Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees byuse of single-sperm typing

In hereditary retinoblastoma, different epidemiological studies have indica ted a preferential paternal transmission of mutant retinoblastoma alleles t o offspring, suggesting the occurrence of a meiotic drive. To investigate t his mechanism, we analyzed sperm samples from six individuals from five unr elated families affected with hereditary retinoblastoma. Single-sperm typin g techniques were performed for each sample by study of two informative sho rt tandem repeats located either in or close to the retinoblastoma gene (RB 1). The segregation probability: of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental param eters, recombination fractions between the markers, and segregation paramet ers. A total of 2,952 single sperm from the six donors were analyzed. We de tected a significant segregation distortion in the data as a whole (P = .00 99) and a significant heterogeneity in the segregation rate across donors ( .0092). Further analysis shows that this result can be explained by segrega tion distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the o ther donors. The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may res ult either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome.