Failure of imprinting at Igf-2: two models of mutation-selection balance.
The failure of maternal imprinting at the insulin-like growth factor II (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 maintained in human populations by recurrent mutation. We propose two models that predict the expected frequency of functionally diploid individuals in a large population, in terms of a mutation rate, mu, and the selection 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 mu. Our second model hypothesizes 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 frequency of affecteds to be 2 mu/s(1 + mu), approximately twice that predicted by the standard one-locus model of a recessive allele in mutation-selection balance. This frequency suggests that < or = 25% of the cases of Wilms tumor are due to the failure to imprint the maternal Igf-2 gene.
Spencer
H G
HG
Department of Zoology, University of Otago, Dunedin, New Zealand.
Williams
M J
MJ
D004171:Diploidy; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D018392:Genomic Imprinting; D006720:Homozygote; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D012641:Selection, Genetic; D009396:Wilms Tumor / Q000235:genetics
D007335:Insulin-Like Growth Factor II