Abstract
The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low frequency variants in a dataset (gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences, and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that their mutation patterns also reflect chromosome-specific biochemical features that distinguish the X from autosomes. We tease these different features apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation signatures to replication timing and recombination, and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C>G as a mutagenic signature of male meiotic double strand breaks on the X, which may result from late repair. These results show how biochemical processes of damage and repair interact with sex-specific life history traits to shape germline mutation patterns across both human X and autosomes.
