Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing

Yasminka A. Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin W. Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Joshua C. Bis, Eric Boerwinkle, Jennifer A. Brody, April P. Carson, Daniel I. Chasman, Jiawen Chen, Michael Cho, Matthew P. Conomos, Nancy Cox, Margaret F. Doyle, Myriam Fornage, Xiuqing GuoSharon L.R. Kardia, Joshua P. Lewis, Ruth J.F. Loos, Xiaolong Ma, Mitchell J. Machiela, Taralynn M. Mack, Rasika A. Mathias, Braxton D. Mitchell, Josyf C. Mychaleckyj, Kari North, Nathan Pankratz, Patricia A. Peyser, Michael H. Preuss, Bruce Psaty, Laura M. Raffield, Ramachandran S. Vasan, Susan Redline, Stephen S. Rich, Jerome I. Rotter, Edwin K. Silverman, Jennifer A. Smith, Aaron P. Smith, Margaret Taub, Kent D. Taylor, Jeong Yun, Yun Li, Pinkal Desai, Alexander G. Bick, Alexander P. Reiner, Paul Scheet, Paul L. Auer

Research output: Contribution to journalArticlepeer-review


Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

Original languageEnglish (US)
Pages (from-to)1912-1919
Number of pages8
JournalNature Genetics
Issue number11
StatePublished - Nov 2023

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