani, Tamio; Hino, Akihiro

    2005-08-10

    Qualitative and quantitative Polymerase Chain Reaction (PCR) systems aimed at the specific detection and quantification of common wheat DNA are described. Many countries have issued regulations to label foods that include genetically modified organisms (GMOs). PCR technology is widely recognized as a reliable and useful technique for the qualitative and quantitative detection of GMOs. Detection methods are needed to amplify a target GM gene, and the amplified results should be compared with those of the corresponding taxon-specific reference gene to obtain reliable results. This paper describes the development of a specific DNA sequence in the waxy-D1 gene for common wheat (Triticum aestivum L.) and the design of a specific primer pair and TaqMan probe on the waxy-D1 gene for PCR analysis. The primers amplified a product (Wx012) of 102 bp. It is indicated that the Wx012 DNA sequence is specific to common wheat, showing homogeneity in qualitative PCR results and very similar quantification accuracy along 19 distantly related common wheat varieties. In Southern blot and real-time PCR analyses, this sequence showed either a single or a low number of copy genes. In addition, by qualitative and quantitative PCR using wx012 primers and a wx012-T probe, the limits of detection of the common wheat genome were found to be about 15 copies, and the reproducibility was reliable. In consequence, the PCR system using wx012 primers and wx012-T probe is considered to be suitable for use as a common wheat-specific taxon-specific reference gene in DNA analyses, including GMO tests. PMID:16076109

  19. Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes

    PubMed Central

    Tare, Archana; Lane, Jacqueline M.; Cade, Brian E.; Grant, Struan F. A.; Chen, Ting-hsu; Punjabi, Naresh M.; Lauderdale, Diane S.; Zee, Phyllis C.; Gharib, Sina A.; Gottlieb, Daniel J.; Scheer, Frank A. J. L.; Redline, Susan; Saxena, Richa

    2014-01-01

    Aims/hypothesis Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits. Methods We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (≤5 h or ≥9 h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene × behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk. Results Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05). Conclusions/interpretation Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes. PMID:24280871

  20. Genetic basis of cell-cell fusion mechanisms

    PubMed Central

    Aguilar, Pablo S.; Baylies, Mary K.; Fleissner, Andre; Helming, Laura; Inoue, Naokazu; Podbilewicz, Benjamin; Wang, Hongmei; Wong, Melissa

    2013-01-01

    Cell-cell fusion in sexually reproducing organisms is a mechanism to merge gamete genomes, and in multicellular organisms, it is a strategy to sculpt organs such as muscles, bones, and placenta. Moreover, this mechanism has been implicated in pathological conditions such as infection and cancer. Study of genetic model organisms has uncovered a unifying principle: cell fusion is a genetically programmed process. This process can be divided in three stages: (i) competence: cell induction and differentiation, (ii) commitment: cell determination, migration and adhesion, and (iii) cell fusion: membrane merging and cytoplasmic mixing. Recent work has led to the discovery of fusogens, cell fusion proteins that are necessary and sufficient to fuse cell membranes. Two unrelated families of fusogens have been discovered, one in mouse placenta and one in Caenorhabditis elegans (Syncytins and F proteins, respectively). Current research aims to identify new fusogens and determine the mechanisms by which fusogens merge membranes. PMID:23453622

  1. Genetic basis of cell-cell fusion mechanisms.

    PubMed

    Aguilar, Pablo S; Baylies, Mary K; Fleissner, Andre; Helming, Laura; Inoue, Naokazu; Podbilewicz, Benjamin; Wang, Hongmei; Wong, Melissa

    2013-07-01

    Cell-cell fusion in sexually reproducing organisms is a mechanism to merge gamete genomes and, in multicellular organisms, it is a strategy to sculpt organs, such as muscle, bone, and placenta. Moreover, this mechanism has been implicated in pathological conditions, such as infection and cancer. Studies of genetic model organisms have uncovered a unifying principle: cell fusion is a genetically programmed process. This process can be divided in three stages: competence (cell induction and differentiation); commitment (cell determination, migration, and adhesion); and cell fusion (membrane merging and cytoplasmic mixing). Recent work has led to the discovery of fusogens, which are cell fusion proteins that are necessary and sufficient to fuse cell membranes. Two unrelated families of fusogens have been discovered, one in mouse placenta and one in Caenorhabditis elegans (syncytins and F proteins, respectively). Current research aims to identify new fusogens and determine the mechanisms by which they merge membranes. PMID:23453622

  2. A Common Mechanism of Multi-timescale Abrupt Global Change

    NASA Astrophysics Data System (ADS)

    Duke, J. H.

    2008-12-01

    The La Nina phase of the El Nino/Southern Oscillation (ENSO) is known to cause global cooling on inter- annual timescales through changes in deep convection patterns and reduced supply of water vapor to the tropical atmosphere. Two distinct means are presented here by which this mechanism may also act on timescales exceeding 100,000 years. Firstly, the hypothesis of millennial tidal forcing is revisited with the view that equatorial buoyancy frequencies and steep internal waves in the Pacific Equatorial Undercurrent make vertical mixing in the equatorial Pacific uniquely susceptible to incremental changes in tidal energy. Hourly Tropical Ocean Array subsurface temperature data show a resonant response to extreme tides associated with the 1997 and 2000 ENSO events. Complimenting the known 1,800 year peak tide cycle, a 550-600 year cycle of three-fold variation in the frequency of deep central eclipses (gamma < 0.05) is consistent with the timing of the Little Ice Age. Fortnightly eclipse triples (FET's) associated with this eclipse cycle are shown to coincide with both warm and cold phase Southern Oscillation Index (SOI) inflection points between 1876 and 2007, and notably the cold phase maxima of 1904 and 1917. In the second proposed trigger, southward migration of the intertropical convergence zone (ITCZ) in the central and eastern Pacific may periodically shift the rising branch of the Hadley circulation over the equatorial cold tongue. The resulting winter monsoon system develops an equatorially symmetric La Nina (ESLN) mode through a positive feedback between diverging surface winds and meridional rather than zonal SST gradients. Exchange of latent heat in the winter monsoon contracts the Hadley Cell, draws circumpolar westerly winds equatorward, and expands high latitude ice volume, as demonstrated in 1998. A three million year record of obliquity and August 10°N minus 10°S insolation (AUG10N-S) shows an ice volume dependence upon the mutual direction of

  3. Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD

    PubMed Central

    Hamshere, Marian; Holmans, Peter; Langley, Kate; Zaharieva, Irina; Hawi, Ziarah; Kent, Lindsey; Gill, Michael; Williams, Nigel; Owen, Michael J.; O'Donovan, Michael

    2012-01-01

    Objective: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. Method: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. Results: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. Conclusions: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways. PMID:22420046

  4. Common genetic variants and gene expression associated with white matter microstructure in the human brain

    PubMed Central

    Sprooten, Emma; Knowles, Emma E; McKay, D Reese; Göring, Harald HH; Curran, Joanne E; Kent, Jack W; Carless, Melanie A; Dyer, Thomas D; Drigalenko, Eugene I; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Kochunov, Peter; Blangero, John; Glahn, David C

    2014-01-01

    Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. PMID:24736177

  5. Common genetic variants and gene expression associated with white matter microstructure in the human brain.

    PubMed

    Sprooten, Emma; Knowles, Emma E; McKay, D Reese; Göring, Harald H; Curran, Joanne E; Kent, Jack W; Carless, Melanie A; Dyer, Thomas D; Drigalenko, Eugene I; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Kochunov, Peter; Blangero, John; Glahn, David C

    2014-08-15

    Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. PMID:24736177

  6. Generation of Compliant Mechanisms using Hybrid Genetic Algorithm

    NASA Astrophysics Data System (ADS)

    Sharma, D.; Deb, K.

    2014-10-01

    Compliant mechanism is a single piece elastic structure which can deform to perform the assigned task. In this work, compliant mechanisms are evolved using a constraint based bi-objective optimization formulation which requires one user defined parameter ( η). This user defined parameter limits a gap between a desired path and an actual path traced by the compliant mechanism. The non-linear and discrete optimization problems are solved using the hybrid Genetic Algorithm (GA) wherein domain specific initialization, two-dimensional crossover operator and repairing techniques are adopted. A bit-wise local search method is used with elitist non-dominated sorting genetic algorithm to further refine the compliant mechanisms. Parallel computations are performed on the master-slave architecture to reduce the computation time. A parametric study is carried out for η value which suggests a range to evolve topologically different compliant mechanisms. The applied and boundary conditions to the compliant mechanisms are considered the variables that are evolved by the hybrid GA. The post-analysis of results unveils that the complaint mechanisms are always supported at unique location that can evolve the non-dominated solutions.

  7. Assignment of symbiotic developmental phenotypes to common and specific nodulation (nod) genetic loci of Rhizobium meliloti.

    PubMed Central

    Debellé, F; Rosenberg, C; Vasse, J; Maillet, F; Martinez, E; Dénarié, J; Truchet, G

    1986-01-01

    Rhizobium meliloti nodulation (nod) genes required for specific infection and nodulation of alfalfa have been cloned. Transposon Tn5 mutagenesis defined three nod regions spanning 16 kilobases of the pSym megaplasmid. Genetic and cytological studies of 62 nodulation-defective mutants allowed the assignment of symbiotic developmental phenotypes to common and specific nod loci. Root hair curling was determined by both common (region I) and specific (region III) nod transcription units; locus IIIb (nodH gene) positively controlled curling on the homologous host alfalfa, whereas loci IIIa (nodFE) and IIIb (nodH) negatively controlled curling on heterologous hosts. Region I (nodABC) was required for bacterial penetration and infection thread initiation in shepherd's crooks, and the nodFE transcription unit controlled infection thread development within the alfalfa root hair. In contrast, induction of nodule organogenesis, which can be triggered from a distance, seemed to be controlled by common nodABC genes and not to require specific nod genes nodFE and nodH. Region II affected the efficiency of hair curling and infection thread formation. Images PMID:3023297

  8. Common Genetic Variants in FOXP2 Are Not Associated with Individual Differences in Language Development.

    PubMed

    Mueller, Kathryn L; Murray, Jeffrey C; Michaelson, Jacob J; Christiansen, Morten H; Reilly, Sheena; Tomblin, J Bruce

    2016-01-01

    Much of our current knowledge regarding the association of FOXP2 with speech and language development comes from singleton and small family studies where a small number of rare variants have been identified. However, neither genome-wide nor gene-specific studies have provided evidence that common polymorphisms in the gene contribute to individual differences in language development in the general population. One explanation for this inconsistency is that previous studies have been limited to relatively small samples of individuals with low language abilities, using low density gene coverage. The current study examined the association between common variants in FOXP2 and a quantitative measure of language ability in a population-based cohort of European decent (n = 812). No significant associations were found for a panel of 13 SNPs that covered the coding region of FOXP2 and extended into the promoter region. Power analyses indicated we should have been able to detect a QTL variance of 0.02 for an associated allele with MAF of 0.2 or greater with 80% power. This suggests that, if a common variant associated with language ability in this gene does exist, it is likely of small effect. Our findings lead us to conclude that while genetic variants in FOXP2 may be significant for rare forms of language impairment, they do not contribute appreciably to individual variation in the normal range as found in the general population. PMID:27064276

  9. [Genetic control of embryo lethality in crosses between common wheat and rye].

    PubMed

    Tikhenko, N D; Tsvetkova, N V; Voĭlokov, A V

    2005-08-01

    The phenotypic manifestation and genetic control of embryo lethality observed in crosses between common wheat and rye were studied. It was found that crosses between common wheat and inbred self-fertile rye lines L2 and 535 gave rise to ungerminating grains, in which the development and differentiation of the hybrid embryo are arrested. Study of the degree of embryo development in the hybrid grains obtained by crossing common wheat varieties with inbred rye lines L2 and 535 showed that genotypes of the parents affected the ratio between undifferentiated embryos of various sizes. Analysis of this trait was performed by test crosses according to a novel pedigree program with the use of interlinear hybrids and a set of fourth-generation hybrid recombinant inbred lines. Rye line L2 was shown to bear the Eml (Embryo lethality) gene, which terminates the development of the hybrid embryo in amphihaploids. The suggestion of complementary interaction between wheat and rye genes during formation of a "n ew" character in wheat-rye F1 hybrids is discussed. A method of detecting an allele not complementary to the rye Eml allele in wheat is proposed. The proposed test program allows appropriate study of the system of wheat and rye genes involved in complementary interaction in the genotype of a distant hybrid. PMID:16161628

  10. Common Genetic Variants in FOXP2 Are Not Associated with Individual Differences in Language Development

    PubMed Central

    Mueller, Kathryn L.; Murray, Jeffrey C.; Michaelson, Jacob J.; Christiansen, Morten H.; Reilly, Sheena; Tomblin, J. Bruce

    2016-01-01

    Much of our current knowledge regarding the association of FOXP2 with speech and language development comes from singleton and small family studies where a small number of rare variants have been identified. However, neither genome-wide nor gene-specific studies have provided evidence that common polymorphisms in the gene contribute to individual differences in language development in the general population. One explanation for this inconsistency is that previous studies have been limited to relatively small samples of individuals with low language abilities, using low density gene coverage. The current study examined the association between common variants in FOXP2 and a quantitative measure of language ability in a population-based cohort of European decent (n = 812). No significant associations were found for a panel of 13 SNPs that covered the coding region of FOXP2 and extended into the promoter region. Power analyses indicated we should have been able to detect a QTL variance of 0.02 for an associated allele with MAF of 0.2 or greater with 80% power. This suggests that, if a common variant associated with language ability in this gene does exist, it is likely of small effect. Our findings lead us to conclude that while genetic variants in FOXP2 may be significant for rare forms of language impairment, they do not contribute appreciably to individual variation in the normal range as found in the general population. PMID:27064276

  11. Genetic mapping of microsatellite markers around the arcelin bruchid resistance locus in common bean.

    PubMed

    Blair, Matthew W; Muñoz, Claritza; Buendía, Héctor F; Flower, José; Bueno, Juan M; Cardona, César

    2010-07-01

    The deployment in common beans (Phaseolus vulgaris L.) of arcelin-based bruchid resistance could help reduce post-harvest storage losses to the Mexican bean weevil [(Zabrotes subfasciatus (Boheman)]. Arcelin is a member of the arcelin-phytohemagglutinin-alpha-amylase inhibitor (APA) family of seed proteins, which has been extensively studied but not widely used in bean breeding programs. The purpose of this study was to evaluate microsatellite markers for genetic analysis of arcelin-based bruchid resistance and to determine the orientation of markers and the rate of recombination around the APA locus. A total of 10 previously developed microsatellites and 22 newly developed markers based on a sequenced BAC from the APA locus were screened for polymorphism and of these 15 were mapped with an F(2) population of 157 individuals resulting from a susceptible x resistant cross of SEQ1006 x RAZ106 that segregated for both the arcelin 1 allele and resistance to the bruchid, Z. subfasciatus. Microsatellites derived from APA gene sequences were linked within 0.8 cM of each other and were placed relative to the rest of the b04 linkage group. In a comparison of genetic to physical distance on the BAC sequence, recombination was found to be moderate with a ratio of 125 kb/cM, but repressed within the APA locus itself. Several markers were predicted to be very effective for genetic studies or marker-assisted selection, based on their significant associations with bruchid resistance and on low adult insect emergence and positions flanking the arcelin and phytohemagglutinin genes. PMID:20358173

  12. The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans

    PubMed Central

    Smith, J. Gustav; Avery, Christy L.; Evans, Daniel S.; Nalls, Michael A.; Meng, Yan A.; Smith, Erin N.; Palmer, Cameron; Tanaka, Toshiko; Mehra, Reena; Butler, Anne M.; Young, Taylor; Buxbaum, Sarah G.; Kerr, Kathleen F.; Berenson, Gerald S.; Schnabel, Renate B.; Li, Guo; Ellinor, Patrick T.; Magnani, Jared W.; Chen, Wei; Bis, Joshua C.; Curb, J. David; Hsueh, Wen-Chi; Rotter, Jerome I.; Liu, Yongmei; Newman, Anne B.; Limacher, Marian C.; North, Kari E.; Reiner, Alexander P.; Quibrera, P. Miguel; Schork, Nicholas J.; Singleton, Andrew B.; Psaty, Bruce M.; Soliman, Elsayed Z.; Solomon, Allen J.; Srinivasan, Sathanur R.; Alonso, Alvaro; Wallace, Robert; Redline, Susan; Zhang, Zhu-Ming; Post, Wendy S.; Zonderman, Alan B.; Taylor, Herman A.; Murray, Sarah S.; Ferrucci, Luigi; Arking, Dan E.; Evans, Michele K.; Fox, Ervin R.; Sotoodehnia, Nona; Heckbert, Susan R.; Whitsel, Eric A.; Newton-Cheh, Christopher

    2013-01-01

    Background Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5×10−8) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2×10−15) and ATP1B1 (rs1320976, p=2×10−10). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10−5) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. Conclusions We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans. PMID:23166209

  13. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

    PubMed Central

    Zhang, Chenan; Doherty, Jennifer A.; Burgess, Stephen; Hung, Rayjean J.; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I.; Sellers, Thomas A.; Monteiro, Alvaro N.A.; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D.; Houlston, Richard S.; Landi, Maria Teresa; Timofeeva, Maria N.; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I.; Chanock, Stephen J.; Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.; Amin Al Olama, Ali; Andrulis, Irene L.; Hopper, John L.; Chang-Claude, Jenny; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Ursin, Giske; Whittemore, Alice S.; Hunter, David J.; Gruber, Stephen B.; Knight, Julia A.; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A.; Hudson, Thomas J.; Chan, Andrew T.; Li, Li; Woods, Michael O.; Ahsan, Habibul; Pierce, Brandon L.

    2015-01-01

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10−15), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10−6). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  14. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

    PubMed

    Zhang, Chenan; Doherty, Jennifer A; Burgess, Stephen; Hung, Rayjean J; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I; Sellers, Thomas A; Monteiro, Alvaro N A; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D; Houlston, Richard S; Landi, Maria Teresa; Timofeeva, Maria N; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I; Chanock, Stephen J; Schumacher, Fredrick; Haiman, Christopher A; Henderson, Brian E; Amin Al Olama, Ali; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Ursin, Giske; Whittemore, Alice S; Hunter, David J; Gruber, Stephen B; Knight, Julia A; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A; Hudson, Thomas J; Chan, Andrew T; Li, Li; Woods, Michael O; Ahsan, Habibul; Pierce, Brandon L

    2015-09-15

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  15. GOOD GIFTS FOR THE COMMON GOOD: Blood and Bioethics in the Market of Genetic Research

    PubMed Central

    REDDY, DEEPA S.

    2008-01-01

    This article is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH–NHGRI-sponsored ethics study and sample collection initiative entitled “Indian and Hindu Perspectives on Genetic Variation Research.” At the heart of this research is one central exchange—blood samples donated for genetic research—that draws both the Indian community and a community of researchers into an encounter with bioethics. I consider the meanings that come to be associated with blood donation as it passes through various hands, agendas, and associated ethical filters on its way to the lab bench: how and why blood is solicited, how the giving and taking of blood is rationalized, how blood as material substance is alienated, processed, documented, and made available for the promised ends of basic science research. Examining corporeal substances and asking what sorts of gifts and problems these represent, I argue, sheds some light on two imbricated tensions expressed by a community of Indians, on the one hand, and of geneticists and basic science researchers, on the other hand: that gifts ought to be free (but are not), and that science ought to be pure (but is not). In this article, I explore how experiences of bioethics are variously shaped by the histories and habits of Indic giving, prior sample collection controversies, commitments to “good science” and the common “good of humanity,” and negotiations of the sites where research findings circulate. PMID:18458755

  16. Biology and genetics of oculocutaneous albinism and vitiligo - common pigmentation disorders in southern Africa.

    PubMed

    Manga, Prashiela; Kerr, Robyn; Ramsay, Michèle; Kromberg, Jennifer G R

    2013-12-01

    Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders.  PMID:24300644

  17. Web-based, participant-driven studies yield novel genetic associations for common traits.

    PubMed

    Eriksson, Nicholas; Macpherson, J Michael; Tung, Joyce Y; Hon, Lawrence S; Naughton, Brian; Saxonov, Serge; Avey, Linda; Wojcicki, Anne; Pe'er, Itsik; Mountain, Joanna

    2010-06-01

    Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R) for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1), freckling (rs2153271, in BNC2), the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7), and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2) illustrates the power of the approach. PMID:20585627

  18. Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits

    PubMed Central

    Eriksson, Nicholas; Macpherson, J. Michael; Tung, Joyce Y.; Hon, Lawrence S.; Naughton, Brian; Saxonov, Serge; Avey, Linda; Wojcicki, Anne; Pe'er, Itsik; Mountain, Joanna

    2010-01-01

    Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R) for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1), freckling (rs2153271, in BNC2), the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7), and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2) illustrates the power of the approach. PMID:20585627

  19. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    PubMed Central

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  20. A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

    PubMed Central

    Dixon, Peter H; Wadsworth, Christopher A; Chambers, Jennifer; Donnelly, Jennifer; Cooley, Sharon; Buckley, Rebecca; Mannino, Ramona; Jarvis, Sheba; Syngelaki, Argyro; Geenes, Victoria; Paul, Priyadarshini; Sothinathan, Meera; Kubitz, Ralf; Lammert, Frank; Tribe, Rachel M; Ch'ng, Chin Lye; Marschall, Hanns-Ulrich; Glantz, Anna; Khan, Shahid A; Nicolaides, Kypros; Whittaker, John; Geary, Michael; Williamson, Catherine

    2014-01-01

    OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility. PMID:24366234

  1. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    PubMed

    Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A; Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Carlson, Christopher S; Casey, Graham; Chang-Claude, Jenny; Conti, David V; Curtis, Keith R; Duggan, David; Gallinger, Steven; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jenkins, Mark A; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M; Newcomb, Polly A; Nickerson, Deborah A; Potter, John D; Schoen, Robert E; Schumacher, Fredrick R; Seminara, Daniela; Slattery, Martha L; Hsu, Li; Chan, Andrew T; White, Emily; Berndt, Sonja I; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  2. A Natural Genetic Variant of Granzyme B Confers Lethality to a Common Viral Infection

    PubMed Central

    Andoniou, Christopher E.; Sutton, Vivien R.; Wikstrom, Matthew E.; Fleming, Peter; Thia, Kevin Y. T.; Matthews, Antony Y.; Kaiserman, Dion; Schuster, Iona S.; Coudert, Jerome D.; Eldi, Preethi; Chaudhri, Geeta; Karupiah, Gunasegaran; Bird, Phillip I.

    2014-01-01

    Many immune response genes are highly polymorphic, consistent with the selective pressure imposed by pathogens over evolutionary time, and the need to balance infection control with the risk of auto-immunity. Epidemiological and genomic studies have identified many genetic variants that confer susceptibility or resistance to pathogenic micro-organisms. While extensive polymorphism has been reported for the granzyme B (GzmB) gene, its relevance to pathogen immunity is unexplored. Here, we describe the biochemical and cytotoxic functions of a common allele of GzmB (GzmBW) common in wild mouse. While retaining ‘Asp-ase’ activity, GzmBW has substrate preferences that differ considerably from GzmBP, which is common to all inbred strains. In vitro, GzmBW preferentially cleaves recombinant Bid, whereas GzmBP activates pro-caspases directly. Recombinant GzmBW and GzmBP induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmBW were unable to control murine cytomegalovirus (MCMV) infection, and succumbed as a result of excessive liver damage. Although similar numbers of anti-viral CD8 T cells were generated in both mouse strains, GzmBW-expressing CD8 T cells isolated from infected mice were unable to kill MCMV-infected targets in vitro. Our results suggest that known virally-encoded inhibitors of the intrinsic (mitochondrial) apoptotic pathway account for the increased susceptibility of GzmBW mice to MCMV. We conclude that different natural variants of GzmB have a profound impact on the immune response to a common and authentic viral pathogen. PMID:25502180

  3. Genetic mapping of two genes conferring resistance to powdery mildew in common bean (Phaseolus vulgaris L.).

    PubMed

    Pérez-Vega, Elena; Trabanco, Noemí; Campa, Ana; Ferreira, Juan José

    2013-06-01

    Powdery mildew (PM) is a serious disease in many legume species, including the common bean (Phaseolus vulgaris L.). This study investigated the genetic control behind resistance reaction to PM in the bean genotype, Cornell 49242. The results revealed evidence supporting a qualitative mode of inheritance for resistance and the involvement of two independent genes in the resistance reaction. The location of these resistance genes was investigated in a linkage genetic map developed for the XC RIL population. Contingency tests revealed significant associations for 28 loci out of a total of 329 mapped loci. Fifteen were isolated or formed groups with less than two loci. The thirteen remaining loci were located at three regions in linkage groups Pv04, Pv09, and Pv11. The involvement of Pv09 was discarded due to the observed segregation in the subpopulation obtained from the Xana genotype for the loci located in this region. In contrast, the two subpopulations obtained from the Xana genotype for the BM161 locus, linked to the Co-3/9 anthracnose resistance gene (Pv04), and from the Xana genotype for the SCAReoli locus, linked to the Co-2 anthracnose resistance gene (Pv11), exhibited monogenic segregations, suggesting that both regions were involved in the genetic control of resistance. A genetic dissection was carried out to verify the involvement of both regions in the reaction to PM. Two resistant recombinant lines were selected, according to their genotypes, for the block of loci included in the Co-2 and Co-3/9 regions, and they were crossed with the susceptible parent, Xana. Linkage analysis in the respective F2 populations supported the hypothesis that a dominant gene (Pm1) was located in the linkage group Pv11 and another gene (Pm2) was located in the linkage group Pv04. This is the first report showing the localization of resistance genes against powdery mildew in Phaseolus vulgaris and the results offer the opportunity to increase the efficiency of breeding

  4. Common Genetic Variation and Haplotypes of the Anion Exchanger SLC4A2 in Primary Biliary Cirrhosis

    PubMed Central

    Juran, Brian D.; Atkinson, Elizabeth J.; Larson, Joseph J.; Schlicht, Erik M.; Lazaridis, Konstantinos N.

    2010-01-01

    Objectives Deficiencies of the anion exchanger SLC4A2 are thought to play a pathogenic role in primary biliary cirrhosis (PBC), evidenced by decreased expression and activity in PBC patients and development of disease features in SLC4A2 knockout mice. We hypothesized that genetic variation in SLC4A2 might influence this pathogenic contribution. Thus, we aimed to perform a comprehensive assessment of SLC4A2 genetic variation in PBC using a linkage disequilibrium (LD)-based haplotype-tagging approach. Methods Twelve single nucleotide polymorphisms (SNPs) across SLC4A2 were genotyped in 409 PBC patients and 300 controls and evaluated for association with disease, as well as with prior orthotopic liver transplant and antimitochondrial antibody (AMA) status among the PBC patients, both individually and as inferred haplotypes, using logistic regression. Results All SNPs were in Hardy–Weinberg equilibrium. No associations with disease or liver transplantation were detected, but two variants, rs2303929 and rs3793336, were associated with negativity for antimitochondrial antibodies among the PBC patients. Conclusions The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. Whether the deficiency of SLC4A2 expression and activity observed earlier in PBC patients is an acquired epiphenomenon of underlying disease or is because of heritable factors in unappreciated regulatory regions remains uncertain. Of note, two SLC4A2 variants appear to influence AMA status among PBC patients. The mechanisms behind this finding are unclear. PMID:19491853

  5. Common genetic variants on 5p14.1 associate with autism spectrum disorders

    PubMed Central

    Wang, Kai; Zhang, Haitao; Ma, Deqiong; Bucan, Maja; Glessner, Joseph T.; Abrahams, Brett S.; Salyakina, Daria; Imielinski, Marcin; Bradfield, Jonathan P.; Sleiman, Patrick M. A.; Kim, Cecilia E.; Hou, Cuiping; Frackelton, Edward; Chiavacci, Rosetta; Takahashi, Nagahide; Sakurai, Takeshi; Rappaport, Eric; Lajonchere, Clara M.; Munson, Jeffrey; Estes, Annette; Korvatska, Olena; Piven, Joseph; Sonnenblick, Lisa I.; Retuerto, Ana I. Alvarez; Herman, Edward I.; Dong, Hongmei; Hutman, Ted; Sigman, Marian; Ozonoff, Sally; Klin, Ami; Owley, Thomas; Sweeney, John A.; Brune, Camille W.; Cantor, Rita M.; Bernier, Raphael; Gilbert, John R.; Cuccaro, Michael L.; McMahon, William M.; Miller, Judith; State, Matthew W.; Wassink, Thomas H.; Coon, Hilary; Levy, Susan E.; Schultz, Robert T.; Nurnberger, John I.; Haines, Jonathan L.; Sutcliffe, James S.; Cook, Edwin H.; Minshew, Nancy J.; Buxbaum, Joseph D.; Dawson, Geraldine; Grant, Struan F. A.; Geschwind, Daniel H.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Hakonarson, Hakon

    2009-01-01

    Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs. PMID:19404256

  6. Gene-Based Single Nucleotide Polymorphism Markers for Genetic and Association Mapping in Common Bean

    PubMed Central

    2012-01-01

    Background In common bean, expressed sequence tags (ESTs) are an underestimated source of gene-based markers such as insertion-deletions (Indels) or single-nucleotide polymorphisms (SNPs). However, due to the nature of these conserved sequences, detection of markers is difficult and portrays low levels of polymorphism. Therefore, development of intron-spanning EST-SNP markers can be a valuable resource for genetic experiments such as genetic mapping and association studies. Results In this study, a total of 313 new gene-based markers were developed at target genes. Intronic variation was deeply explored in order to capture more polymorphism. Introns were putatively identified after comparing the common bean ESTs with the soybean genome, and the primers were designed over intron-flanking regions. The intronic regions were evaluated for parental polymorphisms using the single strand conformational polymorphism (SSCP) technique and Sequenom MassARRAY system. A total of 53 new marker loci were placed on an integrated molecular map in the DOR364 × G19833 recombinant inbred line (RIL) population. The new linkage map was used to build a consensus map, merging the linkage maps of the BAT93 × JALO EEP558 and DOR364 × BAT477 populations. A total of 1,060 markers were mapped, with a total map length of 2,041 cM across 11 linkage groups. As a second application of the generated resource, a diversity panel with 93 genotypes was evaluated with 173 SNP markers using the MassARRAY-platform and KASPar technology. These results were coupled with previous SSR evaluations and drought tolerance assays carried out on the same individuals. This agglomerative dataset was examined, in order to discover marker-trait associations, using general linear model (GLM) and mixed linear model (MLM). Some significant associations with yield components were identified, and were consistent with previous findings. Conclusions In short, this study illustrates the power of intron

  7. Asymmetry in Family History Implicates Nonstandard Genetic Mechanisms: Application to the Genetics of Breast Cancer

    PubMed Central

    Weinberg, Clarice R.; Shi, Min; DeRoo, Lisa A.; Taylor, Jack A.; Sandler, Dale P.; Umbach, David M.

    2014-01-01

    Genome-wide association studies typically target inherited autosomal variants, but less studied genetic mechanisms can play a role in complex disease. Sex-linked variants aside, three genetic phenomena can induce differential risk in maternal versus paternal lineages of affected individuals: 1. maternal effects, reflecting the maternal genome's influence on prenatal development; 2. mitochondrial variants, which are inherited maternally; 3. autosomal genes, whose effects depend on parent of origin. We algebraically show that small asymmetries in family histories of affected individuals may reflect much larger genetic risks acting via those mechanisms. We apply these ideas to a study of sisters of women with breast cancer. Among 5,091 distinct families of women reporting that exactly one grandmother had breast cancer, risk was skewed toward maternal grandmothers (p<0.0001), especially if the granddaughter was diagnosed between age 45 and 54. Maternal genetic effects, mitochondrial variants, or variant genes with parent-of-origin effects may influence risk of perimenopausal breast cancer. PMID:24651610

  8. Common genetic polymorphisms affect the human requirement for the nutrient choline

    PubMed Central

    da Costa, Kerry-Ann; Kozyreva, Olga G.; Song, Jiannan; Galanko, Joseph A.; Fischer, Leslie M.; Zeisel, Steven H.

    2006-01-01

    Humans eating diets deficient in the essential nutrient choline can develop organ dysfunction. We hypothesized that common single nucleotide polymorphisms (SNPs) in genes involved in choline metabolism influence the dietary requirement of this nutrient. Fifty-seven humans were fed a low choline diet until they developed organ dysfunction or for up to 42 days. We tested DNA SNPs for allelic association with susceptibility to developing organ dysfunction associated with choline deficiency. We identified an SNP in the promoter region of the phosphatidylethanolamine N-methyltransferase gene (PEMT; −744 G→C; rs12325817) for which 18 of 23 carriers of the C allele (78%) developed organ dysfunction when fed a low choline diet (odds ratio 25, P=0.002). The first of two SNPs in the coding region of the choline dehydrogenase gene (CHDH; +318 A→C; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (+432 G→T; rs12676) was associated with increased susceptibility to choline deficiency. A SNP in the PEMT coding region (+5465 G→A; rs7946) and a betaine:homocysteine methyl-transferase (BHMT) SNP (+742 G→A; rs3733890) were not associated with susceptibility to choline deficiency. Identification of common polymorphisms that affect dietary requirements for choline could enable us to identify individuals for whom we need to assure adequate dietary choline intake.—da Costa, K.-A., Kozyreva, O. G., Song, J., Galanko, J. A., Fischer, L. M., Zeisel, S. H. Common genetic polymorphisms affect the human requirement for the nutrient choline. PMID:16816108

  9. Fine-scale spatial genetic structure of common and declining bumble bees across an agricultural landscape.

    PubMed

    Dreier, Stephanie; Redhead, John W; Warren, Ian A; Bourke, Andrew F G; Heard, Matthew S; Jordan, William C; Sumner, Seirian; Wang, Jinliang; Carvell, Claire

    2014-07-01

    Land-use changes have threatened populations of many insect pollinators, including bumble bees. Patterns of dispersal and gene flow are key determinants of species' ability to respond to land-use change, but have been little investigated at a fine scale (<10 km) in bumble bees. Using microsatellite markers, we determined the fine-scale spatial genetic structure of populations of four common Bombus species (B. terrestris, B. lapidarius, B. pascuorum and B. hortorum) and one declining species (B. ruderatus) in an agricultural landscape in Southern England, UK. The study landscape contained sown flower patches representing agri-environment options for pollinators. We found that, as expected, the B. ruderatus population was characterized by relatively low heterozygosity, number of alleles and colony density. Across all species, inbreeding was absent or present but weak (FIS  = 0.01-0.02). Using queen genotypes reconstructed from worker sibships and colony locations estimated from the positions of workers within these sibships, we found that significant isolation by distance was absent in B. lapidarius, B. hortorum and B. ruderatus. In B. terrestris and B. pascuorum, it was present but weak; for example, in these two species, expected relatedness of queens founding colonies 1 m apart was 0.02. These results show that bumble bee populations exhibit low levels of spatial genetic structure at fine spatial scales, most likely because of ongoing gene flow via widespread queen dispersal. In addition, the results demonstrate the potential for agri-environment scheme conservation measures to facilitate fine-scale gene flow by creating a more even distribution of suitable habitats across landscapes. PMID:24980963

  10. Fine-scale spatial genetic structure of common and declining bumble bees across an agricultural landscape

    PubMed Central

    Dreier, Stephanie; Redhead, John W; Warren, Ian A; Bourke, Andrew F G; Heard, Matthew S; Jordan, William C; Sumner, Seirian; Wang, Jinliang; Carvell, Claire

    2014-01-01

    Land-use changes have threatened populations of many insect pollinators, including bumble bees. Patterns of dispersal and gene flow are key determinants of species' ability to respond to land-use change, but have been little investigated at a fine scale (<10 km) in bumble bees. Using microsatellite markers, we determined the fine-scale spatial genetic structure of populations of four common Bombus species (B. terrestris, B. lapidarius, B. pascuorum and B. hortorum) and one declining species (B. ruderatus) in an agricultural landscape in Southern England, UK. The study landscape contained sown flower patches representing agri-environment options for pollinators. We found that, as expected, the B. ruderatus population was characterized by relatively low heterozygosity, number of alleles and colony density. Across all species, inbreeding was absent or present but weak (FIS = 0.01–0.02). Using queen genotypes reconstructed from worker sibships and colony locations estimated from the positions of workers within these sibships, we found that significant isolation by distance was absent in B. lapidarius, B. hortorum and B. ruderatus. In B. terrestris and B. pascuorum, it was present but weak; for example, in these two species, expected relatedness of queens founding colonies 1 m apart was 0.02. These results show that bumble bee populations exhibit low levels of spatial genetic structure at fine spatial scales, most likely because of ongoing gene flow via widespread queen dispersal. In addition, the results demonstrate the potential for agri-environment scheme conservation measures to facilitate fine-scale gene flow by creating a more even distribution of suitable habitats across landscapes. PMID:24980963

  11. Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

    PubMed

    Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T; Harrison, Tabitha A; Jeon, Jihyoun; Hutter, Carolyn M; Berndt, Sonja I; Brenner, Hermann; Caan, Bette J; Campbell, Peter T; Chang-Claude, Jenny; Chanock, Stephen J; Cheadle, Jeremy P; Curtis, Keith R; Duggan, David; Fisher, David; Fuchs, Charles S; Gala, Manish; Giovannucci, Edward L; Hayes, Richard B; Hoffmeister, Michael; Hsu, Li; Jacobs, Eric J; Jansen, Lina; Kaplan, Richard; Kap, Elisabeth J; Maughan, Timothy S; Potter, John D; Schoen, Robert E; Seminara, Daniela; Slattery, Martha L; West, Hannah; White, Emily; Peters, Ulrike; Newcomb, Polly A

    2016-01-01

    Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. PMID:26586795

  12. The Last Universal Common Ancestor: emergence, constitution and genetic legacy of an elusive forerunner

    PubMed Central

    Glansdorff, Nicolas; Xu, Ying; Labedan, Bernard

    2008-01-01

    Background Since the reclassification of all life forms in three Domains (Archaea, Bacteria, Eukarya), the identity of their alleged forerunner (Last Universal Common Ancestor or LUCA) has been the subject of extensive controversies: progenote or already complex organism, prokaryote or protoeukaryote, thermophile or mesophile, product of a protracted progression from simple replicators to complex cells or born in the cradle of "catalytically closed" entities? We present a critical survey of the topic and suggest a scenario. Results LUCA does not appear to have been a simple, primitive, hyperthermophilic prokaryote but rather a complex community of protoeukaryotes with a RNA genome, adapted to a broad range of moderate temperatures, genetically redundant, morphologically and metabolically diverse. LUCA's genetic redundancy predicts loss of paralogous gene copies in divergent lineages to be a significant source of phylogenetic anomalies, i.e. instances where a protein tree departs from the SSU-rRNA genealogy; consequently, horizontal gene transfer may not have the rampant character assumed by many. Examining membrane lipids suggest LUCA had sn1,2 ester fatty acid lipids from which Archaea emerged from the outset as thermophilic by "thermoreduction," with a new type of membrane, composed of sn2,3 ether isoprenoid lipids; this occurred without major enzymatic reconversion. Bacteria emerged by reductive evolution from LUCA and some lineages further acquired extreme thermophily by convergent evolution. This scenario is compatible with the hypothesis that the RNA to DNA transition resulted from different viral invasions as proposed by Forterre. Beyond the controversy opposing "replication first" to metabolism first", the predictive arguments of theories on "catalytic closure" or "compositional heredity" heavily weigh in favour of LUCA's ancestors having emerged as complex, self-replicating entities from which a genetic code arose under natural selection. Conclusion Life

  13. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research.

    PubMed

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  14. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research

    PubMed Central

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  15. Cellular and network mechanisms of genetically-determined absence seizures.

    PubMed

    Pinault, Didier; O'Brien, Terence J

    2005-01-01

    The absence epilepsies are characterized by recurrent episodes of loss of consciousness associated with generalized spike-and-wave discharges, with an abrupt onset and offset, in the thalamocortical system. In the absence of detailed neurophysiological studies in humans, many of the concepts regarding the pathophysiological basis of absence seizures are based on studies in animal models. Each of these models has its particular strengths and limitations, and the validity of findings from these models for the human condition cannot be assumed. Consequently, studies in different models have produced some conflicting findings and conclusions. A long-standing concept, based primarily from studies in vivo in cats and in vitro brain slices, is that these paroxysmal electrical events develop suddenly from sleep-related spindle oscillations. More specifically, it is proposed that the initial mechanisms that underlie absence-related spike-and-wave discharges are located in the thalamus, involving especially the thalamic reticular nucleus. By contrast, more recent studies in well-established, genetic models of absence epilepsy in rats demonstrate that spike-and-wave discharges originate in a cortical focus and develop from a wake-related natural corticothalamic sensorimotor rhythm. In this review we integrate recent findings showing that, in both the thalamus and the neocortex, genetically-determined, absence-related spike-and-wave discharges are the manifestation of hypersynchronized, cellular, rhythmic excitations and inhibitions that result from a combination of complex, intrinsic, synaptic mechanisms. Arguments are put forward supporting the hypothesis that layer VI corticothalamic neurons act as 'drivers' in the generation of spike-and-wave discharges in the somatosensory thalamocortical system that result in corticothalamic resonances particularly initially involving the thalamic reticular nucleus. However an important unresolved question is: what are the cellular and

  16. THE GENETICS OF EPIGENETIC INHERITANCE: MODES, MOLECULES, AND MECHANISMS.

    PubMed

    Schaefer, Sabine; Nadeau, Joseph H

    2015-12-01

    Organisms adapt developmental and physiological features to local and transient conditions in part by modulating transcription, translation, and protein functions, usually without changing DNA sequences. Remarkably, these epigenetic changes sometimes endure through meiosis and gametogenesis, thereby affecting phenotypic variation across generations, long after epigenetic changes were triggered. Transgenerational effects challenge our traditional understanding of inheritance. In this review, we focus on patterns of inheritance, molecular features, mechanisms that lead from environmental and genetic perturbations to phenotypic variation in later generations, and issues about study design and replication. PMID:26714351

  17. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    SciTech Connect

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M.

    1994-09-01

    Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

  18. Seascape Genetics of a Globally Distributed, Highly Mobile Marine Mammal: The Short-Beaked Common Dolphin (Genus Delphinus)

    PubMed Central

    Amaral, Ana R.; Beheregaray, Luciano B.; Bilgmann, Kerstin; Boutov, Dmitri; Freitas, Luís; Robertson, Kelly M.; Sequeira, Marina; Stockin, Karen A.; Coelho, M. Manuela; Möller, Luciana M.

    2012-01-01

    Identifying which factors shape the distribution of intraspecific genetic diversity is central in evolutionary and conservation biology. In the marine realm, the absence of obvious barriers to dispersal can make this task more difficult. Nevertheless, recent studies have provided valuable insights into which factors may be shaping genetic structure in the world's oceans. These studies were, however, generally conducted on marine organisms with larval dispersal. Here, using a seascape genetics approach, we show that marine productivity and sea surface temperature are correlated with genetic structure in a highly mobile, widely distributed marine mammal species, the short-beaked common dolphin. Isolation by distance also appears to influence population divergence over larger geographical scales (i.e. across different ocean basins). We suggest that the relationship between environmental variables and population structure may be caused by prey behaviour, which is believed to determine common dolphins' movement patterns and preferred associations with certain oceanographic conditions. Our study highlights the role of oceanography in shaping genetic structure of a highly mobile and widely distributed top marine predator. Thus, seascape genetic studies can potentially track the biological effects of ongoing climate-change at oceanographic interfaces and also inform marine reserve design in relation to the distribution and genetic connectivity of charismatic and ecologically important megafauna. PMID:22319634

  19. A Common Genetic Origin for Early Farmers from Mediterranean Cardial and Central European LBK Cultures.

    PubMed

    Olalde, Iñigo; Schroeder, Hannes; Sandoval-Velasco, Marcela; Vinner, Lasse; Lobón, Irene; Ramirez, Oscar; Civit, Sergi; García Borja, Pablo; Salazar-García, Domingo C; Talamo, Sahra; María Fullola, Josep; Xavier Oms, Francesc; Pedro, Mireia; Martínez, Pablo; Sanz, Montserrat; Daura, Joan; Zilhão, João; Marquès-Bonet, Tomàs; Gilbert, M Thomas P; Lalueza-Fox, Carles

    2015-12-01

    The spread of farming out of the Balkans and into the rest of Europe followed two distinct routes: An initial expansion represented by the Impressa and Cardial traditions, which followed the Northern Mediterranean coastline; and another expansion represented by the LBK (Linearbandkeramik) tradition, which followed the Danube River into Central Europe. Although genomic data now exist from samples representing the second migration, such data have yet to be successfully generated from the initial Mediterranean migration. To address this, we generated the complete genome of a 7,400-year-old Cardial individual (CB13) from Cova Bonica in Vallirana (Barcelona), as well as partial nuclear data from five others excavated from different sites in Spain and Portugal. CB13 clusters with all previously sequenced early European farmers and modern-day Sardinians. Furthermore, our analyses suggest that both Cardial and LBK peoples derived from a common ancient population located in or around the Balkan Peninsula. The Iberian Cardial genome also carries a discernible hunter-gatherer genetic signature that likely was not acquired by admixture with local Iberian foragers. Our results indicate that retrieving ancient genomes from similarly warm Mediterranean environments such as the Near East is technically feasible. PMID:26337550

  20. A Common Genetic Origin for Early Farmers from Mediterranean Cardial and Central European LBK Cultures

    PubMed Central

    Olalde, Iñigo; Schroeder, Hannes; Sandoval-Velasco, Marcela; Vinner, Lasse; Lobón, Irene; Ramirez, Oscar; Civit, Sergi; García Borja, Pablo; Salazar-García, Domingo C.; Talamo, Sahra; María Fullola, Josep; Xavier Oms, Francesc; Pedro, Mireia; Martínez, Pablo; Sanz, Montserrat; Daura, Joan; Zilhão, João; Marquès-Bonet, Tomàs; Gilbert, M. Thomas P.; Lalueza-Fox, Carles

    2015-01-01

    The spread of farming out of the Balkans and into the rest of Europe followed two distinct routes: An initial expansion represented by the Impressa and Cardial traditions, which followed the Northern Mediterranean coastline; and another expansion represented by the LBK (Linearbandkeramik) tradition, which followed the Danube River into Central Europe. Although genomic data now exist from samples representing the second migration, such data have yet to be successfully generated from the initial Mediterranean migration. To address this, we generated the complete genome of a 7,400-year-old Cardial individual (CB13) from Cova Bonica in Vallirana (Barcelona), as well as partial nuclear data from five others excavated from different sites in Spain and Portugal. CB13 clusters with all previously sequenced early European farmers and modern-day Sardinians. Furthermore, our analyses suggest that both Cardial and LBK peoples derived from a common ancient population located in or around the Balkan Peninsula. The Iberian Cardial genome also carries a discernible hunter–gatherer genetic signature that likely was not acquired by admixture with local Iberian foragers. Our results indicate that retrieving ancient genomes from similarly warm Mediterranean environments such as the Near East is technically feasible. PMID:26337550

  1. Evolutionary Insights from a Genetically Divergent Hantavirus Harbored by the European Common Mole (Talpa europaea)

    PubMed Central

    Kang, Hae Ji; Bennett, Shannon N.; Sumibcay, Laarni; Arai, Satoru; Hope, Andrew G.; Mocz, Gabor; Song, Jin-Won; Cook, Joseph A.; Yanagihara, Richard

    2009-01-01

    Background The discovery of genetically distinct hantaviruses in shrews (Order Soricomorpha, Family Soricidae) from widely separated geographic regions challenges the hypothesis that rodents (Order Rodentia, Family Muridae and Cricetidae) are the primordial reservoir hosts of hantaviruses and also predicts that other soricomorphs harbor hantaviruses. Recently, novel hantavirus genomes have been detected in moles of the Family Talpidae, including the Japanese shrew mole (Urotrichus talpoides) and American shrew mole (Neurotrichus gibbsii). We present new insights into the evolutionary history of hantaviruses gained from a highly divergent hantavirus, designated Nova virus (NVAV), identified in the European common mole (Talpa europaea) captured in Hungary. Methodology/Principal Findings Pair-wise alignment and comparison of the full-length S- and L-genomic segments indicated moderately low sequence similarity of 54–65% and 46–63% at the nucleotide and amino acid levels, respectively, between NVAV and representative rodent- and soricid-borne hantaviruses. Despite the high degree of sequence divergence, the predicted secondary structure of the NVAV nucleocapsid protein exhibited the characteristic coiled-coil domains at the amino-terminal end, and the L-segment motifs, typically found in hantaviruses, were well conserved. Phylogenetic analyses, using maximum-likelihood and Bayesian methods, showed that NVAV formed a distinct clade that was evolutionarily distant from all other hantaviruses. Conclusions Newly identified hantaviruses harbored by shrews and moles support long-standing virus-host relationships and suggest that ancestral soricomorphs, rather than rodents, may have been the early or original mammalian hosts. PMID:19582155

  2. Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.

    PubMed

    Harris, M J; Juriloff, D M

    1999-11-01

    of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds. PMID:10525207

  3. Genetic and Biochemical Mechanisms of Pollen Wall Development.

    PubMed

    Shi, Jianxin; Cui, Meihua; Yang, Li; Kim, Yu-Jin; Zhang, Dabing

    2015-11-01

    The pollen wall is a specialized extracellular cell wall matrix that surrounds male gametophytes and plays an essential role in plant reproduction. Uncovering the mechanisms that control the synthesis and polymerization of the precursors of pollen wall components has been a major research focus in plant biology. We review current knowledge on the genetic and biochemical mechanisms underlying pollen wall development in eudicot model Arabidopsis thaliana and monocot model rice (Oryza sativa), focusing on the genes involved in the biosynthesis, transport, and assembly of various precursors of pollen wall components. The conserved and divergent aspects of the genes involved as well as their regulation are addressed. Current challenges and future perspectives are also highlighted. PMID:26442683

  4. Structure of genetic diversity in the two major gene pools of common bean (Phaseolus vulgaris L., Fabaceae).

    PubMed

    Kwak, Myounghai; Gepts, Paul

    2009-03-01

    Domesticated materials with well-known wild relatives provide an experimental system to reveal how human selection during cultivation affects genetic composition and adaptation to novel environments. In this paper, our goal was to elucidate how two geographically distinct domestication events modified the structure and level of genetic diversity in common bean. Specifically, we analyzed the genome-wide genetic composition at 26, mostly unlinked microsatellite loci in 349 accessions of wild and domesticated common bean from the Andean and Mesoamerican gene pools. Using a model-based approach, implemented in the software STRUCTURE, we identified nine wild or domesticated populations in common bean, including four of Andean and four of Mesoamerican origins. The ninth population was the putative wild ancestor of the species, which was classified as a Mesoamerican population. A neighbor-joining analysis and a principal coordinate analysis confirmed genetic relationships among accessions and populations observed with the STRUCTURE analysis. Geographic and genetic distances in wild populations were congruent with the exception of a few putative hybrids identified in this study, suggesting a predominant effect of isolation by distance. Domesticated common bean populations possessed lower genetic diversity, higher F(ST), and generally higher linkage disequilibrium (LD) than wild populations in both gene pools; their geographic distributions were less correlated with genetic distance, probably reflecting seed-based gene flow after domestication. The LD was reduced when analyzed in separate Andean and Mesoamerican germplasm samples. The Andean domesticated race Nueva Granada had the highest F(ST) value and widest geographic distribution compared to other domesticated races, suggesting a very recent origin or a selection event, presumably associated with a determinate growth habit, which predominates in this race. PMID:19130029

  5. Teaching the Common Aspects in Mechanical, Electromagnetic and Quantum Waves at Interfaces and Waveguides

    ERIC Educational Resources Information Center

    Rojas, R.; Robles, P.

    2011-01-01

    We discuss common features in mechanical, electromagnetic and quantum systems, supporting identical results for the transmission and reflection coefficients of waves arriving perpendicularly at a plane interface. Also, we briefly discuss the origin of special notions such as refractive index in quantum mechanics, massive photons in wave guides and…

  6. Association between seven common OPG genetic polymorphisms and osteoporosis risk: a meta-analysis.

    PubMed

    Guo, Liang; Tang, Ke; Quan, Zhengxue; Zhao, Zenghui; Jiang, Dianming

    2014-01-01

    Functional polymorphisms of the osteoprotegerin (OPG) gene are known to be involved in bone mineral density and the development of osteoporosis; however, some conflicting results have been reported. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the relationship between seven common OPG genetic polymorphisms (T149C, A163G, G209A, T245G, T950C, G1181C, and C1217T) and osteoporosis risk. A literature search for eligible studies published before August 1st, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. Pooled odds ratios and their corresponding 95% confidence intervals were used to evaluate the strength of the association under fixed- or random-effect models according to a heterogeneity test. All analyses were performed using the STATA software, version 12.0. Fourteen case-control studies with a total of 2383 osteoporosis cases and 2280 healthy controls were included in this meta-analysis. Among the seven polymorphisms, A163G and G1181C revealed significant associations with osteoporosis risk. For A163G (rs3102735), the combined results showed that the G allele of the A163G polymorphism may be associated with an increased risk of osteoporosis. Stratified analyses showed that the magnitude of the effect was similar in Caucasian and postmenopausal woman subgroups. For G1181C (rs2073618), however, we found that individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asian and postmenopausal woman subgroups. In summary, this meta-analysis indicated that the G allele of the OPG A163G polymorphism might increase osteoporosis risk in Caucasians, whereas individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asians. Both of these effects were observed in postmenopausal women. These polymorphisms could probably be used with other genetic markers

  7. [Sickle cell anemia causes varied symptoms and high morbidity. Serious prognosis in the most common genetic disease in the world].

    PubMed

    Kjellander, Christian; Sennström, Maria K B; Stiller, Viveka; Ågren, Anna

    2015-01-01

    Sickle cell anemia is a life-threatening disease, and the most common genetic disease in the world. The prevalence of sickle cell anemia in Sweden is unknown. Sickle cell anemia is an important disease, because of its variable complications, in many medical and surgical specialties. The overview highlights common medical problems encountered in sickle cell anemia presented through a case report of a pregnant woman. PMID:25734427

  8. High-level DNA amplifications are common genetic aberrations in B-cell neoplasms.

    PubMed Central

    Werner, C. A.; Döhner, H.; Joos, S.; Trümper, L. H.; Baudis, M.; Barth, T. F.; Ott, G.; Möller, P.; Lichter, P.; Bentz, M.

    1997-01-01

    Gene amplification is one of the molecular mechanisms resulting in the up-regulation of gene expression. In non-Hodgkin's lymphomas, such gene amplifications have been identified rarely. Using comparative genomic hybridization, a technique that has proven to be very sensitive for the detection of high-level DNA amplifications, we analyzed 108 cases of B-cell neoplasms (42 chronic B-cell leukemias, 5 mantle cell lymphomas, and 61 aggressive B-cell lymphomas). Twenty-four high-level amplifications were identified in 13% of the patients and mapped to 15 different genomic regions. Regions most frequently amplified were bands Xq26-28, 2p23-24, and 2p14-16 as well as 18q21 (three times each). Amplification of several proto-oncogenes and a cell cycle control gene (N-MYC (two cases), BCL2, CCND2, and GLI) located within the amplified regions was demonstrated by Southern blot analysis or fluorescence in situ hybridization to interphase nuclei of tumor cells. These data demonstrate that gene amplifications in B-cell neoplasms are much more frequent than previously assumed. The identification of highly amplified DNA regions and genes included in the amplicons provides important information for further analyses of genetic events involved in lymphomagenesis. Images Figure 2 Figure 3 PMID:9250147

  9. Rare and common genetic events in type 2 diabetes: what should biologists know?

    PubMed

    Bonnefond, Amélie; Froguel, Philippe

    2015-03-01

    Type 2 diabetes (T2D) had long been referred to as the "geneticist's nightmare." Genome-wide association studies have fully confirmed the polygenic nature of T2D, demonstrating the role of many genes in T2D risk. The increasingly busier picture of T2D genetics is quite difficult to understand for the diabetes research community, which can create misunderstandings with geneticists, and can eventually limit both basic research and translational outcomes of these genetic discoveries. The present review wishes to lift the fog around genetics of T2D with the hope that it will foster integrated diabetes modeling approaches from genetic defects to personalized medicine. PMID:25640731

  10. Genomic Analysis of Storage Protein Deficiency in Genetically Related Lines of Common Bean (Phaseolus vulgaris)

    PubMed Central

    Pandurangan, Sudhakar; Diapari, Marwan; Yin, Fuqiang; Munholland, Seth; Perry, Gregory E.; Chapman, B. Patrick; Huang, Shangzhi; Sparvoli, Francesca; Bollini, Roberto; Crosby, William L.; Pauls, Karl P.; Marsolais, Frédéric

    2016-01-01

    A series of genetically related lines of common bean (Phaseolus vulgaris L.) integrate a progressive deficiency in major storage proteins, the 7S globulin phaseolin and lectins. SARC1 integrates a lectin-like protein, arcelin-1 from a wild common bean accession. SMARC1N-PN1 is deficient in major lectins, including erythroagglutinating phytohemagglutinin (PHA-E) but not α-amylase inhibitor, and incorporates also a deficiency in phaseolin. SMARC1-PN1 is intermediate and shares the phaseolin deficiency. Sanilac is the parental background. To understand the genomic basis for variations in protein profiles previously determined by proteomics, the genotypes were submitted to short-fragment genome sequencing using an Illumina HiSeq 2000/2500 platform. Reads were aligned to reference sequences and subjected to de novo assembly. The results of the analyses identified polymorphisms responsible for the lack of specific storage proteins, as well as those associated with large differences in storage protein expression. SMARC1N-PN1 lacks the lectin genes pha-E and lec4-B17, and has the pseudogene pdlec1 in place of the functional pha-L gene. While the α-phaseolin gene appears absent, an approximately 20-fold decrease in β-phaseolin accumulation is associated with a single nucleotide polymorphism converting a G-box to an ACGT motif in the proximal promoter. Among residual lectins compensating for storage protein deficiency, mannose lectin FRIL and α-amylase inhibitor 1 genes are uniquely present in SMARC1N-PN1. An approximately 50-fold increase in α-amylase inhibitor like protein accumulation is associated with multiple polymorphisms introducing up to eight potential positive cis-regulatory elements in the proximal promoter specific to SMARC1N-PN1. An approximately 7-fold increase in accumulation of 11S globulin legumin is not associated with variation in proximal promoter sequence, suggesting that the identity of individual proteins involved in proteome rebalancing might

  11. Genomic Analysis of Storage Protein Deficiency in Genetically Related Lines of Common Bean (Phaseolus vulgaris).

    PubMed

    Pandurangan, Sudhakar; Diapari, Marwan; Yin, Fuqiang; Munholland, Seth; Perry, Gregory E; Chapman, B Patrick; Huang, Shangzhi; Sparvoli, Francesca; Bollini, Roberto; Crosby, William L; Pauls, Karl P; Marsolais, Frédéric

    2016-01-01

    A series of genetically related lines of common bean (Phaseolus vulgaris L.) integrate a progressive deficiency in major storage proteins, the 7S globulin phaseolin and lectins. SARC1 integrates a lectin-like protein, arcelin-1 from a wild common bean accession. SMARC1N-PN1 is deficient in major lectins, including erythroagglutinating phytohemagglutinin (PHA-E) but not α-amylase inhibitor, and incorporates also a deficiency in phaseolin. SMARC1-PN1 is intermediate and shares the phaseolin deficiency. Sanilac is the parental background. To understand the genomic basis for variations in protein profiles previously determined by proteomics, the genotypes were submitted to short-fragment genome sequencing using an Illumina HiSeq 2000/2500 platform. Reads were aligned to reference sequences and subjected to de novo assembly. The results of the analyses identified polymorphisms responsible for the lack of specific storage proteins, as well as those associated with large differences in storage protein expression. SMARC1N-PN1 lacks the lectin genes pha-E and lec4-B17, and has the pseudogene pdlec1 in place of the functional pha-L gene. While the α-phaseolin gene appears absent, an approximately 20-fold decrease in β-phaseolin accumulation is associated with a single nucleotide polymorphism converting a G-box to an ACGT motif in the proximal promoter. Among residual lectins compensating for storage protein deficiency, mannose lectin FRIL and α-amylase inhibitor 1 genes are uniquely present in SMARC1N-PN1. An approximately 50-fold increase in α-amylase inhibitor like protein accumulation is associated with multiple polymorphisms introducing up to eight potential positive cis-regulatory elements in the proximal promoter specific to SMARC1N-PN1. An approximately 7-fold increase in accumulation of 11S globulin legumin is not associated with variation in proximal promoter sequence, suggesting that the identity of individual proteins involved in proteome rebalancing might

  12. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    PubMed Central

    Guiducci, Candace; Segrè, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B. L.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V.; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. PMID:21060860

  13. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival

    PubMed Central

    Cleveland, Rebecca J.; Gammon, Marilie D.; Long, Chang-Min; Gaudet, Mia M.; Eng, Sybil M.; Teitelbaum, Susan L.; Neugut, Alfred I.; Santella, Regina M.

    2013-01-01

    Objective Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. Methods The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. Results A modest increase in risk of developing breast cancer was associated with the LEP -2548AA genotype when compared to the LEP -2548GG genotype (age-adjusted OR=1.30; 95% CI=1.01–1.66). This association was stronger among postmenopausal women who were obese (OR=1.86; 95% CI=0.95–3.64) although the interaction was of borderline statistical significance (P=0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time=66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. Conclusions In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis. PMID:19697123

  14. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

    PubMed Central

    Pharoah, Paul D. P.; Michailidou, Kyriaki; Tyrer, Jonathan; Brook, Mark N.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Brown, Judith; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Peto, Julian; dos-Santos-Silva, Isabel; Dudbridge, Frank; Johnson, Nichola; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Rutgers, Emiel J.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Figueroa, Jonine; Chanock, Stephen J.; Brinton, Louise; Lissowska, Jolanta; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Pankratz, Vernon S.; Lambrechts, Diether; Wildiers, Hans; Van Ongeval, Chantal; van Limbergen, Erik; Kristensen, Vessela; Grenaker Alnæs, Grethe; Nord, Silje; Borresen-Dale, Anne-Lise; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Trentham-Dietz, Amy; Newcomb, Polly; Titus, Linda; Egan, Kathleen M.; Hunter, David J.; Lindstrom, Sara; Tamimi, Rulla M.; Kraft, Peter; Rahman, Nazneen; Turnbull, Clare; Renwick, Anthony; Seal, Sheila; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Benitez, Javier; Pilar Zamora, M.; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Dörk, Thilo; Anton-Culver, Hoda; Neuhausen, Susan L.; Ziogas, Argyrios; Bernstein, Leslie; Devilee, Peter; Tollenaar, Robert A. E. M.; Seynaeve, Caroline; van Asperen, Christi J.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Khusnutdinova, Elza; Bermisheva, Marina; Prokofyeva, Darya; Takhirova, Zalina; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Schürmann, Peter; Bremer, Michael; Christiansen, Hans; Park-Simon, Tjoung-Won; Hillemanns, Peter; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Pensotti, Valeria; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Sigurdson, Alice J.; Doody, Michele M.; Hamann, Ute; Torres, Diana; Ulmer, Hans-Ulrich; Försti, Asta; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Marie Mulligan, Anna; Chenevix-Trench, Georgia; Balleine, Rosemary; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Lindblom, Annika; Margolin, Sara; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Eilber, Ursula; Wang-Gohrke, Shan; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Koppert, Linetta B.; Carpenter, Jane; Clarke, Christine; Scott, Rodney; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Karina Dieffenbach, Aida; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Offit, Kenneth; Vijai, Joseph; Robson, Mark; Rau-Murthy, Rohini; Dwek, Miriam; Swann, Ruth; Annie Perkins, Katherine; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Eccles, Diana M.; Tapper, William J.; Rafiq, Sajjad; John, Esther M.; Whittemore, Alice S.; Slager, Susan; Yannoukakos, Drakoulis; Toland, Amanda E.; Yao, Song; Zheng, Wei; Halverson, Sandra L.; González-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Simard, Jacques; Hall, Per; Easton, Douglas F.; Garcia-Closas, Montserrat

    2015-01-01

    Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. PMID:25855707

  15. Common genetic variants in NEFL influence gene expression and neuroblastoma risk

    PubMed Central

    Capasso, Mario; Diskin, Sharon; Cimmino, Flora; Acierno, Giovanni; Totaro, Francesca; Petrosino, Giuseppe; Pezone, Lucia; Diamond, Maura; McDaniel, Lee; Hakonarson, Hakon; Iolascon, Achille; Devoto, Marcella; Maris, John M

    2014-01-01

    The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single nucleotide polymorphisms (SNP) associated with neuroblastoma at the LINC00340, BARD1, LMO1, DUSP12, HSD17B12, HACE1 and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated 8 additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNP at these candidate genes were tested for association with disease susceptibility in 2101 cases and 4202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing and cellular differentiation assays. The neurofilament gene NEFL harbored three SNP associated with neuroblastoma (rs11994014; Pcombined=0.0050; OR=0.88, rs2979704; Pcombined=0.0072; OR=0.87, rs105911; Pcombined=0.0049; OR=0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biological investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens was associated with better overall survival (P=0.03; HR=0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression. PMID:25312269

  16. Common Genetic and Nonshared Environmental Factors Contribute to the Association between Socioemotional Dispositions and the Externalizing Factor in Children

    ERIC Educational Resources Information Center

    Taylor, Jeanette; Allan, Nicholas; Mikolajewski, Amy J.; Hart, Sara A.

    2013-01-01

    Background: Childhood behavioral disorders including conduct disorder (CD), oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Prior twin research shows that common sets of genetic and environmental factors are associated with these various disorders and they form a latent factor called…

  17. Genetic Variability and Geographic Diversity of the Common Bed Bug (Hemiptera: Cimicidae) Populations from the Midwest Using Microsatellite Markers.

    PubMed

    Narain, Ralph B; Lalithambika, Sreedevi; Kamble, Shripat T

    2015-07-01

    With the recent global resurgence of the bed bugs (Cimex lectularius L.), there is a need to better understand its biology, ecology, and ability to establish populations. Bed bugs are domestic pests that feed mainly on mammalian blood. Although bed bugs have not been implicated as vectors of pathogens, their biting activity inflicts severe insomnia and allergic reactions. Moreover, they have recently developed resistance to various insecticides, which requires further molecular research to determine genetic variation and appropriate interventions. Population dynamics, including genetic differentiation and genetic distance of 10 populations from the Midwest were analyzed in this study. The bed bug samples collected by pest control companies were genotyped using eight species-specific microsatellite markers. Results showed all eight markers were polymorphic, with 8-16 alleles per locus, suggesting high genetic diversity. The FST values were >0.25, signifying pronounced genetic differentiation. The G-test results also indicated high genetic differentiation among populations. The frequency of the most common allele across all eight loci was 0.42. The coefficient of relatedness between each of the populations was >0.5, indicative of sibling or parent-offspring relationships, while the FIS and its confidence interval values were statistically insignificant within the populations tested. The populations departed from Hardy-Weinberg equilibrium, possibly because of high heterozygosity. The genetic distance analysis using a neighbor-joining tree showed that the populations from Kansas City, MO, were genetically separate from most of those from Nebraska, indicating a geographic pattern of genetic structure. Our study demonstrated the effectiveness of using microsatellite markers to study bed bugs population structure, thereby improving our understanding of bed bug population dynamics in the Midwest. Overall, this study showed a high genetic diversity and identified several

  18. The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes

    PubMed Central

    Sengupta, Supratim; Yang, Xiaoguang

    2007-01-01

    Many cases of nonstandard genetic codes are known in mitochondrial genomes. We carry out analysis of phylogeny and codon usage of organisms for which the complete mitochondrial genome is available, and we determine the most likely mechanism for codon reassignment in each case. Reassignment events can be classified according to the gain-loss framework. The “gain” represents the appearance of a new tRNA for the reassigned codon or the change of an existing tRNA such that it gains the ability to pair with the codon. The “loss” represents the deletion of a tRNA or the change in a tRNA so that it no longer translates the codon. One possible mechanism is codon disappearance (CD), where the codon disappears from the genome prior to the gain and loss events. In the alternative mechanisms the codon does not disappear. In the unassigned codon mechanism, the loss occurs first, whereas in the ambiguous intermediate mechanism, the gain occurs first. Codon usage analysis gives clear evidence of cases where the codon disappeared at the point of the reassignment and also cases where it did not disappear. CD is the probable explanation for stop to sense reassignments and a small number of reassignments of sense codons. However, the majority of sense-to-sense reassignments cannot be explained by CD. In the latter cases, by analysis of the presence or absence of tRNAs in the genome and of the changes in tRNA sequences, it is sometimes possible to distinguish between the unassigned codon and the ambiguous intermediate mechanisms. We emphasize that not all reassignments follow the same scenario and that it is necessary to consider the details of each case carefully. Electronic supplementary material The online version of this article (doi:10.1007/s00239-006-0284-7) contains supplementary material, which is available to authorized users. PMID:17541678

  19. Identification and expression of the laboratory of genetics and physiology 2 gene in common carp Cyprinus carpio.

    PubMed

    Cao, X L; Chen, J J; Cao, Y; Nie, G X; Wan, Q Y; Wang, L F; Su, J G

    2015-01-01

    In this study, a laboratory of genetics and physiology 2 gene (lgp2) from common carp Cyprinus carpio was isolated and characterized. The full-length complementary (c)DNA of lgp2 was 3061 bp and encoded a polypeptide of 680 amino acids, with an estimated molecular mass of 77 341·2 Da and a predicted isoelectric point of 6·53. The predicted protein included four main overlapping structural domains: a conserved restriction domain of bacterial type III restriction enzyme, a DEAD-DEAH box helicase domain, a helicase super family C-terminal domain and a regulatory domain. Real-time quantitative polymerase chain reaction (PCR) showed widespread expression of lgp2, mitochondrial antiviral signalling protein (mavs) and interferon transcription factor 3 (irf3) in tissues of nine organs. lgp2, mavs and irf3 expression levels were significantly induced in all examined organs by infection with koi herpesvirus (KHV). lgp2, mavs and irf3 messenger (m)RNA levels were significantly up-regulated in vivo after KHV infection, and lgp2 transcripts were also significantly enhanced in vitro after stimulation with synthetic, double-stranded RNA polyinosinic polycytidylic [poly(I:C)]. These findings suggest that lgp2 is an inducible protein involved in the innate immune defence against KHV in C. carpio. These results provide the basis for further research into the role and mechanisms of lgp2 in fishes. PMID:25359511

  20. Common Variants of KCNJ10 Are Associated with Susceptibility and Anti-Epileptic Drug Resistance in Chinese Genetic Generalized Epilepsies

    PubMed Central

    Guo, Yong; Yan, Kui Po; Qu, Qiang; Qu, Jian; Chen, Zi Gui; Song, Tao; Luo, Xiang-Ying; Sun, Zhong-Yi; Bi, Chang-Long; Liu, Jin-Fang

    2015-01-01

    To explore genetic mechanism of genetic generalized epilepsies (GGEs) is challenging because of their complex heritance pattern and genetic heterogeneity. KCNJ10 gene encodes Kir4.1 channels and plays a major role in modulating resting membrane potentials in excitable cells. It may cause GGEs if mutated. The purpose of this study was to investigate the possible association between KCNJ10 common variants and the susceptibility and drug resistance of GGEs in Chinese population. The allele-specific MALDI–TOF mass spectrometry method was used to assess 8 single nucleotide polymorphisms (SNPs) of KCNJ10 in 284 healthy controls and 483 Chinese GGEs patients including 279 anti-epileptic drug responsive patients and 204 drug resistant patients. We found the rs6690889 TC+TT genotypes were lower frequency in the GGEs group than that in the healthy controls (6.7% vs 9.5%, p = 0.01, OR = 0.50[0.29–0.86]). The frequency of rs1053074 G allele was lower in the childhood absence epilepsy (CAE) group than that in the healthy controls (28.4% vs 36.2%, p = 0.01, OR = 0.70[0.53–0.93]). The frequency of rs12729701 G allele and AG+GG genotypes was lower in the CAE group than that in the healthy controls (21.2% vs 28.4%, p = 0.01, OR = 0.74[0.59–0.94] and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). The frequency of rs12402969 C allele and the CC+CT genotypes were higher in the GGEs drug responsive patients than that in the drug resistant patients (9.3% vs 5.6%, OR = 1.73[1.06–2.85], p = 0.026 and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). This study identifies potential SNPs of KCNJ10 gene that may contribute to seizure susceptibility and anti-epileptic drug resistance. PMID:25874548

  1. Phylogeography and Conservation Genetics of the Common Wall Lizard, Podarcis muralis, on Islands at Its Northern Range

    PubMed Central

    Michaelides, Sozos; Cornish, Nina; Griffiths, Richard; Groombridge, Jim; Zajac, Natalia; Walters, Graham J.; Aubret, Fabien; While, Geoffrey M.; Uller, Tobias

    2015-01-01

    Populations at range limits are often characterized by lower genetic diversity, increased genetic isolation and differentiation relative to populations at the core of geographical ranges. Furthermore, it is increasingly recognized that populations situated at range limits might be the result of human introductions rather than natural dispersal. It is therefore important to document the origin and genetic diversity of marginal populations to establish conservation priorities. In this study, we investigate the phylogeography and genetic structure of peripheral populations of the common European wall lizard, Podarcis muralis, on Jersey (Channel Islands, UK) and in the Chausey archipelago. We sequenced a fragment of the mitochondrial cytochrome b gene in 200 individuals of P. muralis to infer the phylogeography of the island populations using Bayesian approaches. We also genotyped 484 individuals from 21 populations at 10 polymorphic microsatellite loci to evaluate the genetic structure and diversity of island and mainland (Western France) populations. We detected four unique haplotypes in the island populations that formed a sub-clade within the Western France clade. There was a significant reduction in genetic diversity (HO, HE and AR) of the island populations in relation to the mainland. The small fragmented island populations at the northern range margin of the common wall lizard distribution are most likely native, with genetic differentiation reflecting isolation following sea level increase approximately 7000 BP. Genetic diversity is lower on islands than in marginal populations on the mainland, potentially as a result of early founder effects or long-term isolation. The combination of restriction to specific localities and an inability to expand their range into adjacent suitable locations might make the island populations more vulnerable to extinction. PMID:25659074

  2. Phylogeography and conservation genetics of the common wall lizard, Podarcis muralis, on islands at its northern range.

    PubMed

    Michaelides, Sozos; Cornish, Nina; Griffiths, Richard; Groombridge, Jim; Zajac, Natalia; Walters, Graham J; Aubret, Fabien; While, Geoffrey M; Uller, Tobias

    2015-01-01

    Populations at range limits are often characterized by lower genetic diversity, increased genetic isolation and differentiation relative to populations at the core of geographical ranges. Furthermore, it is increasingly recognized that populations situated at range limits might be the result of human introductions rather than natural dispersal. It is therefore important to document the origin and genetic diversity of marginal populations to establish conservation priorities. In this study, we investigate the phylogeography and genetic structure of peripheral populations of the common European wall lizard, Podarcis muralis, on Jersey (Channel Islands, UK) and in the Chausey archipelago. We sequenced a fragment of the mitochondrial cytochrome b gene in 200 individuals of P. muralis to infer the phylogeography of the island populations using Bayesian approaches. We also genotyped 484 individuals from 21 populations at 10 polymorphic microsatellite loci to evaluate the genetic structure and diversity of island and mainland (Western France) populations. We detected four unique haplotypes in the island populations that formed a sub-clade within the Western France clade. There was a significant reduction in genetic diversity (HO, HE and AR) of the island populations in relation to the mainland. The small fragmented island populations at the northern range margin of the common wall lizard distribution are most likely native, with genetic differentiation reflecting isolation following sea level increase approximately 7000 BP. Genetic diversity is lower on islands than in marginal populations on the mainland, potentially as a result of early founder effects or long-term isolation. The combination of restriction to specific localities and an inability to expand their range into adjacent suitable locations might make the island populations more vulnerable to extinction. PMID:25659074

  3. Identifying Genetic Hotspots by Mapping Molecular Diversity of Widespread Trees: When Commonness Matters.

    PubMed

    Souto, Cintia P; Mathiasen, Paula; Acosta, María Cristina; Quiroga, María Paula; Vidal-Russell, Romina; Echeverría, Cristian; Premoli, Andrea C

    2015-01-01

    Conservation planning requires setting priorities at the same spatial scale at which decision-making processes are undertaken considering all levels of biodiversity, but current methods for identifying biodiversity hotspots ignore its genetic component. We developed a fine-scale approach based on the definition of genetic hotspots, which have high genetic diversity and unique variants that represent their evolutionary potential and evolutionary novelties. Our hypothesis is that wide-ranging taxa with similar ecological tolerances, yet of phylogenetically independent lineages, have been and currently are shaped by ecological and evolutionary forces that result in geographically concordant genetic patterns. We mapped previously published genetic diversity and unique variants of biparentally inherited markers and chloroplast sequences for 9 species from 188 and 275 populations, respectively, of the 4 woody dominant families of the austral temperate forest, an area considered a biodiversity hotspot. Spatial distribution patterns of genetic polymorphisms differed among taxa according to their ecological tolerances. Eight genetic hotspots were detected and we recommend conservation actions for some in the southern Coastal Range in Chile. Existing spatially explicit genetic data from multiple populations and species can help to identify biodiversity hotspots and guide conservation actions to establish science-based protected areas that will preserve the evolutionary potential of key habitats and species. PMID:26245788

  4. A COMMON VARIANT OF THE p16INK4A GENETIC REGION IS ASSOCIATED WITH PHYSICAL FUNCTION IN OLDER PEOPLE

    PubMed Central

    Melzer, David; Frayling, Timothy M; Murray, Anna; Hurst, Alison J; Harries, Lorna W; Song, Honglin; Khaw, KayTee; Luben, Robert; Surtees, Paul G; Bandinelli, Stefania S; Corsi, Anna-Maria; Ferrucci, Luigi; Guralnik, Jack M; Wallace, Robert B; Hattersley, Andrew T; Pharoah, Paul D

    2007-01-01

    p16INK4a is active in cell senescence, ageing and tumor suppression. Deletion of the small p16INK4a / ARF / p15INK4b region occurs in many cancers. We screened 25 common polymorphisms across the region and 3 related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65 to 80yrs) from the EPIC study (Norfolk, UK) the rs2811712 SNP minor allele (located between the shared p16INK4a / ARF locus and p15INK4b) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI Study (n=709, p=0.015), and at one sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372) the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele Odds Ratio=1.48 95%CI: 1.17−1.88, p =0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45: 95%CI 1.09−1.92, p=0.010, n=2434). These findings require further replication, but provide the first direct evidence that the p16INK4a / ARF / p15INK4b genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence. PMID:17459456

  5. Bulimia nervosa and major depression: a study of common genetic and environmental factors.

    PubMed

    Walters, E E; Neale, M C; Eaves, L J; Heath, A C; Kessler, R C; Kendler, K S

    1992-08-01

    A genetic analysis of the co-occurrence of bulimia and major depression (MD) was performed on 1033 female twin pairs obtained from a population based register. Personal interviews were conducted and clinical diagnoses made according to DSM-III-R criteria. Additive genes, but not family environment, are found to play an important aetiological role in both bulimia and MD. The genetic liabilities of the two disorders are correlated 0.456. While unique environmental factors account for around half of the variation in liability to both bulimia and MD, these risk factors appear to be unrelated, i.e., each disorder has its own set of unique environmental risk factors. Thus, the genetic liability of bulimia and MD is neither highly specific nor entirely non-specific. There is some genetic correlation between the two disorders as well as some genetic and environmental risk factors unique to each disorder. Limitations and directions for future research are discussed. PMID:1410087

  6. Genetic mechanisms of electroconvulsive therapy response in depression.

    PubMed

    Benson-Martin, Janine J; Stein, Dan J; Baldwin, David S; Domschke, Katharina

    2016-05-01

    Electroconvulsive therapy (ECT) is known to be one of the most effective treatments for managing depression and other severe mental illnesses. Nevertheless, the exact mechanisms underlying response to ECT remain uncertain. This mini-review presents clinical findings regarding the role of genetic factors in the aetiology of the ECT response. Studies on the role of variation in the catechol-O-methyltransferase (COMT) gene; other dopamine-, serotonin-, and G-protein-related genes; brain-derived neurotrophic factor (BDNF); apolipoprotein E (APOE); angiotensin I-converting enzyme (ACE) and vascular endothelial growth factor (VEGF) genes in mediating response to ECT are summarized. The existing data support the notion that some genetic factors-particularly the functional COMT val158met polymorphism-may play a role in the magnitude of clinical response to ECT, and thus could serve as potential biomarkers for future personalized treatment approaches. However, much of the work to date is preliminary, and large-scale confirmatory studies are still needed. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27062668

  7. Genetic Diversity and Pathogenic Variation of Common Blight Bacteria (Xanthomonas campestris pv. phaseoli and X. campestris pv. phaseoli var. fuscans) Suggests Pathogen Coevolution with the Common Bean.

    PubMed

    Mkandawire, Alexander B C; Mabagala, Robert B; Guzmán, Pablo; Gepts, Paul; Gilbertson, Robert L

    2004-06-01

    ABSTRACT Common bacterial blight (CBB), caused by Xanthomonas campestris pv. phaseoli and X. campestris pv. phaseoli var. fuscans, is one of the most important diseases of common bean (Phaseolus vulgaris) in East Africa and other bean-growing regions. Xanthomonad-like bacteria associated with CBB in Malawi and Tanzania, East Africa, and in Wisconsin, U.S., were characterized based on brown pigment production, pathogenicity on common bean, detection with an X. campestris pv. phaseoli- or X. campestris pv. phaseoli var. fuscans-specific PCR primer pair, and repetitive element polymerase chain reaction (rep-PCR) and restriction fragment length polymorphism (RFLP) analyses. The common bean gene pool (Andean or Middle American) from which each strain was isolated also was determined. In Malawi, X. campestris pv. phaseoli and X. campestris pv. phaseoli var. fuscans were isolated predominantly from Andean or Middle American beans, respectively. In Tanzania, X. campestris pv. phaseoli var. fuscans was most commonly isolated, irrespective of gene pool; whereas, in Wisconsin, only X. campestris pv. phaseoli was isolated from Andean red kidney beans. Three rep-PCR fingerprints were obtained for X. campestris pv. phaseoli strains; two were unique to East African strains, whereas the other was associated with strains collected from all other (mostly New World) locations. RFLP analyses with repetitive DNA probes revealed the same genetic diversity among X. campestris pv. phaseoli strains as did rep-PCR. These probes hybridized with only one or two fragments in the East African strains, but with multiple fragments in the other X. campestris pv. phaseoli strains. East African X. campestris pv. phaseoli strains were highly pathogenic on Andean beans, but were significantly less pathogenic on Middle American beans. In contrast, X. campestris pv. phaseoli strains from New World locations were highly pathogenic on beans of both gene pools. Together, these results indicate the

  8. The genetic assessment of looked after children: common reasons for referral and recent advances.

    PubMed

    Parker, Michael J; Teasdale, Katherine; Parker, Michael J

    2016-06-01

    Looked after children are recognised as generally having greater health needs than their peers. There are numerous potential causes, environmental and genetic, and the aetiology is often multifactorial. Assessments, especially clinical genetic ones, may be limited if the information available is incomplete or not shared. There have been some exciting recent advances in diagnostic genetic testing and more are on the horizon. However, we are currently only able to make a genetic diagnosis in less than half of patients, even when both parents are available for comparative testing. There may, therefore, remain an inevitable degree of residual uncertainty about the genetic contribution to a particular child's problems. There are increasing societal pressures for genetic information to be made available to individuals in general. However, there are significant considerations in carrier/predictive testing in children and we would maintain that looked after children should not be treated differently to other children in this regard, unless there is a compelling 'best interest' justification for so doing. Diagnostic criteria exist for fetal alcohol syndrome and other embryopathies and should be applied. Such should be considered as diagnoses of exclusion, so a child should not be prematurely labelled with these conditions, without fully assessing for the contribution of other factors, genetic or otherwise. PMID:26848122

  9. Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants

    PubMed Central

    Bagley, Steven C.; Sirota, Marina; Chen, Richard; Butte, Atul J.; Altman, Russ B.

    2016-01-01

    Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford), and compared to a large database of published disease-associated genetic variants (VARIMED); data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups. PMID:27115429

  10. 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