Genetics has been invaluable in advancing the understanding of complex trait and disease inheritance, providing insight to the genes and pathways underlying heritable phenotypes. However, the variants contributing to many highly heritable human diseases have remained largely undetectable or ‘missing’ in biomedical research. Many possibilities exist for why the causative variants may remain undetected including the additive effects of many genes with small effects, overestimates of heritability, epistatic interactions between variants and epigenetic inheritance.
The goal of my project was to characterize transgenerational genetic effects, resulting from genetic variants in previous generations that are not inherited in the at-risk individuals, and their role in the inheritance of complex phenotypes. This project involved two components. First, I examined the frequency and magnitude of transgenerational effects using Y-chromosome substitution strains (CSSs) to generate genetically identical females with genetically distinct parents and found that transgenerational genetic effects occur at similar rates and with similarly large effects compared to conventional risk loci in CSSs. I concluded that transgenerational effects contribute to phenotypic inheritance at an appreciable frequency and magnitude. Second, I identified Apobec1 as a novel genetic modifier of testicular cancer risk and characterized the lineage-specific and transgenerational effects of Apobec1, an RNA-editing enzyme, on the prevalence of testicular germ cell tumors (TGCTs) and efficiency of stem cell derivation. Finally, I identified transgenerational genetic epistasis between Apobec1 deficiency and Dnd1Ter, an established TGCT risk enhancer, affecting TGCT prevalence and allele segregation in offspring. I concluded that RNA biology, and possibly RNA-editing, play a role in TGCT pathogenesis and possibly in mediating transgenerational inheritance.