High-Specificity Detection of Chromosomal Mosaicism Reveals Cell-Type-Specific Genomic Alteration Patterns in Aging Tissues

Mosaic chromosomal alterations (mCAs) increase with age and are associated with multiple diseases, yet the cell types and states that harbor these alterations remain largely unknown. We develop CHASM, a method for detecting chromosomal copy number alterations from single-cell chromatin accessibility (scATAC-seq) data. CHASM estimates a CNA-null background for each cell, providing an individualized expectation that is critical in non-neoplastic tissues. In a cohort of 99 human kidney samples spanning age and disease conditions, CHASM identifies enrichment of mCAs in injury-associated VCAM1-high proximal tubule cells and detects the age-associated emergence of mCAs in cancer-relevant genomic regions, including chromosome 3 gains and losses and chromosome 7 gain, in ostensibly normal cell populations.