Overview of the surrogate genetics platform for functional assessment of genetic variants. (A) Humanized yeast as a surrogate genetic system to evaluate functional effects of human genetic variation. (1) Disruption of a yeast gene gives rise to a yeast phenotype (e.g., decreased fitness). (2) The yeast phenotype is rescued by wild-type human alleles. (3) Functional effects of human variants are evaluated based on their ability to rescue the phenotype relative to the wild-type allele. A human variant may be deemed pathogenic if it cannot rescue the phenotype as well as wild type, or in special cases, where it exhibits better-than-wild-type rescue of the phenotype. (B) Overview of functional assessment of variants in disease-associated genes.
