Table 2. SNPs Significant with Empirical p , 0.05 with Both Methods Variable Latitude Summer PC1 Summer PC2 Winter PC1 Genea FABP2 FGF2 FGF2 IPF1 LEPR MEF2A MEF2A PCSK1 RAPTOR RAPTOR RAPTOR RAPTOR RAPTOR RAPTOR ADRA2B CD36 DRD2 DRD2 DSCR1 MAPK1 MAPK14 PIK3CB PON1 PON1 PON1 SCARB2 SOD1 SOD1 TCF7L2 CETP CLOCK DSCR1 DSCR1 EGFR LEPR LEPR LEPR LEPR LEPR NPPA PTK2B PTK2B PTK2B PTK2B RAPTOR RAPTOR SOAT1 ACE DRD2 EGFR EPHX2 FGF2 FGF2 LEPR LEPR LEPR LEPR LEPR LEPR LEPR LEPR LEPR LEPR MAPK1 MEF2A NUDT6 PCSK1 PCSK1 PPARGC1A SNP rs1799883 rs308408 rs308409 rs17826863 rs1475397 rs2570824 rs2570932 rs6892752 rs12946049 rs12946115 rs12946618 rs12950541 rs2589153 rs719781 rs7604842 rs3173798 rs4245148 rs4587762 rs2300386 rs17759796 rs12200998 rs9879784 rs3917542 rs662 rs854555 rs12508223 rs2833479 rs2833483 rs11196175 rs4784744 rs1979605 rs2256666 rs928760 rs11770506 rs1171275 rs1892535 rs7534511 rs9436301 rs970468 rs198414 rs2241655 rs7000364 rs755951 rs9657295 rs9903123 rs9906493 rs7548288 rs7214530 rs4245151 rs11534100 rs751141 rs13118685 rs308428 rs10157275 rs1022981 rs11208654 rs1137100 rs1171275 rs12079231 rs12405556 rs1475397 rs1892535 rs4655518 rs1892848 rs2570932 rs2136424 rs2936428 rs6892752 rs4550905 Table 2. Continued. Variable Winter PC2 Genea PTK2B RAPTOR RAPTOR RAPTOR RAPTOR UCP3 EGFR LPA MMRN1 TCF1 Adaptations to Climate SNP rs1879184 rs12946049 rs12946115 rs12946618 rs7225574 rs7930460 rs13222385 rs7453836 rs7656954 rs11065386 aSNPs significant with p , 0.01 with both methods are bold. doi:10.1371/journal.pgen.0040032.t002 methods. While these nonsynonymous SNPs are likely to have functional effects and are plausible targets of selection, we cannot rule out that selection acted on different SNPs in strong linkage disequilibrium with the non-synonymous ones. Many genes exhibit signiﬁcant climate patterns at non- coding SNPs that cannot be easily accounted for by linkage disequilibrium with nonsynonymous SNPs. Among them, the strongest signal is observed at the RAPTOR gene, which is involved in nutrient signaling, mitochondrial oxygen con- sumption and oxidative capacity [53]. Four SNPs had signiﬁcant patterns with winter PC1 with p , 0.01 for both methods, and several additional SNPs showed signiﬁcant patterns (p , 0.01) with either latitude or winter PC1 (p , 0.05) with both methods (Figure 1A and 1B). A resequencing survey did not detect any common nonsynonymous variants at this gene (Sun and Di Rienzo, unpublished observation). The TCF7L2 gene, which shows the strongest signals in genome-wide association studies of T2D [60–64], harbors several SNPs with strong climate signals; as for RAPTOR, no common nonsynonymous SNPs are known at this gene [65]. SNP rs7903146 in TCF7L2, which is most consistently associated with T2D risk [66], is signiﬁcant with summer PC1 using the Bayesian geographic analysis method (p ¼ 0.019) and was suggestive using the rank correlation method (p ¼ 0.057). However, another TCF7L2 SNP, rs11196175, showed stronger patterns with all methods. This result may reﬂect the presence of multiple SNPs affecting TCF7L2 function or may simply result from stochastic variation in the climate signal due to the partial correlation among alleles within a gene. Among other SNPs reported to inﬂuence T2D risk based on a large number of replication studies [67], the PPARG (P12A) rs1801282 is signiﬁcantly correlated with latitude (p , 0.01 with rank correlation) while the KCNJ11 (E23K) rs5219 is not correlated with any variable. The Signal of Spatially Varying Selection at Candidate SNPs for Skin Pigmentation To better understand the expectations for genetic varia- tion subject to spatially varying selection, we analyzed SNP allele frequencies in candidate genes for variation in skin pigmentation. First, we used publicly available data for 6 SNPs previously genotyped in the HGDP panel [15] and subjected them to the same tests that we used to assess evidence for spatially varying selection in candidate genes for the phenotypes of the PLoS Genetics | www.plosgenetics.org 0005 February 2008 | Volume 4 | Issue 2 | e32