Timing, rates and spectra of human germline mutation

Abstract

Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. Mutation rate increased with paternal age in all families, but the number of additional mutations per year differed more than two-fold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency of germline mutation spectra between the sexes and at different paternal ages. 3.8% of mutations were mosaic in the parental germline, resulting in 1.3% of mutations being shared between siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells, but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.

Causes and evolutionary consequences of primordial germ-cell specification mode in metazoans

“…The male-to-female ratio of de novo mutations in offspring occurred at a 3.5:1 ratio, approximately corresponding to values reported previously for humans and consistent with the higher number of male (than female) germ-line cell divisions per generation (105,106). However, the de novo mutations specifically arising within the cells before PGC specification had a 1:1 ratio of maternal and paternal origin, as would be expected for mutations that arose before PGC formation and male/female differentiation (105). Together, these data empirically support the notion that the pre-PGC stage (before separation of the germ line and soma) can make a significant contribution toward the mutation rate per generation (105,107).…”

“…However, the de novo mutations specifically arising within the cells before PGC specification had a 1:1 ratio of maternal and paternal origin, as would be expected for mutations that arose before PGC formation and male/female differentiation (105). Together, these data empirically support the notion that the pre-PGC stage (before separation of the germ line and soma) can make a significant contribution toward the mutation rate per generation (105,107). Although the pre-PGC-specification mutations occur in a small fraction of embryonic cells, and arise in males and females, their early origin suggests that they may occur in a majority of germ-line cells and in the next generations, depending on cell-cell selection.…”

“…Thus, not only the post-PGC stage, but also the pre-PGC stage appears to be a significant factor contributing toward the genomic mutation rate. Notably, the postpuberty mutation rate per cell division (0.09-0.17) in males was markedly lower than prepuberty (lower than pre-and post-PGC), trends believed to result from selection to reduce the mutation rate to compensate for the high number of cell divisions involved in sperm formation (105). The male-to-female ratio of de novo mutations in offspring occurred at a 3.5:1 ratio, approximately corresponding to values reported previously for humans and consistent with the higher number of male (than female) germ-line cell divisions per generation (105,106).…”

“…Notably, the postpuberty mutation rate per cell division (0.09-0.17) in males was markedly lower than prepuberty (lower than pre-and post-PGC), trends believed to result from selection to reduce the mutation rate to compensate for the high number of cell divisions involved in sperm formation (105). The male-to-female ratio of de novo mutations in offspring occurred at a 3.5:1 ratio, approximately corresponding to values reported previously for humans and consistent with the higher number of male (than female) germ-line cell divisions per generation (105,106). However, the de novo mutations specifically arising within the cells before PGC specification had a 1:1 ratio of maternal and paternal origin, as would be expected for mutations that arose before PGC formation and male/female differentiation (105).…”

“…To better understand whether PGC-specification mode influences cell-cell selection on mutations in the germ-line lineage in metazoans, future studies should also assess the evolution of genes specifically expressed in pre-PGC (and post-PGC) cells to measure the effects of selection (such as dN/dS; ref. 21) and include laboratory techniques involving measures of fitness effects of specific mutations in those cells and of cell-cell competition (44,105).…”