PgmNr M273: Verne Chapman Lecture: Mendel 2.0, revisiting the determinants of inheritance and the origins of phenotypic variation.

Authors:
J. H. Nadeau


Institutes
Pacific Northwest Research Institute, Seattle, WA.


Abstract:

Mendel’s discoveries were a breakthrough in understanding the inherited relations between genotype and phenotype for simple traits. Extending these principles to more complex traits has led to a model of genetic and phenotypic architecture that involves large numbers of genes, each with small additive effects. But considerable evidence suggests that circumstances are more complex. Mendelian traits often depend on strong interactions with genetic background. More recent work with complex traits in genetic reference populations shows that epistasis is pervasive. The strong dependence of both simple and complex traits on genetic background also argues that gene action is conditional rather than constant, although the basis for conditional functions is largely unknown. Strong epistasis implies that a revised picture of genetic architectures is needed.  

Phenotypic variation can also result from environmental exposures and genetic variants in ancestral generations. These inherited epigenetic effects, which are independent of DNA sequence variants, can be as common and strong as conventional genetic effects and they can persist for tens of generations. Their significant contribution to phenotypic variation calls for a rethinking of our concept of inheritance and the formulation of heritability.

Finally, a fundamental tenet of Mendelian inheritance is that, with few exceptions, fertilization results from a random union of gametes. However, reanalysis of many reports with mutant genes shows that both specific genetic variants and gene-diet interactions can lead to a strong bias in gamete preferences at fertilization. These cases are unusual because they depend on genetically-determined interactions between specific egg and sperm, unlike conventional forms of transmission distortion. Fertilization bias would have a profound impact not only on measures of inherited disease risk, but also on inherited gene variation.

Together these discoveries involving epistasis, transgenerational epigenetic effects, and fertilization bias argue that genomes are composed of specific combinations of interacting genetic variants that confer viability and fertility as well as resilience to mutational perturbations, that generations are more continuous than discrete with inherited memories of ancestral genetics and environments, and that fertilization bias helps drive genetic architecture and phenotypic variation across generations.