Volume 33, No 10, Oct 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 10, October 2023: 745-761   |  Open Access

ORIGINAL ARTICLES

The complete and fully-phased diploid genome of a male Han Chinese

Chentao Yang^1,2,3,† , Yang Zhou^3,4,† , Yanni Song^5,† , Dongya Wu^1,2,6,7,† , Yan Zeng^3,† , Lei Nie³ , Panhong Liu³ , Shilong Zhang⁸ , Guangji Chen^3,9 , Jinjin Xu³ , Hongling Zhou⁵ , Long Zhou^2,6,10 , Xiaobo Qian^3,9 , Chenlu Liu¹¹ , Shangjin Tan³ , Chengran Zhou³ , Wei Dai³ , Mengyang Xu^3,12 , Yanwei Qi¹² , Xiaobo Wang⁵ , Lidong Guo^9,12 , Guangyi Fan¹² , Aijun Wang¹² , Yuan Deng³ , Yong Zhang³ , Jiazheng Jin³ , Yunqiu He^1,2 , Chunxue Guo^3,13 , Guoji Guo¹⁴ , Qing Zhou^6,11 , Xun Xu³ , Huanming Yang³ , Jian Wang³ , Shuhua Xu^{15,16,17,18,19} , Yafei Mao⁸ , Xin Jin³ , Jue Ruan^5,* , Guojie Zhang^{1,2,6,10,20,*}

¹Center for Genomic Research, International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
²Center for Evolutionary & Organismal Biology, & Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
³BGI-ShenZhen, Shenzhen, Guangdong, China
⁴BGI Research-Wuhan, BGI, Wuhan, Hubei, China
⁵Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, China
⁶Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
⁷Institute of Crop Science & Institute of Bioinformatics, Zhejiang University, Hangzhou, Zhejiang, China
⁸Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
⁹College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
¹⁰Innovation Center of Yangtze River Delta, Zhejiang University, Hangzhou, Zhejiang, China
¹¹Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
¹²BGI-Qingdao, BGI-Shenzhen, Qingdao, Shandong, China
¹³BGI-Hangzhou, Hangzhou, Zhejiang, China
¹⁴School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
¹⁵State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
¹⁶Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China
¹⁷Jiangsu Key Laboratory of Phylogenomics & Comparative Genomics, International Joint Center of Genomics of Jiangsu Province School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, China
¹⁸Department of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
¹⁹Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China
²⁰State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
^†These authors contributed equally: Chentao Yang, Yang Zhou, Yanni Song, Dongya Wu, Yan Zeng
Correspondence: Jue Ruan(ruanjue@caas.cn)Guojie Zhang(guojiezhang@zju.edu.cn)

Since the release of the complete human genome, the priority of human genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid human genome from a Han Chinese male individual (CN1), in which the assemblies of both haploids achieve the telomere-to-telomere (T2T) level. Comparison of this diploid genome with the CHM13 haploid T2T genome revealed significant variations in the centromere. Outside the centromere, we discovered 11,413 structural variations, including numerous novel ones. We also detected thousands of CN1 alleles that have accumulated high substitution rates and a few that have been under positive selection in the East Asian population. Further, we found that CN1 outperforms CHM13 as a reference genome in mapping and variant calling for the East Asian population owing to the distinct structural variants of the two references. Comparison of SNP calling for a large cohort of 8869 Chinese genomes using CN1 and CHM13 as reference respectively showed that the reference bias profoundly impacts rare SNP calling, with nearly 2 million rare SNPs miss-called with different reference genomes. Finally, applying the CN1 as a reference, we discovered 5.80 Mb and 4.21 Mb putative introgression sequences from Neanderthal and Denisovan, respectively, including many East Asian specific ones undetected using CHM13 as the reference. Our analyses reveal the advances of using CN1 as a reference for population genomic studies and paleo-genomic studies. This complete genome will serve as an alternative reference for future genomic studies on the East Asian population.

https://doi.org/10.1038/s41422-023-00849-5

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