Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing
Authors: Jakubek Yasminka A. , Zhou Ying , Stilp Adrienne , Bacon Jason , Wong Justin , Ozcan Zuhal , Arnett Donna , Barnes Kathleen , Bis Josh , Boerwinkle Eric , Carson April , Chasman Daniel , Cho Michael , Conomos Matthew P. , Cox Nancy , Doyle Margaret , Fornage Myriam , Guo Xiuqing , Kardia Sharon , Lewis Joshua P. , Loos Ruth J. , Ma Xiaolong , Machiela Mitchell , Mack Taralynn M. , Mathias Rasika , Mitchell Braxton D. , North Kari , Pankratz Nathan , Peyser Patricia , Preuss Michael H. , Psaty Bruce , Raffield Laura M. , Vasan Ramachandran S. , Redline Susan , Rich Stephen S. , Rotter Jerome I. , Silverman Edwin , Smith Jennifer , Taub Margaret , Yun Jeong , Li Yun , Desai Pinkal , Bick Alexander G. , Reiner Alexander P. , Scheet Paul , Auer Paul L. 
Published: November 2022

ABSTRACTMosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants inATMandMPLshowed strong associations with mCAs incis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants inATMandMPLwith mCAs incis. Individual rare variants inDCPS, ADM17, PPP1R16B, andTET2were all associated with autosomal mCAs and rare variants inOR4C16were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genesTET2, DNMT3A, JAK2, CUX1, andTP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation.