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. 2009 Jun;84(6):740-59.
doi: 10.1016/j.ajhg.2009.05.001. Epub 2009 Jun 4.

Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock

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Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock

Pedro Soares et al. Am J Hum Genet. .
Free PMC article

Abstract

There is currently no calibration available for the whole human mtDNA genome, incorporating both coding and control regions. Furthermore, as several authors have pointed out recently, linear molecular clocks that incorporate selectable characters are in any case problematic. We here confirm a modest effect of purifying selection on the mtDNA coding region and propose an improved molecular clock for dating human mtDNA, based on a worldwide phylogeny of > 2000 complete mtDNA genomes and calibrating against recent evidence for the divergence time of humans and chimpanzees. We focus on a time-dependent mutation rate based on the entire mtDNA genome and supported by a neutral clock based on synonymous mutations alone. We show that the corrected rate is further corroborated by archaeological dating for the settlement of the Canary Islands and Remote Oceania and also, given certain phylogeographic assumptions, by the timing of the first modern human settlement of Europe and resettlement after the Last Glacial Maximum. The corrected rate yields an age of modern human expansion in the Americas at approximately 15 kya that-unlike the uncorrected clock-matches the archaeological evidence, but continues to indicate an out-of-Africa dispersal at around 55-70 kya, 5-20 ky before any clear archaeological record, suggesting the need for archaeological research efforts focusing on this time window. We also present improved rates for the mtDNA control region, and the first comprehensive estimates of positional mutation rates for human mtDNA, which are essential for defining mutation models in phylogenetic analyses.

Figures

Figure 1
Figure 1
Hot Spots in the mtDNA Genome, Showing All the Positions that Appear > 25 Times in the Tree
Figure 2
Figure 2
mtDNA Saturation Curves (A) Control-region mutations. (B) Synonymous mutations.
Figure 3
Figure 3
Relation between Overall ρ Values and the Synonymous ρ Proportion Individual data points for each node in the tree are displayed as filled gray circles, and grouped points are displayed as empty circles. The solid curve is a model fit to the empty circles.
Figure 4
Figure 4
Variation of the mtDNA Mutation Rate through Time The black curve represents the mtDNA mutation rate. The gray curve represents the interspecific mutation rate.
Figure 5
Figure 5
Comparison of the Age of Each Node with the Time-Dependent Complete mtDNA Genome Sequence Molecular Clock and the Synonymous Clock
Figure 6
Figure 6
A New Chronology for the Human mtDNA Tree The tree was obtained by combining six trees constructed separately, with branch lengths estimated with maximum likelihood and the time-dependent molecular clock. Number and presence of clades is dependent on availability of data and not on worldwide frequencies. Ages are expressed in kya.

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