Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Determinants of mosaic chromosomal alteration fitness

“…We calculated passenger mutation counts, representing clock-like C > T or T > C somatic mutations (see Methods), in individuals with a single mCA and no CH-associated SNVs 20 . Within this cohort, the minimum total passenger mutation count for a patient with an mCA was 3, maximum was 933, and median was 53 (Fig.…”

“…However, of those mCAs, only CN-LOH of chromosome 14 occurred in more than 25 individuals in TOPMed. Of all mCAs, only a gain in chromosome 1 had a higher fitness than driver SNVs in non-R882 DNMT3A , which is the slowest growing CHIP mutation 20 .…”

“…The SNP rs1122138 and another SNP in the core promoter of TCL1A , rs2887399, which has been reported to modulate stem cell expansion for SNV CH 20 , are in high linkage disequilibrium (R 2 = 0.826) in the 1,000 Genome Project. The risk alleles, rs1122138(A) and rs2887399(T), were correlated and our conditional analysis of our GWAS summary statistics demonstrated that rs1122138 did not remain significant after adjusting for the effect of rs2887399.…”

“…Here, we estimated the rate of clonal expansion in individuals with gain, loss, and CN-LOH mCAs in TOPMed. The PACER method has been previously validated in SNVs that cause clonal hematopoiesis of indeterminate potential (CHIP) 20 . Here, we extend the approach to a distinct form of somatic mosaicism highlighting the generalizability of the approach and permitting several observations.…”

“…We recently developed a method called passenger-approximated clonal expansion rate (PACER), which uses the abundance of passenger mutations accompanying a driver mutation to estimate the clonal expansion rate of a SNV with a single blood sample from an individual 20 . Here, we apply PACER to 6,381 individuals with gain, loss, and CN-LOH mCAs, detected by whole genome sequencing (WGS), in the NHLBI Trans-Omics for Precision Medicine (TOPMed) dataset to calculate a PACER score per individual and identify determinants and consequences of mCA clonal expansion rate (Fig.…”