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Appropriate Assignment of Fossil Calibration Information Minimizes the Difference Between Phylogenetic and Pedigree Mutation Rates in Humans


Appropriate Assignment of Fossil Calibration Information Minimizes the Difference Between Phylogenetic and Pedigree Mutation Rates in Humans

Renata T Capellão et al. Life (Basel).


Studies that measured mutation rates in human populations using pedigrees have reported values that differ significantly from rates estimated from the phylogenetic comparison of humans and chimpanzees. Consequently, exchanges between mutation rate values across different timescales lead to conflicting divergence time estimates. It has been argued that this variation of mutation rate estimates across hominoid evolution is in part caused by incorrect assignment of calibration information to the mean coalescent time among loci, instead of the true genetic isolation (speciation) time between humans and chimpanzees. In this study, we investigated the feasibility of estimating the human pedigree mutation rate using phylogenetic data from the genomes of great apes. We found that, when calibration information was correctly assigned to the human⁻chimpanzee speciation time (and not to the coalescent time), estimates of phylogenetic mutation rates were statistically equivalent to the estimates previously reported using studies of human pedigrees. We conclude that, within the range of biologically realistic ancestral generation times, part of the difference between whole-genome phylogenetic and pedigree mutation rates is due to inappropriate assignment of fossil calibration information to the mean coalescent time instead of the speciation time. Although our results focus on the human⁻chimpanzee divergence, our findings are general, and relevant to the inference of the timescale of the tree of life.

Keywords: coalescent; generation time; primate evolution; speciation; species tree.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Difference between the genetic divergence (T), which is calculated by the mean coalescent time between human–chimpanzee gene pairs (dT/2), and the speciation time (τ), which is the time of the genetic isolation between species (d1/2). dT is the total genetic distance between humans and chimpanzees; d1 is the total genetic distance accumulated after the speciation time τ; and d2 is the amount of sequence divergence existent in the ancestral population, before the complete genetic isolation between species. To correctly calibrate the hominoid timescale, the age of the oldest fossil belonging to the Homo or Pan lineages should be assigned to τ, which is equivalent to the time that d1/2 requires to accumulate. Assigning the calibration to T will overestimate the phylogenetic mutation rate, because dT > d1. The values of dT, d1, and d2 are measured in substitutions/site.
Figure 2
Figure 2
Plot of the estimated pedigree rates (µg) assigning the calibration information to 0.00473 s/s, i.e., the inferred average number of substitutions per site accumulated since the speciation of Homo and Pan. To calculate the pedigree rates, a wide range of ancestral Homo–Pan generation times (g) and ages of the human–chimpanzee speciation (Tfossil) were used. The blue area establishes the minimum and maximum limits of µg obtained from empirical the studies of Campbell et al. [30] (lower estimate) and Lipson et al. [34] (upper estimate), respectively. We also show the line for the average rate calculated from the estimates published so far (~1.0 × 10−8 s/s/g). The boxplot shows the distribution of estimates of Tfossil from various studies available in the database.

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