Parent-of-origin phasing of somatic mutations shows equal mutation burden between parental genomes in human cancers

Abstract

Somatic mutations accumulate independently in the two parental genome copies of our cells throughout life and shape cancer evolution. Although local mutation rates are influenced by allele-specific features such as DNA sequence, epigenetic marks, and chromatin structure, whether these translate into genome-wide differences in mutation accrual between the two parental copies is unknown. Cancer genomics analyses, including copy-number gain timing and molecular archaeology, assume that mutations accrue symmetrically on the two homologous parental genomes, yet this assumption has never been tested. Here we present PhaSoMix, a framework exploiting the genetic differentiation between parental haplotypes in admixed cancer patients to assign somatic mutations to their parent of origin without parent or parent-surrogate sequencing. Applying it with explicit modeling and propagation of phasing and ancestry-inference uncertainty across 21 tumor whole genomes from the Pan-Cancer Analysis of Whole Genomes cohort, we find mutation burdens highly symmetric between maternal and paternal genomes, across cancer types, genomic annotations, clonal timing categories, and mutational processes including clock-like CpG sites, bounding any asymmetry to within 4-5%. Simulations show that violations would substantially bias gain-timing estimates in late evolutionary windows. This provides the first quantification of parental mutation-burden symmetry in vivo, validating a key assumption of cancer evolutionary analyses.