Table 1.
Genomic Regions Showing the Strongest Signals of Positive Selection in the Himalayan Populations.
| Candidate Gene | Cluster of Selected SNPs: GRCh37 Coordinates | Number of SNPs in Cluster | Top SNP: Combined P Value | Top SNP | Top SNP Frequency High-Altitude Populations | Top SNP Frequency East Asian Populations | Allele Under Selection | eQTLs | Comments |
|---|---|---|---|---|---|---|---|---|---|
| EPAS1 | 2: 46468276–46852033 | 26 | 1.83E-27 | rs4953359 | 68% | 14% | D | 9 | Known high-altitude selection signal |
| EGLN1 | 1: 231204794–231897303 | 21 | 3.45E-14 | rs6655954 | 58%a | 27%a | A | 10 | Known high-altitude selection signal |
| HLA-DQB1/HLA-DPB1 | 6: 32582075–33175824 | 15 | 1.66E-11 | rs10484569 | 77% | 39% | D | 6 | Known high-altitude selection signal. Region associated with susceptibility to HBV infection in East Asians (Guo et al. 2011) |
| ANKH | 5: 14908578–149285033 | 5 | 2.63E-11 | rs4702062 | 84%a | 64%a | A | – | Novel: regulatory region. Gene has hypoxia responsive element (HREs) in promoter region and it has been reported as a candidate for high-altitude adaptation in Tibetan pigs (Ai et al. 2014) |
| RP11-384F7.2 AC068633.1 | 3: 117427214–118549344 | 5 | 6.68E-09 | rs1081896 | 79%a | 64%a | A | 2 | Novel |
| ZNF532 | 18: 56562356–56648324 | 3 | 8.37E-09 | rs3826597 | 18% | 8% | D | – | Novel |
| COL4A4 | 2: 227770592–227922321 | 8 | 1.19E-07 | rs3769641 | 46% | 19% | D | 1 | Novel: include synonymous and splice region variants. This gene encodes one of the subunits of collagen type IV. Collagen metabolism plays an important role in angiogenesis during hypoxia (Tajima et al. 2001; Sudhakar et al. 2005) |
| SLC52A3 | 20: 744415–745963 | 2 | 1.22E-06 | rs3746804 | 63% | 25% | D | 1 | Novel: missense and synonymous variants. Riboflavin transporter that could be involved in counteracting alterations of energetic metabolism under acute hypoxia (Ghosal et al. 2015) |
| MKL1 | 22: 40827319–40905072 | 3 | 3.97E-06 | rs17001997 | 47% | 24% | D | 3 | Novel: gene involved in the regulation of cellular response to hypoxia in the vasculature of rats (Yuan et al. 2014) |
| GRB2 | 17: 73326965–73374945 | 4 | 3.66E-05 | rs4789182 | 94% | 83% | D | 4 | Novel: associated with reduction of hypoxia-induced oxidative stress in Tibetan individuals (Li et al. 2016) |
NOTE.—Bold candidate genes: Decisive (log10Bayes Factor >2) candidates from BayEnv v2.
a
Frequency of ancestral allele.
A, Ancestral; D, Derived.