Revisiting the thrifty gene hypothesis via 65 loci associated with susceptibility to type 2 diabetes

Abstract

We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles.

Figure 1

Tests for Positive Selection in the Group of 64 Autosomal T2D Susceptibility Loci Tests were based on (A) the site frequency spectrum (Tajima’s D, Fay and Wu’s H, and Nielsen et al.’s CLR), (B) the composite of multiple signals (CMS), (C) haplotype diversity, or (D) population differentiation (pairwise F_ST) in a window of 25 kb on either side of the index SNP, except haplotype diversity, which used a window of 5 kb on each side. In each test, we examined either the combined set of loci (All) or subsets based on biological function (BF), the ancestral/derived status of the risk allele (RAS), or the effect size (ES), in each population or population pair. The results are summarized as the combined –log₁₀ of the p value; the threshold for significance after Bonferroni correction is shown by the dotted line.

Figure 2

Tests for Positive Selection in the 64 Individual Autosomal T2D Susceptibility Loci Tests were based on the site frequency spectrum (Tajima’s D, Fay and Wu’s H, and Nielsen et al.’s CLR), haplotype diversity, or population differentiation (pairwise F_ST), and each region or each index SNP was examined separately in each population. The results are summarized as the combined –log₁₀ of the p value; the threshold for significance after Bonferroni correction is shown by the dotted line.

Figure 3

Positive Selection at the NOTCH2 Locus (A) Region on chromosome 1 that spans NOTCH2 showing GENCODE (v. 14) transcript annotation (blue, protein coding transcripts; green, non-protein coding transcripts) and variant (dbSNP 137, NHLBI Exome SNPs and Indels) tracks (red, nonsynonymous and essential splice site variants; green, synonymous; black, splice site). The NHGRI GWAS Catalog track displays the position of the index SNP (rs10923931) and a highly differentiated variant (rs835574) observed between the AFR and EUR populations in the 1000 Genomes Project. The –log₁₀p of the combined p value (boxed area) were generated from the separate probabilities of Tajima’s D, Fay and Wu’s H, and Nielsen et al.’s CLR. The threshold, represented by the dashed line, incorporates the 5% FDR for each population. Peaks above the cut-off represent regions enriched for positive selection in the CEU and CHB+JPT. (B) A closer look at the haplotype networks in a region that is in high LD (r² ≥ 0.95) in CEU (gray area in A). Phased haplotypes were used to make the median joining networks. ENCODE annotation shows regions of open chromatin (Digital DNase I Hypersensitivity Clusters) and chromatin state segmentation in four cell lines (lymphoblastoid [GM12878], human umbilical vein endothelial [HUVEC], liver [HepG2], and human skeletal muscle myoblast [HSMM]). The region is associated with transcription and candidate enhancer regions are observed in HSMM. This is also supported by presence of binding sites for transcription factors (including IRF7) in its vicinity.

Figure 4

Positive Selection near HMGA2 (A) Region on chromosome 12 upstream of HMGA2 showing GENCODE (v. 14) transcript annotation (blue, protein coding transcripts; green, non-protein coding transcripts) variant (dbSNP 137) and NHGRI GWAS Catalog tracks with the index SNP (rs1531343) highlighted. ENCODE annotation shows regions of open chromatin (Digital DNase I Hypersensitivity Clusters), CpG islands, and chromatin state segmentation in four cell lines (GM12878, HUVEC, HepG2, and HSMM). The region is associated with transcription and candidate enhancer and promoter regions are observed in three cell lines. deCode Recombination Maps tracks show a male specific recombination region (blue). The –log₁₀p of the combined p value (boxed area) show peaks above the cut-off that represent regions enriched for positive selection in the CEU. (B) A closer look at the haplotype networks in a region that is in high LD (r² ≥ 0.95) in CEU (gray area in A). Candidate enhancer regions are observed in HUVEC and HSMM cell lines. There is a binding site for the transcription factor IRF7 in their vicinity.