Identifying the favored mutation in a positive selective sweep.

Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis

Detecting Natural Selection in Genomic Data

The past fifty years have seen the development and application of numerous statistical methods to identify genomic regions that appear to be shaped by natural selection. These methods have been used to investigate the macro- and microevolution of a broad range of organisms, including humans. Here, we provide a comprehensive outline of these methods, explaining their conceptual motivations and statistical interpretations. We highlight areas of recent and future development in evolutionary genomics methods and discuss ongoing challenges for researchers employing such tests. In particular, we emphasize the importance of functional follow-up studies to characterize putative selected alleles and the use of selection scans as hypothesis-generating tools for investigating evolutionary histories.Organismic and Evolutionary Biolog

Identifying the favored mutation in a positive selective sweep.

Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations

A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.Wellcome Trust (London, England) (Core Award 090532/Z/09/Z)Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z )Wellcome Trust (London, England) (WT095908)Wellcome Trust (London, England) (WT109497)Wellcome Trust (London, England) (WT098051)Wellcome Trust (London, England) (WT086084/Z/08/Z)Wellcome Trust (London, England) (WT100956/Z/13/Z )Wellcome Trust (London, England) (WT097307)Wellcome Trust (London, England) (WT0855322/Z/08/Z )Wellcome Trust (London, England) (WT090770/Z/09/Z )Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z)Medical Research Council (Great Britain) (grant G0801823)Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1)Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1)Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201)National Basic Research Program of China (2011CB809201)National Basic Research Program of China (2011CB809202)National Basic Research Program of China (2011CB809203)National Natural Science Foundation of China (31161130357)Shenzhen Municipal Government of China (grant ZYC201105170397A)Canadian Institutes of Health Research (grant 136855)Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195)Germany. Bundesministerium für Bildung und Forschung (0315428A)Germany. Bundesministerium für Bildung und Forschung (01GS08201)Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A)Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1)Beatriu de Pinos Program (2006 BP-A 10144)Beatriu de Pinos Program (2009 BP-B 00274)Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER)Japan Society for the Promotion of Science (fellowship number PE13075)Marie Curie Actions Career Integration (grant 303772)Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342)National Center for Biotechnology Information (U.S.) (U54HG3067)National Center for Biotechnology Information (U.S.) (U54HG3273)National Center for Biotechnology Information (U.S.) (U01HG5211)National Center for Biotechnology Information (U.S.) (U54HG3079)National Center for Biotechnology Information (U.S.) (R01HG2898)National Center for Biotechnology Information (U.S.) (R01HG2385)National Center for Biotechnology Information (U.S.) (RC2HG5552)National Center for Biotechnology Information (U.S.) (U01HG6513)National Center for Biotechnology Information (U.S.) (U01HG5214)National Center for Biotechnology Information (U.S.) (U01HG5715)National Center for Biotechnology Information (U.S.) (U01HG5718)National Center for Biotechnology Information (U.S.) (U01HG5728)National Center for Biotechnology Information (U.S.) (U41HG7635)National Center for Biotechnology Information (U.S.) (U41HG7497)National Center for Biotechnology Information (U.S.) (R01HG4960)National Center for Biotechnology Information (U.S.) (R01HG5701)National Center for Biotechnology Information (U.S.) (R01HG5214)National Center for Biotechnology Information (U.S.) (R01HG6855)National Center for Biotechnology Information (U.S.) (R01HG7068)National Center for Biotechnology Information (U.S.) (R01HG7644)National Center for Biotechnology Information (U.S.) (DP2OD6514)National Center for Biotechnology Information (U.S.) (DP5OD9154)National Center for Biotechnology Information (U.S.) (R01CA166661)National Center for Biotechnology Information (U.S.) (R01CA172652)National Center for Biotechnology Information (U.S.) (P01GM99568)National Center for Biotechnology Information (U.S.) (R01GM59290)National Center for Biotechnology Information (U.S.) (R01GM104390)National Center for Biotechnology Information (U.S.) (T32GM7790)National Center for Biotechnology Information (U.S.) (P01GM99568)National Center for Biotechnology Information (U.S.) (R01HL87699)National Center for Biotechnology Information (U.S.) (R01HL104608)National Center for Biotechnology Information (U.S.) (T32HL94284)National Center for Biotechnology Information (U.S.) (HHSN268201100040C)National Center for Biotechnology Information (U.S.) (HHSN272201000025C)Lundbeck Foundation (grant R170-2014-1039Simons Foundation (SFARI award SF51)National Science Foundation (U.S.) (Research Fellowship DGE-1147470