Comparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversity

Am J Hum Genet. 2011 Apr 8;88(4):433-9. doi: 10.1016/j.ajhg.2011.03.006. Epub 2011 Mar 31.


We used detailed phylogenetic trees for human mtDNA, combined with pathogenicity predictions for each amino acid change, to evaluate selection on mtDNA-encoded protein variants. Protein variants with high pathogenicity scores were significantly rarer in the older branches of the tree. Variants that have formed and survived multiple times in the human phylogenetics tree had significantly lower pathogenicity scores than those that only appear once in the tree. We compared the distribution of pathogenicity scores observed on the human phylogenetic tree to the distribution of all possible protein variations to define a measure of the effect of selection on these protein variations. The measured effect of selection increased exponentially with increasing pathogenicity score. We found no measurable difference in this measure of purifying selection in mtDNA across the global population, represented by the macrohaplogroups L, M, and N. We provide a list of all possible single amino acid variations for the human mtDNA-encoded proteins with their predicted pathogenicity scores and our measured selection effect as a tool for assessing novel protein variations that are often reported in patients with mitochondrial disease of unknown origin or for assessing somatic mutations acquired through aging or detected in tumors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • DNA, Mitochondrial / genetics*
  • Evolution, Molecular
  • Female
  • Genes, Mitochondrial
  • Genetic Variation*
  • Humans
  • Male
  • Mitochondrial Proteins / genetics
  • Mutation
  • Phylogeny*
  • Selection, Genetic*


  • DNA, Mitochondrial
  • Mitochondrial Proteins