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

By Karen H. Miga, Sergey Koren, Arang Rhie, Mitchell R. Vollger, Ariel Gershman, Andrey V. Bzikadze, Shelise Y. Brooks, Edmund Howe, David Porubsky, Glennis A. Logsdon and 42 more. Nature, 2019

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After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a 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 centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes. High-coverage, ultra-long-read nanopore sequencing is used to create a new human genome assembly that improves on the coverage and accuracy of the current reference (GRCh38) and includes the gap-free, telomere-to-telomere sequence of the X chromosome.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/621d723fcd8be5a8790c74e67a3cb3914115238c

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Citations in the corpus

Nanopore sequencing and the Shasta toolkit enable efficient de novo assembly of eleven human genomes (2020, methodology): “For CHM13, we used the v.0.6 release of CHM13 assembly by the T2T consortium 32 .”
Long-read human genome sequencing and its applications (2020, neutral): “Our findings are consistent with previous reports 34,36,56 .”
Nanopore sequencing technology, bioinformatics and applications (2021, methodology): “Moreover, ONT enabled the first gapless telomere-to-telomere assembly of the human X chromosome, including reconstruction of a ~2.8 Mb centromeric satellite DNA array and closing of all remaining 29 gaps (totaling 1.1 Mb) 134 .”
Haplotype-resolved diverse human genomes and integrated analysis of structural variation (2021, background): “Recent advances coupling both HiFi and ultralong-readOxfordNanopore data show promise in resolving the sequence of these more complex regions fromboth haploid (64) and diploid human genome assemblies (65).”
HiCanu: accurate assembly of segmental duplications, satellites, and allelic variants from high-fidelity long reads (2020, methodology): “7 (Miga et al. 2020) after each step of HiCanu processing (Supplemental Note 1).”