Determinants of mosaic chromosomal alteration fitness

Yash Pershad, Taralynn Mack, Hannah Poisner, Yasminka A. Jakubek, Adrienne M. Stilp, Braxton D. Mitchell, Joshua P. Lewis, Eric Boerwinkle, Ruth J. F. Loos, Nathalie Chami, Zhe Wang, Kathleen Barnes, Nathan Pankratz, Myriam Fornage, Susan Redline, Bruce M. Psaty, Joshua C. Bis, Ali Shojaie, Edwin K. Silverman, Michael H. Cho, Jeong H. Yun, Dawn DeMeo, Daniel Levy, Andrew D. Johnson, Rasika A. Mathias, Margaret A. Taub, Donna Arnett, Kari E. North, Laura M. Raffield, April P. Carson, Margaret F. Doyle, Stephen S. Rich, Jerome I. Rotter, Xiuqing Guo, Nancy J. Cox, Dan M. Roden, Nora Franceschini, Pinkal Desai, Alex P. Reiner, Paul L. Auer, Paul A. Scheet, Siddhartha Jaiswal, Joshua S. Weinstock and Alexander G. Bick ()
Additional contact information
Yash Pershad: Vanderbilt University
Taralynn Mack: Vanderbilt University
Hannah Poisner: Vanderbilt University
Yasminka A. Jakubek: University of Kentucky
Adrienne M. Stilp: University of Washington
Braxton D. Mitchell: Baltimore
Joshua P. Lewis: Baltimore
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Nathalie Chami: Icahn School of Medicine at Mount Sinai
Zhe Wang: Icahn School of Medicine at Mount Sinai
Kathleen Barnes: University of Colorado Anschutz
Nathan Pankratz: University of Minnesota Medical School
Myriam Fornage: The University of Texas Health Science Center at Houston
Susan Redline: Harvard Medical School
Bruce M. Psaty: University of Washington
Joshua C. Bis: University of Washington
Ali Shojaie: University of Washington
Edwin K. Silverman: Brigham and Women’s Hospital
Michael H. Cho: Brigham and Women’s Hospital
Jeong H. Yun: Brigham and Women’s Hospital
Dawn DeMeo: Brigham and Women’s Hospital
Daniel Levy: Population Sciences Branch
Andrew D. Johnson: Population Sciences Branch
Rasika A. Mathias: Johns Hopkins University School of Medicine
Margaret A. Taub: Johns Hopkins University
Donna Arnett: University of Texas M.D. Anderson Cancer Center
Kari E. North: University of North Carolina Chapel-Hill
Laura M. Raffield: University of North Carolina at Chapel Hill
April P. Carson: University of Mississippi Medical Center
Margaret F. Doyle: The University of Vermont Larner College of Medicine
Stephen S. Rich: University of Virginia School of Medicine
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Xiuqing Guo: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Nancy J. Cox: Vanderbilt University and Vanderbilt University Medical Center
Dan M. Roden: Vanderbilt University Medical Center
Nora Franceschini: University of North Carolina Chapel-Hill
Pinkal Desai: Weill Cornell Medical College
Alex P. Reiner: Fred Hutchinson Cancer Center
Paul L. Auer: Medical College of Wisconsin
Paul A. Scheet: University of Texas M. D. Anderson Cancer Center
Siddhartha Jaiswal: Stanford University
Joshua S. Weinstock: University of Michigan School of Public Health
Alexander G. Bick: Vanderbilt University and Vanderbilt University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Date: 2024
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DOI: 10.1038/s41467-024-48190-8

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