There are many reasons to believe that multiple rare variants, both within the same gene and across different genes, collectively influence the expression and prevalence of traits and diseases in the population at large. First, it has been argued that population phenomena, such as the recent expansion of the human population, are likely to have resulted in a large number of segregating, functionally-relevant, rare variants that mediate phenotypic variation.14, 15 Second, the discovery of rare independent somatic mutations within and across genes contributing to tumorigenesis may parallel the functional effects of inherited variants contributing to congenital disease.11, 16, 17 Third, the identification of multiple rare variants within the same gene contributing to largely monogenic disorders such as Cystic Fibrosis and BRCA1 and BRCA2-associated breast cancer18, 19 suggests that rare variants might also influence common complex traits and diseases. Fourth, the identification of multiple functional variants within the same gene and the association of these variants with both in vitro and clinical phenotypes indicates that multiple rare variants could influence general clinical phenotypic expression20. Fifth, importantly, sequencing studies focusing on specific genes have shown that collections of rare variants can indeed associate with particular phenotypes (Table 1).
