Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations

Mitochondrion. 2021 May:58:111-122. doi: 10.1016/j.mito.2021.02.004. Epub 2021 Feb 20.


Investigation of human mitochondrial (mt) genome variation has been shown to provide insights to the human history and natural selection. By analyzing 24,167 human mt-genome samples, collected for five continents, we have developed a co-mutation network model to investigate characteristic human evolutionary patterns. The analysis highlighted richer co-mutating regions of the mt-genome, suggesting the presence of epistasis. Specifically, a large portion of COX genes was found to co-mutate in Asian and American populations, whereas, in African, European, and Oceanic populations, there was greater co-mutation bias in hypervariable regions. Interestingly, this study demonstrated hierarchical modularity as a crucial agent for these co-mutation networks. More profoundly, our ancestry-based co-mutation module analyses showed that mutations cluster preferentially in known mitochondrial haplogroups. Contemporary human mt-genome nucleotides most closely resembled the ancestral state, and very few of them were found to be ancestral-variants. Overall, these results demonstrated that subpopulation-based biases may favor mitochondrial gene specific epistasis.

Keywords: Co-mutation network; Epistasis; Genome evolution; Hierarchical modularity; Human mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epistasis, Genetic*
  • Evolution, Molecular*
  • Genes, Mitochondrial*
  • Humans
  • Mutation
  • Population Groups / genetics*