A complete reference genome improves analysis of human genetic variation

Published

April 1, 2022

Author(s)

Sergey Aganezov, Stephanie Yan, Daniela Soto, Melanie Kirsche, Samantha Zarate, Justin Wagner, Jennifer McDaniel, Nathanael David Olson, Rajiv McCoy, Megan Dennis, Justin Zook, Michael Schatz

Abstract

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 million base pairs of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for clinical and functional study. We show how this reference universally improves read mapping and variant calling for 3202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of variants per sample in previously unresolved regions, showcasing the promise of the T2T-CHM13 reference for evolutionary and biomedical discovery. Simultaneously, this reference eliminates tens of thousands of spurious variants per sample, including reduction of false positives in 269 medically relevant genes by up to a factor of 12. Because of these improvements in variant discovery coupled with population and functional genomic resources, T2T-CHM13 is positioned to replace GRCh38 as the prevailing reference for human genetics.

Citation

Science/AAAS

Volume

376

Issue

6588

Pub Type

Journals

Download Paper

https://doi.org/10.1126/science.abl3533

Local Download

Keywords

human genome sequencing, reference genome, variant calling, benchmark

Citation

Aganezov, S. , Yan, S. , Soto, D. , Kirsche, M. , Zarate, S. , Wagner, J. , McDaniel, J. , Olson, N. , McCoy, R. , Dennis, M. , Zook, J. and Schatz, M. (2022), A complete reference genome improves analysis of human genetic variation, Science/AAAS, [online], https://doi.org/10.1126/science.abl3533, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=932858 (Accessed May 1, 2024)