The rate of DNA evolution: effects of body size and temperature on the molecular clock

Abstract

Observations that rates of molecular evolution vary widely within and among lineages have cast doubts on 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 accuracy of molecular clocks. Here, we present a model of nucleotide substitution that combines theory on metabolic rate with the now-classic neutral theory of molecular evolution. The model quantitatively predicts rate heterogeneity and may reconcile 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, this model explains heterogeneity in rates of nucleotide substitution in different genes, taxa, and thermal environments. This model also suggests that there is indeed a single molecular clock, as originally proposed by Zuckerkandl and Pauling [Zuckerkandl, E. & Pauling, L. (1965) in Evolving Genes and Proteins, eds. Bryson, V. & Vogel, H. J. (Academic, New York), pp. 97-166], but that it "ticks" at a constant substitution rate per unit of mass-specific metabolic energy rather than per unit of time. This model therefore links energy flux and genetic change. More generally, the model suggests that body size and temperature combine to control the overall rate of evolution through their effects on metabolism.

Fig. 1.

Effect of temperature on nucleotide substitution rates after correcting for body mass by using Eq. 3. Plots show four commonly used molecular clocks: the mitochondrial genome (mtDNA) (A), rRNA (12s and 16s combined) (B), all substitutions in the cytochrome b gene (C), and transversions in the cytochrome b gene (D). The solid lines were fitted by using type II linear regression; the dashed lines show the predicted slope of -0.65 eV. Data and sources are listed in Appendix 2.

Fig. 2.

Effect of body mass on nucleotide substitution rates after correcting for temperature by using Eq. 4. Plots show the same data from the same four molecular clocks as in Fig. 1. The solid lines were fitted by using type II linear regression; the dashed lines show the predicted slope of -1/4. Data and sources are listed in Appendix 2.

Fig. 3.

Effect of body mass on silent rates of nucleotide substitution (% substitutions per site per My) in coding regions of the globin gene in primates (A) (6) and multiple coding regions of the nuclear genome for 23 pairs of mammalian lineages (B) (ref. and Appendix 3).

Fig. 4.

Correcting for body size gives estimates of divergence dates that agree more closely with the fossil record (see Appendix 3). Open circles represent molecular clock estimates of divergence before accounting for effects of body size (18), and closed circles represent molecular clock estimates of divergence after accounting for effects of body size. Mass-corrected divergence dates were estimated by using the regression model in Fig. 3B. Arrows connect pairs of mass-corrected and uncorrected estimates, except for Homo-Pan, where these estimates are effectively indistinguishable. Correcting for mass has a much greater effect on clock-estimated divergences of small mammals, such as the rodent pair Mus-Rattus, because the uncorrected molecular clock in ref. was calibrated mostly with large mammals. The horizontal, dashed line represents equality between molecular and fossil estimates.