Determinants of mosaic chromosomal alteration fitness

• DOI: 10.1101/2023.10.20.23297280
• Publication Date: 2023-10-22T04:45:20Z
• Authors: Yash Pershad; Taralynn Mack; Hannah Poisner; Yasminka A Jakubek; Adrienne M Stilp; Braxton D Mitchell; Joshua P Lewis; Eric Boerwinkle; Ruth J 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 Yun; Dawn DeMeo; Daniel Levy; Andrew Johnson; Rasika Mathias; Margaret Taub; Donna Arnett; Kari North; Laura M Raffield; April Carson; Margaret F Doyle; Stephen S. Rich; Jerome I. Rotter; Xiuqing Guo; Nancy Cox; Dan M Roden; Nora Franceschini; Pinkal Desai; Alex Reiner; Paul L Auer; Paul Scheet; Siddhartha Jaiswal; Joshua S Weinstock; Alexander G Bick
• Keywords: Linkage Disequilibrium

Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in hematopoietic stem cell that results clonal expansion. These driver mutations can be single nucleotide variants cancer genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors influence variations mCA fitness and ultimately result different expansion rates are not well-understood. We used Passenger-Approximated Expansion Rate (PACER) method to estimate rate for 6,381 individuals NHLBI TOPMed cohort with gain, loss, copy-neutral loss heterozygosity mCAs. Our estimates were correlated (R 2 = 0.49) an alternative approach estimated mCAs UK Biobank using theoretical probability distribution. Individuals lymphoid-associated had significantly higher white blood count faster rate. In cross-sectional analysis, genome-wide association study identified TCL1A , NRIP1 TERT locus as modulators