Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing

Jinlong Shi, Zhilong Jia, Jinxiu Sun, Xiaoreng Wang, Xiaojing Zhao, Chenghui Zhao, Fan Liang, Xinyu Song, Jiawei Guan, Xue Jia, Jing Yang, Qi Chen, Kang Yu, Qian Jia, Jing Wu, Depeng Wang, Yuhui Xiao, Xiaoman Xu, Yinzhe Liu, Shijing Wu, Qin Zhong, Jue Wu, Saijia Cui, Xiaochen Bo, Zhenzhou Wu, Minsung Park, Manolis Kellis and Kunlun He ()
Additional contact information
Jinlong Shi: Medical Innovation Research Division of Chinese PLA General Hospital
Zhilong Jia: Chinese PLA General Hospital
Jinxiu Sun: Medical Innovation Research Division of Chinese PLA General Hospital
Xiaoreng Wang: Medical Innovation Research Division of Chinese PLA General Hospital
Xiaojing Zhao: Chinese PLA General Hospital
Chenghui Zhao: Chinese PLA General Hospital
Fan Liang: NextOmics Biosciences Inc
Xinyu Song: Chinese PLA General Hospital
Jiawei Guan: Medical Innovation Research Division of Chinese PLA General Hospital
Xue Jia: Medical Innovation Research Division of Chinese PLA General Hospital
Jing Yang: Medical Innovation Research Division of Chinese PLA General Hospital
Qi Chen: Medical Innovation Research Division of Chinese PLA General Hospital
Kang Yu: Chinese PLA General Hospital
Qian Jia: Chinese PLA General Hospital
Jing Wu: Medical Innovation Research Division of Chinese PLA General Hospital
Depeng Wang: NextOmics Biosciences Inc
Yuhui Xiao: NextOmics Biosciences Inc
Xiaoman Xu: NextOmics Biosciences Inc
Yinzhe Liu: NextOmics Biosciences Inc
Shijing Wu: Chinese PLA General Hospital
Qin Zhong: Medical Innovation Research Division of Chinese PLA General Hospital
Jue Wu: Chinese PLA General Hospital
Saijia Cui: Chinese PLA General Hospital
Xiaochen Bo: Beijing Institute of Radiation Medicine
Zhenzhou Wu: BioMind Inc
Minsung Park: NextOmics Biosciences Inc
Manolis Kellis: Broad Institute of MIT and Harvard
Kunlun He: Medical Innovation Research Division of Chinese PLA General Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Structural variants (SVs), accounting for a larger fraction of the genome than SNPs/InDels, are an important pool of genetic variation, enabling environmental adaptations. Here, we perform long-read sequencing data of 320 Tibetan and Han samples and show that SVs are highly involved in 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 enhancers, target genes and biological functions. We reveal diverse Tibetan-specific SVs affecting the regulatory circuitry of biological functions, including the hypoxia response, energy metabolism and pulmonary function. We find a Tibetan-specific deletion disrupts a super-enhancer and downregulates EPAS1 using enhancer reporter, cellular knock-out and DNA pull-down assays. Our study expands the global SV landscape, reveals the role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles of SVs in human biology.

Date: 2023
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DOI: 10.1038/s41467-023-44034-z

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