Wellcome Trust Centre for Human Genetics

About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.

Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum

Abstract: The malaria parasite Plasmodium falciparum has a great capacity for evolutionary adaptation to evade host immunity and develop drug resistance. Current understanding of parasite evolution is impeded by the fact that a large fraction of the genome is either highly repetitive or highly variable and thus difficult to analyze using short-read sequencing technologies. Here, we describe a resource of deep sequencing data on parents and progeny from genetic crosses, which has enabled us to perform the first genome-wide, integrated analysis of SNP, indel and complex polymorphisms, using Mendelian error rates as an indicator of genotypic accuracy. These data reveal that indels are exceptionally abundant, being more common than SNPs and thus the dominant mode of polymorphism within the core genome. We use the high density of SNP and indel markers to analyze patterns of meiotic recombination, confirming a high rate of crossover events and providing the first estimates for the rate of non-crossover events and the length of conversion tracts. We observe several instances of meiotic recombination within copy number variants associated with drug resistance, demonstrating a mechanism whereby fitness costs associated with resistance mutations could be compensated and greater phenotypic plasticity could be acquired.

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Abstract: Wellcome Trust (080952/Z/06/Z, 078986/Z/06/Z); United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases; Canadian Institutes of Health Research; NIHR Cambridge Biomedical Research Centre; Cardiovascular Institute of the University of Pennsylvania; GlaxoSmithKline; Center for Applied Genomics at the Children's Hospital of Philadelphia; Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research; Cardiogenics (LSHM-CT-2006-037593); GSF National Research Centre for Environment and Health; German Federal Ministry of Education and Research and the State of Bavaria; Cancer Research United Kingdom and the Medical Research Council; British Heart Foundation (BHF) Family Heart Study Research Group; UK Medical Research Council; University of Bristol; British Heart Foundation (MRC PG/07/002); Genome Quebec; Genome Canada; National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); Affymetrix (N02-HL-6-4278); Framingham Heart Study SNP Health Association Resource (SHARe) project; the National Institutes of Health, National Center for Research Resources; General Clinical Research Centers Program (M01-RR-01066); American Diabetes Association; sanofi-aventis; National Institues of Health and National Center for Research Resources (1S10RR163736-01A1); Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195), National Institute for Diabetes and Digestive and Kidney Diseases (R01 DK078616, NIDDK K24 DK080140, K23 DK65978) a Massachusetts General Hospital; Doris Duke Charitable Foundation; Centre de Recherche Medicale de l'Universite de Sherbrooke; European Community's Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, FP7/2007-2013); ENGAGE project (HEALTH-F4-2007-201413; FP-5 GenomEUtwin Project (QLG2-CT-2002-01254); National Institute for Health Research

Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians

Abstract: The region of conserved synteny on mouse chromosome 11/human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

Smoking is associated with mosaic loss of chromosome Y

Abstract: Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared with females. This observation, together with the fact that males have a higher incidence of and mortality from most non–sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.8 to 6.7; Uppsala Longitudinal Study of Adult Men: OR = 2.4, 95% CI = 1.6 to 3.6; and Prospective Investigation of the Vasculature in Uppsala Seniors: OR = 3.5, 95% CI = 1.4 to 8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

A Linkage Map of the Rat Genome Derived from Three F2 Crosses

Abstract: We report the construction of a dense linkage map of the rat genome integrating 767 simple sequence length polymorphism markers, combined over three crosses with high rates of polymorphism. F2 populations from WKY x S (n = 159), BN x S (n = 91), and BN x GK (n = 139) were selected and genotyped for combinations of microsatellite markers. The loci define 21 linkage groups corresponding to the 20 rat autosomal chromosomes and the X chromosome. The map spans a genetic length of 1998 cM. This combined linkage map should facilitate the advancement of genetic studies for a wide variety of rat models characterized for complex phenotypes.