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


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.





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Publication Info

Miga, Karen H, Sergey Koren, Arang Rhie, Mitchell R Vollger, Ariel Gershman, Andrey Bzikadze, Shelise Brooks, Edmund Howe, et al. (2020). Telomere-to-telomere assembly of a complete human X chromosome. Nature, 585(7823). pp. 79–84. 10.1038/s41586-020-2547-7 Retrieved from

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Beth Ann Sullivan

James B. Duke Distinguished Professor

Research in the Sullivan Lab is focused on chromosome organization, with a specific emphasis on the genomics and epigenetics of the chromosomal locus called the centromere. The centromere is a specialized chromosomal site involved in chromosome architecture and movement, and when defective, is linked to cancer, birth defects, and infertility. The lab has described a unique type of chromatin (CEN chromatin) that forms exclusively at the centromere by replacement of core histone H3 by the centromeric histone variant CENP-A. Their studies also explore the composition of CEN chromatin and its relationship to the underlying highly repetitive alpha satellite DNA at the centromere. The Sullivan lab also discovered that genomic variation within alpha satellite DNA affects where the centromere is built and how well it functions. The Sullivan lab was part of the Telomere-to-Telomere T2T Consortium that used ultra long read sequencing and optical mapping to completely assemble each human chromosome, including through millions of basepairs of alpha satellite DNA at each centromere. Dr. Sullivan's group also builds human artificial chromosomes (HACs), using them as tools to test components required for a viable, transmissible chromosome and to study centromeric transcription and chromosome stability. The lab also studies formation and fate of chromosome abnormalities associated with birth defects, reproductive abnormalities, and cancer. Specifically, they study chromosomal abnormalities with two centromeres, called dicentric chromosomes. Originally described by Nobelist Barbara McClintock in the 1930s, dicentrics in most organisms are considered inherently unstable chromosomes because they trigger genome instability. However, dicentric chromosomes in humans are very stable and are often transmitted through multiple generations of a family. Using several approaches to experimentally reproduce dicentric chromosomes in human cells, the lab explores mechanisms of dicentric formation and their long-term fate.

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