Institution
Wellcome Trust Centre for Human Genetics
Facility•Oxford, United Kingdom•
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.
Topics: Population, Genome-wide association study, Single-nucleotide polymorphism, Gene, Locus (genetics)
Papers published on a yearly basis
Papers
More filters
••
University of Oxford1, Wellcome Trust Sanger Institute2, Mahidol University3, Charles Darwin University4, Wellcome Trust Centre for Human Genetics5, University of Bamako6, Papua New Guinea Institute of Medical Research7, Wellcome Trust8, National Institutes of Health9, University of London10, Sapienza University of Rome11, University of Notre Dame12, University of Maryland, Baltimore13
TL;DR: Methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture are described.
Abstract: methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genomewide estimates of allele frequency distribution, population structure and linkage disequilibrium By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P falciparum genome The genetic diversity and evolutionary plasticity of P falciparum are major obstacles for malaria elimination New forms of resistance against antimalarial drugs are continually emerging 1,2 , and new forms of antigenic variation are a critical point of vulnerability for future malaria vaccines Effective tools are needed to detect evolutionary changes in the parasite population and to monitor the spread of genetic variants that affect malaria control Here we describe the use of deep sequencing to analyse P falciparum diversity, using blood samples from patients with malaria The P falciparum genome has several unusual features that greatly complicate sequence analysis, such as extreme AT bias, large tracts of nonunique sequence and several large families of intensely polymorphic genes 3 Our aim was therefore not to determine the entire genome sequence of individual field samples—which would be prohibitively expensive with current technologies—but to define an initial set of single nucleotide polymorphisms (SNPs) distributed across the P falciparum genome, whose genotype can be ascertained with confidence in parasitized blood samples by deep sequencing An additional complication in the analysis of P falciparum genome variation is that the billions of haploid parasites that infect a single individual can be a complex mixture of genetic types Previous studies 4–8 have largely focused on laboratory-adapted parasite clones, but the within-host diversity of natural infections is of fundamental biological interest Parasites in the blood replicate asexually, but when they are taken up in the blood meal of an Anopheles mosquito they undergo sexual mating If the parasites in the blood are of diverse genetic types, this process of sexual mating can generate novel recombinant forms Deep sequencing provides new ways of investigating within-host diversity and the role of sexual recombination in parasite evolution
442 citations
••
TL;DR: Results revealed striking concordance between patterns of gene expression induced by hypoxia and by DMOG, indicating the central involvement of 2-OG-dependent dioxygenases in oxygen-regulated gene expression.
441 citations
••
TL;DR: Using a positional-cloning strategy, mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP) are identified in unrelated CMT4B patients.
Abstract: A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22. Using a positional-cloning strategy, we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP).
440 citations
••
TL;DR: Data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer.
Abstract: To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.
440 citations
••
Medical Research Council1, Wellcome Trust Centre for Human Genetics2, Wellcome Trust Sanger Institute3, National Institutes of Health4, University for Development Studies5, University of Oxford6, Mahidol University7, University of Maryland, Baltimore8, World Health Organization9, Pasteur Institute10, University of London11, Charles Darwin University12
TL;DR: An analysis of genome variation in 825 P. falciparum samples from Asia and Africa is described that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia, and a catalog of SNPs that show high levels of differentiation in the art Artemisinin-resistant subpopulations are provided.
Abstract: We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist in its elimination.
438 citations
Authors
Showing all 2127 results
Name | H-index | Papers | Citations |
---|---|---|---|
Mark I. McCarthy | 200 | 1028 | 187898 |
John P. A. Ioannidis | 185 | 1311 | 193612 |
Gonçalo R. Abecasis | 179 | 595 | 230323 |
Simon I. Hay | 165 | 557 | 153307 |
Robert Plomin | 151 | 1104 | 88588 |
Ashok Kumar | 151 | 5654 | 164086 |
Julian Parkhill | 149 | 759 | 104736 |
James F. Wilson | 146 | 677 | 101883 |
Jeremy K. Nicholson | 141 | 773 | 80275 |
Hugh Watkins | 128 | 524 | 91317 |
Erik Ingelsson | 124 | 538 | 85407 |
Claudia Langenberg | 124 | 452 | 67326 |
Adrian V. S. Hill | 122 | 589 | 64613 |
John A. Todd | 121 | 515 | 67413 |
Elaine Holmes | 119 | 560 | 58975 |