Explaining the Imperfection of the Molecular Clock of Hominid Mitochondria

Abstract

The molecular clock of mitochondrial DNA has been extensively used to date various genetic events. However, its substitution rate among humans appears to be higher than rates inferred from human-chimpanzee comparisons, limiting the potential of interspecies clock calibrations for intraspecific dating. It is not well understood how and why the substitution rate accelerates. We have analyzed a phylogenetic tree of 3057 publicly available human mitochondrial DNA coding region sequences for changes in the ratios of mutations belonging to different functional classes. The proportion of non-synonymous and RNA genes substitutions has reduced over hundreds of thousands of years. The highest mutation ratios corresponding to fast acceleration in the apparent substitution rate of the coding sequence have occurred after the end of the Last Ice Age. We recalibrate the molecular clock of human mtDNA as 7990 years per synonymous mutation over the mitochondrial genome. However, the distribution of substitutions at synonymous sites in human data significantly departs from a model assuming a single rate parameter and implies at least 3 different subclasses of sites. Neutral model with 3 synonymous substitution rates can explain most, if not all, of the apparent molecular clock difference between the intra- and interspecies levels. Our findings imply the sluggishness of purifying selection in removing the slightly deleterious mutations from the human as well as the Neandertal and chimpanzee populations. However, for humans, the weakness of purifying selection has been further exacerbated by the population expansions associated with the out-of Africa migration and the end of the Last Ice Age.

West Eurasian mtDNA lineages in India: an insight into the spread of the Dravidian language and the origins of the caste system

“…The shared ancestry of the Dravidian of South India and Iranian of Near East populations has been shown in the HV14 and U1a1 phylogeny (Fig. 1a) and their time estimates are consistent with the proto-Elamo-Dravidian language diffusion Mishmar et al (2003) b Mutation rate of Perego et al (2009) c Mutation rate of Kivisild et al (2006) d Mutation rate of Soares et al (2009) e Mutation rate of Loogväli et al (2009) 11,900 ± 5100 10,800 ± 4600 10,200 ± 6200 9000 ± 5500 10,500 ± 6400 10,650 ± 6500…”

Genetic differentiation of the house mouse around the Mediterranean basin: matrilineal footprints of early and late colonization

“…This date is probably much too old as discussed by Rajabi-Maham et al [8] who, with a somewhat higher modal value of 10 pairwise differences and a global sample one-third smaller than the present one, ascribed this expansion to the Holocene warming some 12 000 years ago on the basis of reasonable palaeobiological and archaeological arguments, and the observation that intraspecific and pedigree-based estimates of substitution rates are generally higher than interspecific phylogenetically calibrated rates [29]. Although this statement is still a matter of controversy, recent re-evaluations in the hominoid and human mitochondrial genome [30,31], all show that this nonlinearity of substitution rates is indeed the case (but see also [32]). Mutational hotspots represent one possible cause of this nonlinearity, since they may create an excess of undetected homoplasy in longer branches and an excess of detectable mutations in short branches.…”

Endogenous viruses: Connecting recent and ancient viral evolution

“…3; see Ho et al (2011) for review). One explanation is that short-term rate estimates tend to include transient deleterious variations that have not yet been purged by purifying selection, and thus appear to be very high (Ho et al, 2011;Jenkins et al, 2002;Loogväli et al, 2009). Viral adaptive changes resulting from positive selection or viral-host evolutionary arm races are also lineage-specific, and hence will tend to manifest themselves as recent changes, inevitably elevating the short-term rate of evolution.…”