The Role of Selection in the Evolution of Human Mitochondrial Genomes

Abstract

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P , 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNA Thr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P ¼ 0.003) between populations with neutral (22/58) and populations with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

Reply to letter from Felice L. Bedford and Doron Yacobi

“…This has been detected previously in mtDNA phylogeny (younger mutations are enriched in the first type, so that they often define branch tips) and a lot of debate on the selective pressures acting upon is ongoing [11][12][13][14][15][16] (and was also detected in animal models as our group has shown in lab mouse 17 ). The issue is, however, extraneous to the topic and goals of our paper; we can nevertheless clarify, as requested, that the finding does not result from a 'special clinical population of subjects'.…”

How closely does genetic diversity in finite populations conform to predictions of neutral theory? Large deficits in regions of low recombination

“…Selection and variation in mutation rates have been suggested as the reason for the equivocal relationship between mtDNA diversity and population size Eyre-Walker, 2006). First, there are multiple lines of evidence that selective sweeps and/or background selection affect mtDNA (see Rand, 2001;Ballard and Rand, 2005;Bazin et al, 2006;Kivisild et al, 2006;Meiklejohn et al, 2007;Wares, 2009).…”

Revisiting the role of the Himalayas in peopling Nepal: insights from mitochondrial genomes

“…1,18 Mutations are recorded by comparing with the revised Cambridge reference sequence (rCRS). 19 All the individuals were allocated into specific haplogroup based on their control-region information; the assignments were further confirmed by typing additional diagnostic coding-region mutations according to the reconstructed phylogenetic trees of East Asian, 1,20-25 South Asian 5,7,12,[26][27][28][29][30][31][32][33] and Southeast Asian [34][35][36][37][38] (Supplementary Table S1, Supplementary Material online). For the mtDNA sample of interest, entire genome was amplified and sequenced as described elsewhere.…”

“…The phylogenetic tree was reconstructed on the basis of 58 mitochondrial genomes, among which 21 mtDNAs were sampled from Katmandu, Nepal and generated in this study, whereas the rest 37 related mtDNAs were collected from the literature. 5,26,27,[31][32][33] Mutations are recorded according to the rCRS. 19 Suffixes A, C, G, and T indicate transversions, ''d'' signifies a deletion and a plus (+) signs an insertion; recurrent mutations are underlined.…”