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Telomere-to-telomere assembly of a complete human X chromosome

Abstract

After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a de novo human genome assembly that surpasses the continuity of GRCh382, along with the first gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the ~3.1 megabase centromeric satellite DNA array and closed all 29 remaining gaps in the current reference, including new sequence from the human pseudoautosomal regions and cancer-testis ampliconic gene families (CT-X and GAGE). These novel sequences will be integrated into future human reference genome releases. Additionally, a complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays for the first time. Our results demonstrate that finishing the entire human genome is now within reach and the data presented here will enable ongoing efforts to complete the remaining human chromosomes.

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Correspondence to Karen H. Miga or Adam M. Phillippy.

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This file contains Supplementary Notes 1-8, which detail analyses from the main text, Supplementary Table 1 that provides genome annotation results, Supplementary Table 2 that provides inversion calls, Supplementary Table 3, which provides a description of all human genome assemblies in NCBI with contig NG50 >25 Mb or originating from CHM13; Supplementary Table 4 provides DXZ1 array estimates, Supplementary Table 5 lists structural variants identified by BioNano optical maps, and additional references (see Contents for more details).

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Miga, K.H., Koren, S., Rhie, A. et al. Telomere-to-telomere assembly of a complete human X chromosome. Nature (2020). https://doi.org/10.1038/s41586-020-2547-7

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