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

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.

Automated summary

Investigating human mitochondrial genome variations can provide insights into human history and natural selection. Analysis of 24,167 human mt-genome samples from five continents revealed different co-mutation patterns among populations, with a stronger COX gene co-mutation bias in Asian and American populations. The study also showed a hierarchical modularity in the co-mutation networks and mutations clustered preferentially in known mitochondrial haplogroups.