Pathogenic Amino Acid Variants In Mitochondrial Proteins More Frequently Arise In Lineages Closely Related To Human Than In Distant Lineages

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. We show that substitutions giving rise to the human amino acid variant 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. Therefore, a pathogenic variant still tends to be more acceptable in human mitochondria than a variant that may only be fit after a substantial perturbation of the protein structure.\n\nSignificanceHomologous proteins can carry different amino acids at the same position in different species. These changes can be neutral, or can reflect differences in the pressure of selection on these sites. We hypothesized that amino acids observable in human population appear on average more frequently in close than in distant human relatives. For mitochondrial proteins, we observe this for both frequent and rare human alleles. Unexpectedly, substitutions that would be pathogenic in humans also more frequently appear in species more closely related to humans than in distantly related ones. Therefore, despite their pathogenicity, these variants are on average more acceptable in humans than other amino acids that were observed at this site in distantly related species.