Genome-sequencing technologies bring extraordinary opportunities in identifying genetic variations. Interpretation of functional consequences of genetic variations in a give individual, however, remains to be a daunting challenge. This is in part due to our limited understanding of the effect of any single genetic variation on cellular and organismal function. More difficult is to interpret functional impact of multiple genetic changes simultaneously occurring in an individual. We recently discovered that, despite vast evolutionary separation, human and yeast proteins still widely retain the ability to mediate inter-species protein-protein interactions. Surprisingly, such human-yeast inter-species interactions are not limited to proteins conserved between the two species, but frequently correspond to functional links between proteins mediating new species-specific functions and conserved ancestral cellular machinery. Based on these findings, we have developed three experimental platforms to systematically measure effects of human genes on cellular functions and to rapidly classify genetic interactions between human gene alleles using yeast cells as the "mediator" host. Our data demonstrates the feasibility and value of using yeast a a model system to characterize evolutionarily conserved human gene function. Such inter-species genetic approaches may help identify both genetic and environmental factors that modulate complex phenotypes in human disease.