FAILURE OF IMPRINTING AT IGF-2 - 2 MODELS OF MUTATION-SELECTION BALANCE

The failure of maternal imprinting at the insulin-like growth factor I I (Igf-2) locus predisposes individuals to several clinical conditions , including Wilms tumor. Having two functional Igf-2 genes, therefore, is selectively disadvantageous, and the condition is probably maintai ned in human populations by recurrent mutation. We propose two models that predict the expected frequency of functionally diploid individual s in a large population, in terms of a mutation rate, mu, and the sele ction coefficient against functionally diploid individuals, s. In the first model a mutant Igf-2 allele that cannot be imprinted arises from the standard, imprintable allele at a rate it. Our second model hypot hesizes a second modifier locus at which a recessive allele arises at rate mu. Mothers who are homozygous for this recessive modifier allele fail to imprint their eggs. Both models predict the expected frequenc y of affecteds to be 2 mu/s(1 + mu), approximately twice that predicte d by the standard one-locus model of a recessive allele in mutation-se lection balance. This frequency suggests that less than or equal to 25 % of the cases of Wilms tumor are due to the failure to imprint the ma ternal Igf-2 gene.