Mutation Rate Variability across Human Y-Chromosome Haplogroups

Abstract

A common assumption in dating patrilineal events using Y-chromosome sequencing data is that the Y-chromosome mutation rate is invariant across haplogroups. Previous studies revealed inter-haplogroup heterogeneity in phylogenetic branch length. Whether this heterogeneity is caused by inter-haplogroup mutation rate variation or non-genetic confounders remains unknown. Here we analyzed whole-genome sequences from cultured cells derived from > 1,700 males. We confirmed the presence of branch length heterogeneity. We demonstrate that sex chromosome mutations that appear within cell lines, which likely occurred somatically or in vitro (and are thus not influenced by non-genetic confounders) are informative for germline mutational processes. Using within-cell-line mutations, we computed a relative Y-chromosome somatic mutation rate, and uncovered substantial variation (up to 83.3%) in this proxy for germline mutation rate among haplogroups. This rate positively correlates with phylogenetic branch length, indicating that inter-haplogroup mutation rate variation is a likely cause of branch length heterogeneity.

Improved Models of Coalescence Ages of Y-DNA Haplogroups

“…Applying this rate to modern individuals, the overall mutation rate was not found to vary with statistical significance between haplogroups (including the basal A00 clade), showing that Y-SNP mutation must be indistinguishable from evolutionary neutrality. By contrast, the variation in total branch length of haplotree suggests mild (perhaps ±10-20%) variation in the mutation rate between haplogroups is possible, with the suggested cause being replication timing during cell division caused by differing amounts of heterochromatin [37].…”