Investigating mitonuclear interactions in human admixed populations

To function properly, mitochondria utilize products of 37 mitochondrial and >1,000 nuclear genes, which should be compatible with each other. Discordance between mitochondrial and nuclear genetic ancestry could contribute to phenotypic variation in admixed populations. Here, we explored potential mitonuclear incompatibility in six admixed human populations from the Americas: African Americans, African Caribbeans, Colombians, Mexicans, Peruvians and Puerto Ricans. By comparing nuclear versus mitochondrial ancestry in these populations, we first show that mitochondrial DNA (mtDNA) copy number decreases with increasing discordance between nuclear and mtDNA ancestry. The direction of this effect is consistent across mtDNA haplogroups of different geographic origins. This observation indicates suboptimal regulation of mtDNA replication when its components are encoded by nuclear and mtDNA genes with different ancestry. Second, while most populations analysed exhibit no such trend, in African Americans and Puerto Ricans, we find a significant enrichment of ancestry at nuclear-encoded mitochondrial genes towards the source populations contributing the most prevalent mtDNA haplogroups (African and Native American, respectively). This possibly reflects compensatory effects of selection in recovering mitonuclear interactions optimized in the source populations. Our results provide evidence of mitonuclear interactions in human admixed populations and we discuss their implications for human health and disease.