The third section of an anticipated four paper series distinguishes two different forms of genetic interactions. The first paper of our discussion on genetic interactions described interactions arising from correlation between genotypic and/or environmental states. In this, the second paper, we describe interactions arising from non-additivity between uncorrelated factors (epistasis). We also discuss in detail the concept of "missing heritability.” While this phrase is sometimes used to mean what might more precisely be called "still unidentified heritable factors," this phrase also describes the observation that heritability when studied in close relatives almost always produces estimates significantly larger than when studied in distant relatives. While still unidentified heritable factors can be discovered via whole genome sequencing in ever increasing sample sizes, differing estimates of heritability from close versus distant relatives implies the existence of some form of interaction. Several types of interaction could explain this phenomenon. We conclude by focusing on a particular form of interaction that has been widely ignored, interactions caused by non-additivity arising from the cis-regulation of gene expression. By exploring varying patterns of two-locus haplotypic effects, we show that the existence of two or more variants each influencing the expression of the same gene can give rise to substantial non-additive interactions, and that those interactions can be particularly large when the variants are rare. Additive-by-additive genetic interactions induced by gene regulation have the potential to fully explain the observation of missing heritability.

quantitative genetics, human disease, genetic interactions, missing heritability, gene regulation