Human Germline Mutation and the Erratic Evolutionary Clock
Fig 2
Schematic illustration of mutations occurring during embryonic development and gametogenesis.
For simplicity, we show only mutations that arose in the father and one offspring (child 1). Stars represent mutations that originate in different stages of embryogenesis and gametogenesis of the father and the offspring; solid stars are mutations that arise in the father, and hollow stars are those that occur in the offspring. Shown below each individual are the expected frequencies of the labeled mutations in his or her blood sample. Red, brown, and green stars are heritable and should be included in an estimate of germline mutation rates, whereas blue stars are somatic mutations present only in blood samples, which should be excluded. The detection of mutations that are mosaic in both soma and germline strongly suggests that, in the cell lineage tree of human development, soma and germline are not reciprocally monophyletic [46,64]. The standard pipelines require allelic balance in the child and no (or very low) read depths in the parents, leading to inclusion of some postzygotic mutations in the child and exclusion of a fraction of germline mutations in the parents. The two effects partially balance, so the overall mutation rate is unlikely to be greatly biased. However, there is a tendency to detect child-specific mutations and to miss ones shared among siblings. As a consequence, the mutation rates during early development are likely underestimated, with potentially important practical implications for predictions of recurrence risk of diseases caused by de novo mutations.