Variation in genome-wide mutation rates within and between human families

Abstract

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.

Figure 1. Overview of study design

The two phases of the project: discovery and validation are shown schematically, including the samples from each family that were used in each phase. LCL – Lymphoblastoid Cell Line, WG – Whole Genome

Figure 2. Comparison of mutation rate estimates

Mutation rates estimated from previous studies are shown above the dashed green line. Solid lines encompassing point estimates represent 95% confidence intervals. Dashed lines encompassing point estimates represent reported plausible ranges. ‘Disease-gene Sex-averaged’ rate comes from , with 95% confidence intervals calculated as 1.96 times the standard error. ‘Species-divergence Sex averaged rate’ comes from , which specifies the plausible range shown here. Species-divergence sex-specific rates come from scaling the sex-averaged point estimate and upper and lower bounds by the ratio of male/female mutation rate of 6.11 estimated by . ‘Family Genome-wide Sex-average’ comes from , ‘Families Sex-average’ comes from .