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 (Genome Aggregation Database, 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 they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components 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 patterns 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. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.
Highlights
The sources of human germline mutations are poorly understood
Males and females differ in life history traits such as the timing of puberty and age of reproduction [18], which modulate the exposure of the gamete to the biochemical states associated with particular stages of development and alter their mutagenic impact
Individual chromosomes that replicate later, on average, show greater enrichment of C > A and T > A mutation types: differences in mean replication timing for individual autosomes explain ∼90% of the variation in C > A and T > A enrichment at the chromosome level (P < < 10−5), while they explain ∼50% or less for other mutation types (Fig. 2C). These results demonstrate that replication timing, and potentially other genomic features such as methylation and propensity for accidental double-strand break damage, lead to chromosome-level differences in diversity, hinting at some plausible sources for observed but unexplained chromosomelevel differences in average divergence [37]
Summary
We use whole genome SNP data from 15,496 individuals made available by gnomAD, which includes 9,256 Europeans and 4,368 African or AfricanAmerican individuals [40, 41]. We compare the diversity levels of different mutation types in pairs of genomic compartments (Fig. 1A) In these data, there are ∼120 million SNPs, of which 53% of the variants are singletons (i.e., variants seen only once in the sample, with an allele count of 1), and 11% are doubletons (allele count = 2) (Fig. 1B). Mutation types are considered significantly different in their frequencies between the 2 compartments if the 2-tailed P value from the binomial test is below the Bonferroni-corrected 5% significance threshold This approach implicitly ignores sampling error in the estimate of diversity of the designated reference compartment; we verify that our results are insensitive to this assumption by using alternative approaches to calculate significances that do not make this assumption, but have other limitations (Dataset S1).
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