Journal Article

Genome-wide detection and characterization of positive selection in human populations

Lohmueller, Jason, Byrne, Elizabeth H., McCarroll, Steven A., Fry, Ben, Varilly, Patrick, Cotsapas, Chris, Sabeti, Pardis C., Hostetter, Elizabeth, Xie, Xiaohui, Lander, Eric S., Gaudet, Rachelle, Schaffner, Stephen F.

2007

Overview

HapMap2 raises the bar The International HapMap Consortium has produced a second-generation version of its remarkable haplotype map of the human genome. The Phase II HapMap charts human genetic variation even more extensively than the original, tripling of the number of genetic markers included. The original HapMap was instrumental in making large-scale genome-wide association studies possible. An indication of how this type of work will be extended with 'HapMap2' is presented in this issue: Sabeti et al . build on previous work detecting signs of positive natural selection on human genes. With many more markers now available, they have discovered three examples of apparent population-specific selection based on geographic area — involving gene pairs linked to Lassa virus in West Africa, skin pigmentation in Europe and hair follicle development in Asia — and they speculate on how these may relate to human biology. Sabeti et al . build on their This paper builds on previous work of detecting selection on human genes, using the many more markers available in the Phase II HapMap project. Three examples of apparent population-specific selection based on geographic area are described, and how these may relate to human biology is discussed. With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2) 1 . We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection 2 , and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD , both related to infection by the Lassa virus 3 , in West Africa; SLC24A5 and SLC45A2 , both involved in skin pigmentation 4 , 5 , in Europe; and EDAR and EDA2R , both involved in development of hair follicles 6 , in Asia.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Antiporters - genetics / Biological and medical sciences / Edar Receptor - chemistry / Edar Receptor - genetics / Evolutionary biology / Fundamental and applied biological sciences. Psychology / Gene Frequency / Genes / Genetic diversity / Genetic research / Genetics of eukaryotes. Biological and molecular evolution / Genetics, Population / Genome, Human - genetics / Genomics / Geography / Haplotypes - genetics / Human / Human genome / Human populations / Humanities and Social Sciences / Humans / Lassa virus / letter / Methods / Models, Molecular / multidisciplinary / Pigmentation / Polymorphism / Polymorphism, Single Nucleotide - genetics / Population genetics / Population genetics, reproduction patterns / Protein Structure, Tertiary / Science / Science (multidisciplinary) / Selection, Genetic