A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence

Abstract

Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.

Evolutionary history of Tibetans inferred from whole-genome sequencing

“…Our estimate is consistent with a previous estimate of 12 kya to 15 kya[44]. Using this point estimate of selection start time and assuming that the adaptive haplotype indeed originated from Denisovans or a closely related population, we further inferred that the introgression of this haplotype most likely occurred between 32 and 12 kya.…”

Sherpas share genetic variations with Tibetans for high‐altitude adaptation

“…A 3.4‐kb deletion (TED) located 80 kb downstream of EPAS1 gene is highly prevalent in Tibetans (90%), but rare in Han Chinese and other world populations (3–7%), suggesting its potential role in HAA (Lou et al. ). We genotyped the TED locus in 582 Sherpas, and we found that 94% of them are TED carriers with 73% of them being TED homozygotes and 21% TED heterozygotes.…”

“…In addition, genotyping of TED was done following the method described in the previous study (Lou et al. ).…”

“…In addition, a recent study (Lou et al. ) identified a novel Tibetan‐enriched deletion (TED), where a 3.4‐kb deletion occurred at 80 kb downstream of EPAS1 in about 90% of Tibetans, but absent or extremely rare in other world populations including Han Chinese, implying its possible role in HAA. For Sherpas, previous studies have tested a limited number of sequence variants of several candidate genes likely involved in HAA, such as HIF‐1α (Suzuki et al.…”

Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas

“…WGS was performed using either the Illumina HiSequation 2000 or Hiseq X10 platform (Illumina, San Diego, CA). 9,41,42 SeekSV, an in-house method, was used for the detection of SVs. Further details are provided in the supplemental Methods.…”