The alternative view is that most of the variance for certain complex diseases is due to relatively highly penetrant rare variants, the allele frequency of which is typically less than 1%, most of which are recently derived alleles in the human population. Under this model, expressivity may be modified by other loci or the environment16,17, but the notion is that the rare susceptibility genotype is largely responsible for disease. The rare allele model generally refers to dominant effects, due either to haploinsufficient or gain of function alleles, where risk is elevated 2-fold or more over background. Under these conditions, penetrance need not be anywhere near 100%. In fact, as shown in Figure 2b, the vast majority of unaffected individuals are expected to carry one or more risk alleles. The notion is that a disease such as schizophrenia is actually a collection of hundreds, or possibly even thousands, of similar conditions attributable to rare variants at individual loci18. If each of these variants explains most of the risk in just a handful of people, their effects will not explain enough of
