Metabolic Rate Calibrates the Molecular Clock: Reconciling Molecular and Fossil Estimates of Evolutionary Divergence

Observations that rates of molecular evolution vary widely within and among lineages have cast doubts upon the existence of a single molecular clock. Differences in the timing of evolutionary events estimated from genetic and fossil evidence have raised further questions about the existence of molecular clocks and their use. Here we present a model of nucleotide substitution that combines new theory on metabolic rate with the now classic neutral theory of molecular evolution. The model quantitatively predicts rate heterogeneity, and reconciles differences in molecular- and fossil-estimated dates of evolutionary events. Model predictions are supported by extensive data from mitochondrial and nuclear genomes. By accounting for the effects of body size and temperature on metabolic rate, a single molecular clock explains heterogeneity in rates of nucleotide substitution in different genes, taxa, and thermal environments. This model suggests that there is indeed a general molecular clock, as originally proposed by Zuckerkandl and Pauling, but that it ticks at a constant substitution rate per unit mass-specific metabolic energy rather than per unit time. More generally, the model suggests that body size and temperature combine to control the overall rate of evolution through their effects on metabolism.