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

Abstract

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.

Human ancestry inference at scale, from genomic data

“…2b) and haploid KOREF 20 (Fig. S6) genome assemblies of three individuals places the prevalent ancestry based on highest composition (EUR:54%, EAS:87%, EAS:87%, respectively), consistent with both highest GAI scores, and the published European 18 , Chinese 19 and Korean 20 ancestry for each (Tables S6-S7). Further, ntRoot correctly infers EAS and EUR as the two most prevalent super-population ancestries from a synthetic diploid genome admix of HuRef and CN1 (Fig.…”

“…5 ntRoot LAI inferences using the chromosome-scale diploid HuRef 18 (Fig. 2a), CN1 19 (Fig. 2b) and haploid KOREF 20 (Fig.…”

The Hitchhiker’s Guide to Sequencing Data Types and Volumes for Population-Scale Pangenome Construction

“…Over the past two decades, the human reference genome employed in genetic studies has been meticulously crafted from genomic segments sourced from thousands of individuals (Lander et al 2001; Schneider et al 2017). Despite efforts to assemble high-quality, gapless genomes such as T2T-CHM13 (Nurk et al 2022), T2T-YAO (He et al 2023), CN1 (Yang et al 2023), I002C (https://github.com/LHG-GG/I002C) or HG002 (https://github.com/marbl/HG002), such references raise concerns regarding their abilities to represent genetic variations across diverse human populations accurately. The prevailing consensus is that no singular reference sequence can adequately encapsulate the complex genomic diversity across global populations (Yang et al 2019).…”

Comparative genomics of macaques and integrated insights into genetic variation and population history

“…Currently, haplotype-resolved genome assemblies can be generated with trio-based, Hi-C-based, or Strand-seq-based approaches [21][22][23] . These assemblies can then be utilized to construct high-quality pangenome graphs, enhancing our understanding of genetic structure and the evolutionary history of complex genomic regions [24][25][26] . However, generating haplotype-resolved diploid T2T genome assemblies remains challenging, primarily due to the complexities associated with phasing centromeres, subtelomeres, and SDRs 22 .…”