Browsing by Subject "genetics"
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Item Open Access 1997 Delegates to the Second International Strategy Meeting on Human Genome Sequencing in Bermuda from Gert-Jan van Ommen(2016-08-31)Photographs from the February 1997 Bermuda meeting. Courtesy of Gert-Jan van Ommen.Item Open Access 2000 NHGRI e-mail request for HGP sequencing center information, and corresponding aggregate data from NHGRI, compiled by Kris Wetterstrand(2016-08-31)Email exchange in 2013 between Kathryn Maxson (Duke) and Kris Wetterstrand (NHGRI), regarding country funding and other data for the HGP sequencing centers. Also includes the email request for such information, from NHGRI to the centers, in 2000, and the aggregate data collected.Item Open Access 2011 18 August Mark Guyer-Jane Peterson interview(2011-08-18)Mark Guyer and Jane Peterson, in-person interview with Kathryn Maxson and Robert Cook-Deegan, conducted in Rockville, MD (NIH campus), 18 August 2011. Mark Guyer and Jane Peterson were grants program officers at the NIH during the HGP, and were some of the longest-standing employees in the HGP administrative structure. Both witnessed the transformation of the Office of Genome Research into the National Center for Human Genome Research and, finally, the National Human Genome Research Institute. They were close participants in the history of the Bermuda Principles within the NIH.Item Open Access 2012 09 February Jean Weissenbach interview(2016-08-31)Jean Weissenbach, telephone interview by Kathryn Maxson and Robert Cook-Deegan, conducted from Durham, NC 09 February 2012. Jean Weissenbach, a leader in French genetic mapping, directed the French national sequencing center, Généthon, during the HGP and was instrumental in helping to build agreement to the Bermuda Principles in France.Item Open Access Item Open Access Item Open Access An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.(Circulation, 2020-02) Roberts, Jason D; Asaki, S Yukiko; Mazzanti, Andrea; Bos, J Martijn; Tuleta, Izabela; Muir, Alison R; Crotti, Lia; Krahn, Andrew D; Kutyifa, Valentina; Shoemaker, M Benjamin; Johnsrude, Christopher L; Aiba, Takeshi; Marcondes, Luciana; Baban, Anwar; Udupa, Sharmila; Dechert, Brynn; Fischbach, Peter; Knight, Linda M; Vittinghoff, Eric; Kukavica, Deni; Stallmeyer, Birgit; Giudicessi, John R; Spazzolini, Carla; Shimamoto, Keiko; Tadros, Rafik; Cadrin-Tourigny, Julia; Duff, Henry J; Simpson, Christopher S; Roston, Thomas M; Wijeyeratne, Yanushi D; El Hajjaji, Imane; Yousif, Maisoon D; Gula, Lorne J; Leong-Sit, Peter; Chavali, Nikhil; Landstrom, Andrew P; Marcus, Gregory M; Dittmann, Sven; Wilde, Arthur AM; Behr, Elijah R; Tfelt-Hansen, Jacob; Scheinman, Melvin M; Perez, Marco V; Kaski, Juan Pablo; Gow, Robert M; Drago, Fabrizio; Aziz, Peter F; Abrams, Dominic J; Gollob, Michael H; Skinner, Jonathan R; Shimizu, Wataru; Kaufman, Elizabeth S; Roden, Dan M; Zareba, Wojciech; Schwartz, Peter J; Schulze-Bahr, Eric; Etheridge, Susan P; Priori, Silvia G; Ackerman, Michael JBACKGROUND:Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS:Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS:A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS:The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.Item Open Access apex: phylogenetics with multiple genes.(Mol Ecol Resour, 2017-01) Jombart, Thibaut; Archer, Frederick; Schliep, Klaus; Kamvar, Zhian; Harris, Rebecca; Paradis, Emmanuel; Goudet, Jérome; Lapp, HilmarGenetic sequences of multiple genes are becoming increasingly common for a wide range of organisms including viruses, bacteria and eukaryotes. While such data may sometimes be treated as a single locus, in practice, a number of biological and statistical phenomena can lead to phylogenetic incongruence. In such cases, different loci should, at least as a preliminary step, be examined and analysed separately. The r software has become a popular platform for phylogenetics, with several packages implementing distance-based, parsimony and likelihood-based phylogenetic reconstruction, and an even greater number of packages implementing phylogenetic comparative methods. Unfortunately, basic data structures and tools for analysing multiple genes have so far been lacking, thereby limiting potential for investigating phylogenetic incongruence. In this study, we introduce the new r package apex to fill this gap. apex implements new object classes, which extend existing standards for storing DNA and amino acid sequences, and provides a number of convenient tools for handling, visualizing and analysing these data. In this study, we introduce the main features of the package and illustrate its functionalities through the analysis of a simple data set.Item Open Access Behavior Genetics and Post Genomics(Behavioral and Brain Sciences, 2012-12) Charney, EThe science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. DNA, once held to be the unchanging template of heredity, now appears subject to a good deal of environmental change; considered to be identical in all cells and tissues of the body, there is growing evidence that somatic mosaicism is the normal human condition; and treated as the sole biological agent of heritability, we now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, these phenomena appear to be particularly prevalent in the human brain, and likely are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period, and in enabling phenotypic plasticity in offspring in particular. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of “minimal shared maternal effects,” in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biologyItem Open Access Environmental fate and effects of Bacillus thuringiensis (Bt) proteins from transgenic crops: a review.(Journal of agricultural and food chemistry, 2005-06) Clark, BW; Phillips, TA; Coats, JRThis paper reviews the scientific literature addressing the environmental fate and nontarget effects of the Cry protein toxins from Bacillus thuringiensis (Bt), specifically resulting from their expression in transgenic crops. Published literature on analytical methodologies for the detection and quantification of the Cry proteins in environmental matrices is also reviewed, with discussion of the adequacy of the techniques for determining the persistence and mobility of the Bt proteins. In general, assessment of the nontarget effects of Bt protein toxins indicates that there is a low level of hazard to most groups of nontarget organisms, although some investigations are of limited ecological relevance. Some published reports on the persistence of the proteins in soil show short half-lives, whereas others show low-level residues lasting for many months. Improvements in analytical methods will allow a more complete understanding of the fate and significance of Bt proteins in the environment.Item Open Access Evolution of ASPM coding variation in apes and associations with brain structure in chimpanzees.(Genes, brain, and behavior, 2019-05-23) Singh, Sheel V; Staes, Nicky; Guevara, Elaine E; Schapiro, Steven J; Ely, John J; Hopkins, William D; Sherwood, Chet C; Bradley, Brenda JStudying genetic mechanisms underlying primate brain morphology can provide insight into the evolution of human brain structure and cognition. In humans, loss-of-function mutations in the gene coding for ASPM (Abnormal Spindle Microtubule Assembly) have been associated with primary microcephaly, which is defined by a significantly reduced brain volume, intellectual disability and delayed development. However, less is known about the effects of common ASPM variation in humans and other primates. In this study, we characterized the degree of coding variation at ASPM in a large sample of chimpanzees (N = 241), and examined potential associations between genotype and various measures of brain morphology. We identified and genotyped five non-synonymous polymorphisms in exons 3 (V588G), 18 (Q2772K, K2796E, C2811Y) and 27 (I3427V). Using T1-weighted magnetic resonance imaging of brains, we measured total brain volume, cerebral gray and white matter volume, cerebral ventricular volume, and cortical surface area in the same chimpanzees. We found a potential association between ASPM V588G genotype and cerebral ventricular volume but not with the other measures. Additionally, we found that chimpanzee, bonobo, and human lineages each independently show a signature of accelerated ASPM protein evolution. Overall, our results suggest the potential effects of ASPM variation on cerebral cortical development, and emphasize the need for further functional studies. These results are the first evidence suggesting ASPM variation might play a role in shaping natural variation in brain structure in nonhuman primates.Item Open Access GWAS Identifies New Loci for Painful Temporomandibular Disorder.(J Dent Res, 2017-01-01) Sanders, AE; Jain, D; Sofer, T; Kerr, KF; Laurie, CC; Shaffer, JR; Marazita, ML; Kaste, LM; Slade, GD; Fillingim, RB; Ohrbach, R; Maixner, W; Kocher, T; Bernhardt, O; Teumer, A; Schwahn, C; Sipilä, K; Lähdesmäki, R; Männikkö, M; Pesonen, P; Järvelin, M; Rizzatti-Barbosa, CM; Meloto, CB; Ribeiro-Dasilva, M; Diatchenko, L; Serrano, P; Smith, SBTemporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 10(6)) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10(-8)) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10(-8)) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10(-8)) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10(-7)) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.Item Open Access Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.(Molecular Genetics & Genomic Medicine, 2019-06) Headrick, Andrew T; Rosenfeld, Jill A; Yang, Yaping; Tunuguntla, Hari; Allen, Hugh D; Penny, Daniel J; Kim, Jeffrey J; Landstrom, Andrew PBACKGROUND:With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. METHODS:WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). RESULTS:Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals. CONCLUSIONS:Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic.Item Open Access Modifiers of Plasma 25-hydroxyvitamin D and Chronic Kidney Disease Outcomes in Black Americans: The Jackson Heart Study Supplemental FileLunyera, J; Davenport, Clemontina; Bhavsar, Nrupen; Sims, Mario; Pendergast, Jane; Musani, Solomon; Mwasongwe, Stanford; Wolf, Myles; Diamantidis, Clarissa; Boulware, Ebony; Scialla, JuliaItem Open Access Outcomes Associated With Familial Versus Nonfamilial Atrial Fibrillation: A Matched Nationwide Cohort Study.(J Am Heart Assoc, 2016-11-19) Gundlund, Anna; Olesen, Jonas Bjerring; Staerk, Laila; Lee, Christina; Piccini, Jonathan P; Peterson, Eric D; Køber, Lars; Torp-Pedersen, Christian; Gislason, Gunnar H; Fosbøl, Emil LoldrupBACKGROUND: We examined all-cause mortality and long-term thromboembolic risk (ischemic stroke, transient ischemic attack, systemic thromboembolism) in patients with and without familial atrial fibrillation (AF). METHODS AND RESULTS: Using Danish nationwide registry data, we identified all patients diagnosed with AF (1995-2012) and divided them into those with familial AF (having a first-degree family member with a prior AF admission) and those with nonfamilial AF. We paired those with and without familial AF according to age, year of AF diagnosis, and sex in a 1:1 match. Using cumulative incidence and multivariable Cox models, we examined the risk of long-term outcomes. We identified 8658 AF patients (4329 matched pairs) with and without familial AF. The median age was 50 years (interquartile range 43-54 years), and 21.4% were women. Compared with nonfamilial AF patients, those with familial AF had slightly less comorbid illness but similar overall CHA2DS2-VASc score (P=0.155). Median follow-up was 3.4 years (interquartile range 1.5-6.5 years). Patients with familial AF had risk of death and thromboembolism similar to those with nonfamilial AF (adjusted hazard ratio 0.91 [95% CI 0.79-1.04] for death and 0.90 [95% CI 0.71-1.14] for thromboembolism). CONCLUSIONS: Although family history of AF is associated with increased likelihood for development of AF, once AF developed, long-term risks of death and thromboembolic complications were similar in familial and nonfamilial AF patients.Item Open Access Sex and the Single Gametophyte: Revising the Homosporous Vascular Plant Life Cycle in Light of Contemporary Research(BIOSCIENCE, 2016-11) Haufler, CH; Pryer, KM; Schuettpelz, E; Sessa, EB; Farrar, DR; Moran, R; Schneller, JJ; Watkins Jr, JE; Windham, MDItem Open Access The Genetics of Success: How Single-Nucleotide Polymorphisms Associated With Educational Attainment Relate to Life-Course Development.(Psychol Sci, 2016-07) Belsky, Daniel W; Moffitt, Terrie E; Corcoran, David L; Domingue, Benjamin; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sugden, Karen; Williams, Benjamin S; Poulton, Richie; Caspi, AvshalomA previous genome-wide association study (GWAS) of more than 100,000 individuals identified molecular-genetic predictors of educational attainment. We undertook in-depth life-course investigation of the polygenic score derived from this GWAS using the four-decade Dunedin Study (N = 918). There were five main findings. First, polygenic scores predicted adult economic outcomes even after accounting for educational attainments. Second, genes and environments were correlated: Children with higher polygenic scores were born into better-off homes. Third, children's polygenic scores predicted their adult outcomes even when analyses accounted for their social-class origins; social-mobility analysis showed that children with higher polygenic scores were more upwardly mobile than children with lower scores. Fourth, polygenic scores predicted behavior across the life course, from early acquisition of speech and reading skills through geographic mobility and mate choice and on to financial planning for retirement. Fifth, polygenic-score associations were mediated by psychological characteristics, including intelligence, self-control, and interpersonal skill. Effect sizes were small. Factors connecting DNA sequence with life outcomes may provide targets for interventions to promote population-wide positive development.