Transgenerational Genetic Effects

Abstract

Since Mendel, studies of phenotypic variation and disease risk have emphasized associations between genotype and phenotype among affected individuals in families and populations. Although this paradigm has led to important insights into the molecular basis for many traits and diseases, most of the genetic variants that control the inheritance of these conditions continue to elude detection. Recent studies suggest an alternative mode of inheritance where genetic variants that are present in one generation affect phenotypes in subsequent generations, thereby decoupling the conventional relations between genotype and phenotype, and perhaps, contributing to ‘missing heritability’. Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans.

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

“…Many environmental factors and genetic variants are known to induce heritable epigenetic changes that can persist for multiple generations, affecting a broad range of traits, and that often are as frequent and strong as direct environmental exposures and conventional genetic inheritance (18,(51)(52)(53)(54)(55)(56)(57). These transgenerational effects challenge our understanding of the modes and mechanisms for inherited phenotypic variation and disease risk, as well as the premise of most genetic studies in which causal DNA sequence variants are sought within the genome of affected individuals.…”

“…Several molecular mechanisms have been implicated, ranging from inherited RNAs to chemically modified DNA and proteins (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These transgenerational effects have important implications for our understanding of adaptation and evolution, the origins of phenotypic variation and disease risk, and the molecules in addition to DNA that can be the basis for inheritance (18,62,63).…”

“…cells (18,31); whether heritable epigenetic changes in the germline involve methylation, histone modifications, RNAs, or perhaps other molecules (18,(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61); whether the relevant Apobec1 functions involve RNA editing or DNA demethylation (37-41, 60, 61); and whether the same epigenetic changes are transmitted to subsequent generations or are responsible for reversing heritable epigenetic changes.…”

“…Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10)(11)(12)(13)(14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15)(16)(17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TGCT risk (18).…”

“…Studies of interactions between these modifier genes in mice reveal remarkable evidence for transgenerational genetic effects on TGCT risk (29). In these cases, genetic variants in ancestral generations induce heritable epigenetic changes that lead to phenotypic variation in subsequent generations (18). These epigenetic changes can affect a remarkable variety of traits including behaviors, blood chemistry, pigmentation, heart development, embryonic viability, feeding habits, and susceptibility to diet-induced obesity (30)(31)(32)(33)(34)(35).…”