Phenotypic variability can be attributed to other aspects of nature and nurture. Undoubtedly, the phenotypic expression of rare high-penetrance alleles is modulated by other genetic factors, including rare variants, as well as common (polygenic) variation (Purcell et al., 2009) or epigenetic regulation (Hirasawa and Feil, 2010). Indeed, evidence from CNV studies supports an oligogenic model where multiple rare variants contribute to genetic risk (Girirajan et al., 2010). Another model has been proposed that attributes phenotypic variability to a combination of locus heterogeneity and pleiotropic effects of the individual alleles (State and Levitt, 2011).
