Journal Article

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

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

2023

Overview

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 . A method that allows for the detection of mosaic chromosomal alterations from blood whole-genome sequencing data highlights ancestry-specific differences in the distribution of common and rare germline susceptibility variants.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 631/208 / 631/67 / Agriculture / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Black People - genetics / Blood / Cancer Research / Chromosomes / Chronic illnesses / Gene Function / Gene sequencing / Genome, Human / Genome-Wide Association Study / Genomes / Haplotypes / Hematology / Hispanic or Latino - genetics / Human Genetics / Humans / Mosaicism / Mutation / Population genetics / Population studies / Populations / Precision Medicine / Whole genome sequencing / Womens health