Timing, rates, and spectra of human germline mutations

Germline mutations are a driving force behind genome evolution and genetic disease. Authors [attached] investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold among families. Metadata analysis of 6,570 mutations showed that germline methylation influences mutation rates.

In contrast to somatic mutations, authors found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. These data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells, but mutation rate is decreased substantially during post-pubertal spermatogenesis. These findings most likely will have important consequences for the recurrence risks of human disorders caused by de novo mutations.

 Nat Genet  Feb 2o16; 48: 126-133

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