Adaptations to Climate in Candidate Genes for Common Metabolic Disorders Angela M. Hancock1, David B. Witonsky1, Adam S. Gordon1, Gidon Eshel2¤, Jonathan K. Pritchard1, Graham Coop1, Anna Di Rienzo1* 1 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America, 2 Department of Geophysical Sciences, University of Chicago, Illinois, United States of America Evolutionary pressures due to variation in climate play an important role in shaping phenotypic variation among and within species and have been shown to influence variation in phenotypes such as body shape and size among humans. Genes involved in energy metabolism are likely to be central to heat and cold tolerance. To test the hypothesis that climate shaped variation in metabolism genes in humans, we used a bioinformatics approach based on network theory to select 82 candidate genes for common metabolic disorders. We genotyped 873 tag SNPs in these genes in 54 worldwide populations (including the 52 in the Human Genome Diversity Project panel) and found correlations with climate variables using rank correlation analysis and a newly developed method termed Bayesian geographic analysis. In addition, we genotyped 210 carefully matched control SNPs to provide an empirical distribution for spatial patterns of allele frequency due to population history alone. For nearly all climate variables, we found an excess of genic SNPs in the tail of the distributions of the test statistics compared to the control SNPs, implying that metabolic genes as a group show signals of spatially varying selection. Among our strongest signals were several SNPs (e.g., LEPR R109K, FABP2 A54T) that had previously been associated with phenotypes directly related to cold tolerance. Since variation in climate may be correlated with other aspects of environmental variation, it is possible that some of the signals that we detected reflect selective pressures other than climate. Nevertheless, our results are consistent with the idea that climate has been an important selective pressure acting on candidate genes for common metabolic disorders. Citation: Hancock AM, Witonsky DB, Gordon AS, Eshel G, Pritchard JK, et al. (2008) Adaptations to climate in candidate genes for common metabolic disorders. PLoS Genet 4(2): e32. doi:10.1371/journal.pgen.0040032 Introduction The ability to cope with heat and cold stress is important for survival and reproduction of organisms in general, and especially for those exposed to extreme temperatures [1]. If phenotypes that increase heat or cold tolerance were acted upon by natural selection, the genes responsible for these phenotypes would be expected to carry detectable signatures of selection in the spatial distribution of genetic variation. Indeed, latitudinal clines of allele frequencies have been observed for several polymorphisms in humans (e.g. [2,3]) as well as in natural populations of model organisms, including Drosophila melanogaster (e.g. [4–8]), and Arabidopsis thaliana ([9– 11]). Interestingly, many of the variants with latitudinal clines in Drosophila reside in genes involved in energy metabolism. Adaptations to spatially varying selective pressures, such as climates, may be particularly important in human popula- tions. Because the human species ﬁrst arose in equatorial Africa, the ability to tolerate high temperatures was likely under strong long-term selection in ancestral human pop- ulations. As humans spread out of equatorial Africa to regions at higher latitudes, cold temperatures likely became important selective forces. As a consequence, traits under stabilizing selection at near-equatorial latitudes may have become deleterious at higher latitudes. In addition to thermal stress, this scenario is likely to apply to a range of selective pressures, e.g. exposure to UV radiation and to different pathogens, which may be directly inﬂuenced by and partly correlated with climate. A striking example of adaptation to an environmental variable is variation in skin pigmentation, a phenotype known to vary worldwide as a function of UV radiation [12]. Consistent with the notion that variation in skin pigmentation is adaptive, genome-wide scans for selection have detected strong signals at candidate genes for melanin production and melanocyte function [13–18]. An- other possible example of spatial variation in selective pressures is sodium homeostasis. It was proposed that climate-related selection acted on the genes inﬂuencing salt and water retention and that variation in the intensity of selection partly accounts for the large inter-ethnic differ- ences in the prevalence of salt-sensitive hypertension [19,20]. In support of this hypothesis, two recent studies reported a strong correlation between the frequencies of candidate risk variants for hypertension and latitude; this correlation was signiﬁcant also when compared to that observed for a genome-wide set of random markers [21,22]. In addition to skin pigmentation and sodium homeostasis, human body shape and size also show clines with climate variables, suggesting that humans conform to the classical Editor: Dmitri A. Petrov, Stanford University, United States of America Received November 5, 2007; Accepted December 26, 2007; Published February 15, 2008 Copyright: 2008 Hancock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: HGDP, Human Genome Diversity Project; T2D, type 2 diabetes * To whom correspondence should be addressed. E-mail: dirienzo@genetics. uchicago.edu ¤ Current address: Division of Science, Mathematics and Computing, Bard College at Simon’s Rock, Great Barrington, Massachusetts, United States of America PLoS Genetics | www.plosgenetics.org 0001 February 2008 | Volume 4 | Issue 2 | e32