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Structural variant selection for high-altitude adaptation using single-molecule long-read sequencing

By Jinlong Shi, Zhilong Jia, Xiaojing Zhao, Jinxiu Sun, Fan Liang, Minsung Park, Chenghui Zhao, Xiaoreng Wang, Qi Chen, Xinyu Song, Kang Yu, Qian Jia, Depeng Wang, Yuhui Xiao, Yinzhe Liu, Shijing Wu, Qin Zhong, Jue Wu, Saijia Cui, Xiaochen Bo, Zhenzhou Wu, Manolis Kellis, Kunlun He

Posted 27 Mar 2021
bioRxiv DOI: 10.1101/2021.03.27.436702

Structural variants (SVs) can be important drivers of human adaptation with strong effects, but previous studies have focused primarily on common variants with weak effects. Here, we used large-scale single-molecule long-read sequencing of 320 Tibetan and Han samples, to show that SVs are key drivers of selection under high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict driver enhancers, target genes, upstream regulators, and biological functions, which we validate using enhancer reporter and DNA pull-down assays. We reveal diverse Tibetan-specific SVs affecting the cis- and trans-regulatory circuitry of diverse biological functions, including hypoxia response, energy metabolism, lung function, etc. Our study greatly expands the global SV landscape, reveals the central role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles that SVs can play in human biology.

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