Human germline mutation and the erratic molecular clock

Our understanding of the chronology of human evolution relies on the " molecular clock " provided by the steady accumulation of substitutions on an evolutionary lineage. This understanding has been called into question by recent analyses of human pedigrees, suggesting that mutations accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. In this Unsolved Mystery, we dissect the steps involved, emphasizing that dating evolutionary events requires not " a mutation rate, " but a precise characterization of how germline mutations accumulate in development, in males and females—knowledge that remains elusive.