Distorted Mendelian transmission as a function of genetic background in Rai1-haploinsufficient mice

The retinoic acid induced 1 gene (RAI1) is the primary causative gene for Smith-Magenis syndrome (SMS). Chromosomal deletion encompassing RAI1 or mutation in RAI1 is responsible for the majority of SMS features. Mouse models with targeted disruption of Rai1 have recapitulated overt SMS phenotypes, including craniofacial abnormalities, obesity, and neurobehavioral anomalies. Penetrance and expressivity of most phenotypes in mice were incomplete due to the mixed genetic background in which they were created. While increased penetrance of craniofacial phenotypes was observed in relatively homogeneous backgrounds, the effect of Rai1 haploinsufficiency on breeding outcome and fitness has not been studied. We analyzed mating results of Rai1^+/- mice in a pure C57BL/6J background (≥N10 generations). A significant distortion (P < 0.05) of Mendelian transmission ratio with skewing against Rai1^+/- mice was observed. Consequently, a decreased number of Rai1^+/- pups and no Rai1^-/- pups were obtained from all the breeding pairs. The decreased yield of Rai1^+/- pups precluded penetrance studies of other phenotypes in these mice. However, when Rai1^+/- alleles were transferred to a slightly variable (∼1% 129/∼99% C57BL/6J) genetic background expected numbers of Rai1^+/- pups were obtained. Our results indicate that selection against Rai1-haploinsufficient alleles is governed primarily by modifier genes. Our data show that genetic background or modifier genes also significantly contribute to the severity of the phenotypes in SMS mouse models, mirroring the phenotypic variation observed in humans with Smith-Magenis syndrome and support the need for investigation of modifier loci for both single gene and complex genetic syndromes.