A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
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EPAS1 附近的 3.4 kb 拷贝数缺失在高海拔藏族人群中显着丰富，但在丹尼索瓦序列中不存在
DOI：
10.1016/j.ajhg.2015.05.005
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发表时间：
2015-07-02
影响因子：
9.8
通讯作者：
Xu, Shuhua
中科院分区：
文献类型：
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作者：
Lou, Haiyi;Lu, Yan;Xu, Shuhua
藏族高原适应性（HAA）已被广泛研究，并已报道了许多候选基因。然而，随后针对HAA功能变体的努力并没有那么成功（例如，对于最佳候选HAA基因EPAS 1没有提出功能变体）。使用WinXPCNVer（本研究开发的一种方法），我们在微阵列数据中检测到90%的藏人携带藏人富集缺失（TED）; 50%的藏人是纯合缺失，而在2，792个全球样本中，只有3%携带TED，0%携带纯合缺失（p < 10（-15））。我们采用长PCR和桑格测序技术，以确定确切的拷贝数和断裂点的TED在70个额外的藏族和182个不同的样品。TED具有相同的边界（chr 2：46，694，276 - 46，697，683; hg 19），并且在EPAS 1下游80 kb处。值得注意的是，TED与EPAS 1变异体处于强连锁不平衡（LD; r（2）= 0.8），EPAS 1变异体与血红蛋白的血液浓度降低相关。它也与5-SNP基序完全LD，怀疑是从丹尼索瓦人渗入的，但丹尼索瓦人序列中不存在缺失本身。相应地，我们发现TED的正选择足迹发生在12，803年前（95%置信区间= 12，075 - 14，725）。我们进一步对七名西藏人进行了全基因组深度测序（> 60 x）并验证了TED，但未能发现任何其他具有可比模式的拷贝数变异，因此将TED作为进一步研究的首要任务。我们推测，TED的特定模式是由其自身在西藏人HAA或LD中的功能与EPAS 1的功能变体造成的。
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 Tibetanen-riched 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 (>60x) 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.