Mitonuclear linkage disequilibrium in human populations

Abstract

There is extensive evidence from model systems that disrupting associationsbetween co-adapted mitochondrial and nuclear genotypes can lead to deleteriousand even lethal consequences. While it is tempting to extrapolatefrom these observations and make inferences about the human-health effectsof altering mitonuclear associations, the importance of such associationsmay vary greatly among species, depending on population genetics, demographichistory and other factors. Remarkably, despite the extensive study ofhuman population genetics, the statistical associations between nuclear andmitochondrial alleles remain largely uninvestigated. We analysed publishedpopulation genomic data to test for signatures of historical selection to maintainmitonuclear associations, particularly those involving nuclear genes thatencode mitochondrial-localized proteins (N-mt genes). We found that significantmitonuclear linkage disequilibrium (LD) exists throughout the humangenome, but these associations were generally weak, which is consistentwith the paucity of population genetic structure in humans. Although mitonuclearLD varied among genomic regions (with especially high levels onthe X chromosome), N-mt genes were statistically indistinguishable frombackground levels, suggesting that selection on mitonuclear epistasis has notpreferentially maintained associations involving this set of loci at a specieswidelevel. We discuss these findings in the context of the ongoing debateover mitochondrial replacement therapy.