Abstract
The origin and transmission of de novo chromosome mutations were reviewed on the basis of our chromosome studies in retinoblastoma patients and male infertility. In a series of 264 sporadic retinoblastoma families, gross chromosome rearrangements involving the RB1 locus were identified in 23 cases (8.7%), of which 16 were non-mosaic and 7 were mosaic mutations. The newly formed chromosome mutations, whether they were non-mosaic or mosaic, had a strong bias towards paternally derived chromosome, indicating that they shared a common mechanism where a pre-mutational event or instability is carried over to zygote by sperm and manifested as gross chromosome mutation at the early stages of development. The de novo chromosome mutations are preferentially transmitted through female carriers. This transmission bias is consistent with the finding of higher frequencies of translocation carriers in infertile men (7.69% versus 0.27% in general populations) in whom meiotic progression is severely suppressed, possibly through activation of meiotic checkpoints. Such a meiotic surveillance mechanism may minimize the spreading of newly-arisen chromosome mutations in populations. A quantitative model of meiotic surveillance mechanism is proposed and successfully applied to the published data on `humped' dose-response curves for radiation-induced spermatogonial reciprocal translocations in several mammalian species.
