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

View ORCID ProfileJinlong Shi, View ORCID ProfileZhilong Jia, Xiaojing Zhao, View ORCID ProfileJinxiu 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, View ORCID ProfileKunlun He
doi: https://doi.org/10.1101/2021.03.27.436702
Jinlong Shi
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
4Research Center of Medical Big Data, Chinese PLA General Hospital, Beijing, China
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  • ORCID record for Jinlong Shi
Zhilong Jia
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
3Research Center of Medical Artificial Intelligence, Chinese PLA General Hospital, Beijing, China
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Xiaojing Zhao
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Jinxiu Sun
4Research Center of Medical Big Data, Chinese PLA General Hospital, Beijing, China
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Fan Liang
5GrandOmics Biosciences Inc, Beijing, China
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Minsung Park
5GrandOmics Biosciences Inc, Beijing, China
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Chenghui Zhao
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
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Xiaoreng Wang
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Qi Chen
4Research Center of Medical Big Data, Chinese PLA General Hospital, Beijing, China
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Xinyu Song
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
3Research Center of Medical Artificial Intelligence, Chinese PLA General Hospital, Beijing, China
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Kang Yu
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
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Qian Jia
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Depeng Wang
5GrandOmics Biosciences Inc, Beijing, China
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Yuhui Xiao
5GrandOmics Biosciences Inc, Beijing, China
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Yinzhe Liu
5GrandOmics Biosciences Inc, Beijing, China
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Shijing Wu
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
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Qin Zhong
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Jue Wu
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Saijia Cui
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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Xiaochen Bo
6Beijing Institute of Radiation Medicine, Beijing, China
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Zhenzhou Wu
7BioMind Inc, Beijing, China
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Manolis Kellis
8Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
9Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Kunlun He
1Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
2Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, China
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  • ORCID record for Kunlun He
  • For correspondence: kunlunhe@plagh.org
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • High-quality figures (Fig1-5) have been updated in this version.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 30, 2021.
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Structural variant selection for high-altitude adaptation using single-molecule long-read sequencing
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
bioRxiv 2021.03.27.436702; doi: https://doi.org/10.1101/2021.03.27.436702
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Structural variant selection for high-altitude adaptation using single-molecule long-read sequencing
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
bioRxiv 2021.03.27.436702; doi: https://doi.org/10.1101/2021.03.27.436702

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