Improved calibration of the human mitochondrial clock using ancient genomes

Abstract

Reliable estimates of the rate at which DNA accumulates mutations (the substitution rate) are crucial for our understanding of the evolution and past demography of virtually any species. In humans, there are considerable uncertainties around these rates, with substantial variation among recent published estimates. Substitution rates have traditionally been estimated by associating dated events to the root (e.g., the divergence between humans and chimpanzees) or to internal nodes in a phylogenetic tree (e.g., first entry into the Americas). The recent availability of ancient mitochondrial DNA sequences allows for a more direct calibration by assigning the age of the sequenced samples to the tips within the human phylogenetic tree. But studies also vary greatly in the methodology employed and in the sequence panels analyzed, making it difficult to tease apart the causes for the differences between previous estimates. To clarify this issue, we compiled a comprehensive data set of 350 ancient and modern human complete mitochondrial DNA genomes, among which 146 were generated for the purpose of this study and estimated substitution rates using calibrations based both on dated nodes and tips. Our results demonstrate that, for the same data set, estimates based on individual dated tips are far more consistent with each other than those based on nodes and should thus be considered as more reliable.