@article {Klink119792, author = {Galya V. Klink and Georgii A. Bazykin}, title = {Pathogenic amino acid variants in mitochondrial proteins more frequently arise in lineages closely related to human than in distantly related lineages}, elocation-id = {119792}, year = {2017}, doi = {10.1101/119792}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Propensities for different amino acids within a protein site change in the course of evolution, so that an amino acid deleterious in a particular species may be acceptable at the same site in a different species. Here, we study the amino acid-changing variants in human mitochondrial genes, and analyze their occurrence in non-human species. By reconstructing the phylogeny of mitochondrial proteins from several thousand opisthokonts, we study the changes in the rate at which either the human or the non-human allele originated, and thus determine how the fitness conferred by different human alleles changes with evolutionary distance from the human. Substitutions giving rise to the amino acid that is fixed at this site in humans, and to the non-reference allele at human polymorphic sites, tend to occur in lineages closely related to human more frequently than in more distantly related lineages, indicating that a human variant is more likely to be deleterious in more distant species. Unexpectedly, amino acids corresponding to pathogenic alleles in humans also more frequently originate at more closely related lineages, indicating that they, too, become even more deleterious with increased phylogenetic distance from human. The pathogenic variants are more similar to the human reference variant in their physico-chemical properties than a random amino acid occurring at the site in other species. Therefore, a pathogenic variant still tends to be more acceptable in human mitochondria than a variant that may only be observed after a substantial perturbation of the protein structure that occurs over long evolutionary times.}, URL = {https://www.biorxiv.org/content/early/2017/03/23/119792}, eprint = {https://www.biorxiv.org/content/early/2017/03/23/119792.full.pdf}, journal = {bioRxiv} }