Functional characterization of archaic-specific variants in mitonuclear genes: power of the yeast model

Hybridization between modern humans and archaic hominins like Neanderthals and Denisovans resulted in the introgression of archaic genomic regions. However, these regions are unevenly distributed across the modern human genome, with introgressed archaic sequences notably underrepresented in mitonuclear genes, i.e. nuclear-encoded genes essential for mitochondrial function. This pattern likely reflects natural selection against functionally divergent archaic alleles. To investigate this, we searched for non-synonymous, fixed, archaic-derived variants in mitonuclear genes that are present in Neanderthals or Denisovans but rare or absent in humans. These variants were introduced into Saccharomyces cerevisiae strains lacking the corresponding human orthologs to compare the functional effects of archaic and human variants on mitochondrial function. While most variants caused mild effects, one variant in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) led to a strong decrease in respiratory activity, reduced Cox2 protein levels, and accumulation of immature YARS2, indicating impaired mitochondrial function. These findings support the idea that mitonuclear incompatibilities contributed to the purging of deleterious archaic variants. Yeast proves to be a powerful, versatile and cost-effective model system for experimentally validating the functional consequences of ancient genetic variation, helping to link evolutionary history with molecular phenotypes.