Towards a reference genome that captures global genetic diversity

Karen H. Y. Wong, Walfred Ma, Chun-Yu Wei, Erh-Chan Yeh, Wan-Jia Lin, Elin H. F. Wang, Jen-Ping Su, Feng-Jen Hsieh, Hsiao-Jung Kao, Hsiao-Huei Chen, Stephen K. Chow, Eleanor Young, Catherine Chu, Annie Poon, Chi-Fan Yang, Dar-Shong Lin, Yu-Feng Hu, Jer-Yuarn Wu, Ni-Chung Lee, Wuh-Liang Hwu, Dario Boffelli, David Martin, Ming Xiao and Pui-Yan Kwok ()
Additional contact information
Karen H. Y. Wong: Cardiovascular Research Institute, University of California, San Francisco
Walfred Ma: Cardiovascular Research Institute, University of California, San Francisco
Chun-Yu Wei: Institute of Biomedical Sciences, Academia Sinica
Erh-Chan Yeh: Institute of Biomedical Sciences, Academia Sinica
Wan-Jia Lin: Institute of Biomedical Sciences, Academia Sinica
Elin H. F. Wang: Institute of Biomedical Sciences, Academia Sinica
Jen-Ping Su: Institute of Biomedical Sciences, Academia Sinica
Feng-Jen Hsieh: Institute of Biomedical Sciences, Academia Sinica
Hsiao-Jung Kao: Institute of Biomedical Sciences, Academia Sinica
Hsiao-Huei Chen: Institute of Biomedical Sciences, Academia Sinica
Stephen K. Chow: Cardiovascular Research Institute, University of California, San Francisco
Eleanor Young: School of Biomedical Engineering, Drexel University
Catherine Chu: Institute for Human Genetics, University of California, San Francisco
Annie Poon: Institute for Human Genetics, University of California, San Francisco
Chi-Fan Yang: Institute of Biomedical Sciences, Academia Sinica
Dar-Shong Lin: Department of Pediatrics, Mackay Memorial Hospital
Yu-Feng Hu: Institute of Biomedical Sciences, Academia Sinica
Jer-Yuarn Wu: Institute of Biomedical Sciences, Academia Sinica
Ni-Chung Lee: Departments of Pediatrics and Medical Genetics, National Taiwan University Hospital
Wuh-Liang Hwu: Departments of Pediatrics and Medical Genetics, National Taiwan University Hospital
Dario Boffelli: Children’s Hospital Oakland Research Institute
David Martin: Children’s Hospital Oakland Research Institute
Ming Xiao: School of Biomedical Engineering, Drexel University
Pui-Yan Kwok: Cardiovascular Research Institute, University of California, San Francisco

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.

Date: 2020
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DOI: 10.1038/s41467-020-19311-w

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