Higher-order Co-Mutation Interactions in Mitochondrial Genomes

Pair-wise co-mutation networks of the mitochondrial genome have already provided ample evidences about the roles of genetic interactions in the manifestation of phenotype under altered environmental conditions. Here, we present a method to construct and analyze higher-order interactions, namely, three-uniform hypergraphs of the mitochondrial genome for different altitude populations to decipher the role of co-mutating variable sites beyond pair-wise interactions. We considered the human mitochondrial DNA residing at different altitudes with respect to Tibet in Asia as a case study. We found that in 50% of the gene triangles, two positions were occupied by coding genes, which suggested that coding genes are dominantly involved in forming the hyperedges. Based on weights of the gene triangles, we identified altitude-specific genes such as, in low-altitude ATP6 and ND genes, in mid-altitude CO1 and ND genes, and in high-altitude ATP6, CO1, CYB and ND genes. This framework of three-uniform hypergraph serves an avenue for future investigation of nuclear genomes in context of phenotypic association and genetic disorders beyond the pair-wise interactions.