Abstract
BackgroundMany efforts have been made to detect signatures of positive selection in the human genome, especially those associated with expansion from Africa and subsequent colonization of all other continents. However, most approaches have not directly probed the relationship between the environment and patterns of variation among humans. We have designed a method to identify regions of the genome under selection based on Mantel tests conducted within a general linear model framework, which we call MAntel-GLM to Infer Clinal Selection (MAGICS). MAGICS explicitly incorporates population-specific and genome-wide patterns of background variation as well as information from environmental values to provide an improved picture of selection and its underlying causes in human populations.ResultsOur results significantly overlap with those obtained by other published methodologies, but MAGICS has several advantages. These include improvements that: limit false positives by reducing the number of independent tests conducted and by correcting for geographic distance, which we found to be a major contributor to selection signals; yield absolute rather than relative estimates of significance; identify specific geographic regions linked most strongly to particular signals of selection; and detect recent balancing as well as directional selection.ConclusionsWe find evidence of selection associated with climate (P < 10-5) in 354 genes, and among these observe a highly significant enrichment for directional positive selection. Two of our strongest 'hits’, however, ADRA2A and ADRA2C, implicated in vasoconstriction in response to cold and pain stimuli, show evidence of balancing selection. Our results clearly demonstrate evidence of climate-related signals of directional and balancing selection.
Highlights
Many efforts have been made to detect signatures of positive selection in the human genome, especially those associated with expansion from Africa and subsequent colonization of all other continents
We aim simultaneously to reduce the impact of false positives, by radically reducing the necessary number of independent tests, and to minimize the impact of observations that are unusual for reasons other than natural selection, for example genotyping errors
MAntel-GLM to Infer Clinal Selection (MAGICS) is based on the identification of genomic regions where genetic similarity between populations correlates with climatic similarity, after correcting for factors such as genome-wide relatedness and geographic distance
Summary
Many efforts have been made to detect signatures of positive selection in the human genome, especially those associated with expansion from Africa and subsequent colonization of all other continents. Many genetic studies on humans have attempted to identify genes and genomic regions associated with regional adaptation by looking for signatures of selection [2,9,10,11,12,13,14,15] These studies have relied on a diverse range of approaches that mostly identify outliers in the empirical genome-wide data, including searches for markers exhibiting unusually high levels of geographic differentiation [2,9], for genomic regions with high linkage disequilibrium and derived allele frequency [10], and for markers where the loss of genetic variability that occurred when humans migrated out of Africa has been high or low [11,12,13,14]. Wherever signatures of selection are sought by considering patterns of genetic variation in isolation, i.e. without reference to a specific hypothesis, it can become difficult to separate genuine signals from those that arise from other sources including genotyping errors and other artifacts
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