Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions

Abstract

Different populations suffer from different rates of obesity and type-2 diabetes (T2D). Little is known about the genetic or adaptive component, if any, that underlies these differences. Given the cultural, geographic, and dietary variation that accumulated among humans over the last 60,000 years, we examined whether loci identified by genome-wide association studies for these traits have been subject to recent selection pressures. Using genome-wide SNP data on 938 individuals in 53 populations from the Human Genome Diversity Panel, we compare population differentiation and haplotype patterns at these loci to the rest of the genome. Using an “expanding window” approach (100 to 1,600 kb) for the individual loci as well as the loci as ensembles, we find a high degree of differentiation for the ensemble of T2D loci. This differentiation is most pronounced for East Asians and sub-Saharan Africans, suggesting that these groups experienced natural selection at loci associated with T2D. Haplotype analysis suggests an excess of obesity loci with evidence of recent positive selection among South Asians and Europeans, compared to sub-Saharan Africans and Native Americans. We also identify individual loci that may have been subjected to natural selection, such as the T2D locus, HHEX, which displays both elevated differentiation and extended haplotype homozygosity in comparisons of East Asians with other groups. Our findings suggest that there is an evolutionary genetic basis for population differences in these traits, and we have identified potential group-specific genetic risk factors.

Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia

“…19 Milk consumption is indeed widespread among Kyrgyz populations (even though the frequency of lactase persistency is low 58 ), as in the Hausa population, where a signal of selection has been detected in CAPN10. 23 On the other hand, evidence of recent selection for the protective haplotype at LEPR and TCF7L2 (as we found in Kyrgyz) is also documented in other East Asian populations 20,31,33,49 (see also the high F ST and iHS values in ASN, Table 2), from which the Kyrgyz are genetically closer than the Tajiks. 34 These signatures of selection are, therefore, more likely to reflect a differential adaptation between East For each mutation, we determined the ancestral and derived alleles (given on the þ strand) using the chimpanzee as outgroup.…”

“…Much effort has been devoted so far in the search for thrifty variants, and the thrifty genotype hypothesis has a deep impact into the therapeutic diet strategies adopted in modern societies to manage chronic diseases. 59,60 Yet our results, along with those from other authors, 20,[29][30][31]33 support a radically different scenario, in which protective (non-thrifty) haplotypes have been and might still be under positive selection in many populations worldwide. This suggests that the biological constraints driving the evolution of genetic variants associated with T2D are still poorly understood.…”

“…Interestingly, the KCNQ1 protective haplotype (which frequency is higher in Kyrgyz than in Tajiks, see Table 2) has been shown to be at low frequency in populations where cereals are the main dietary component 57 and under recent selection in four out of seven pastoral populations from South Asia. 33 It seems therefore that this protective haplotype was recently targeted by selection in response to specific pastoral dietary habits. However, we have shown in this study that signals of selection toward protective variants have been found in both herders and farmers from Central Asia, suggesting that the same phenotype is favored in both the lifestyles.…”

“…Protective variants for T2D under recent selection L Ségurel et al Intriguingly, we did not find signals of selection for the mutation rs7903146 in TCF7L2, although it represents the strongest signal of association with T2D to date in other populations and the most consistent signal of selection. 20,31,33 However, the estimated growth rate of the protective allele in Kyrgyz was higher than that of the risk variant (1.027, CI 95% : 1.019-1-040 vs 1.009, CI 95% : 1.007-1.017) and pointed to a selective event starting 12 000 years ago. Tajiks did not show such a signal (growth rate of 1.018, CI 95% : 1.013-1.026 for the protective vs 1.017, CI 95% : 1.012-1.027 for the risk allele).…”

“…Hancock et al 20 analyzed worldwide correlations between climate variables and allele frequencies at metabolic genes and found evidence of selection on both protective (in LEPR and PON1) and risk haplotypes (in FABP2 and EPHX2). Klimentidis et al 33 found that for three genes, selection targeted the risk haplotypes (in IGF2BP2, WFS1 and SLC30A8) and that T2D-associated loci are highly differentiated on a worldwide scale, with Sub-Saharan Africans and East Asians being particularly prone to positive selection. Given the latter two studies did not provide estimates of the timing of the selective event, it remains unclear which evolutionary hypothesis is supported by the genetic data.…”