Recalibrating the human mutation rate: insights from trios, tissues, and new technologies

Studies of human origins depend on an estimate of the human mutation rate to translate patterns of genetic differentiation into dates. Collection of mutation data from tens of thousands of families has now pinpointed this rate to within a narrow range: we review evidence that a rate of 4.1×10^-10 muts/site/year accurately calibrates demographic inference within the last 500 000 years, with departure from this rate expected only for deeper events involving hominins with substantially shorter generation times than modern humans. Though this rate is not much different from previous per-year mutation rates estimated from smaller datasets in past decades, modern germline and somatic datasets have uncovered new biological knowledge regarding how mutations are distributed across tissues, life histories, and rates of cell division. These discoveries have led to the recognition that CpG transitions track cell divisions while most other germline mutations arise from DNA damage and translesion synthesis, reversing the longstanding view that CpG transitions reflect spontaneous cytosine deamination while non-CpG mutations arise from replication errors. The human germline mutational portrait is further complicated by rare heritable mutator alleles, population-specific mutational processes, and tradeoffs between single-nucleotide and indel mutagenesis. Such phenomena complicate simple molecular clock analyses, but enrich our power to use large datasets for complex evolutionary inference.