On the parental origin of de novo mutation in man

Abstract

Studies tracing parental origins of human mutations by means of cytogenetic polymorphisms and RFLPs show that most trisomics arise out of maternal errors of segregation at the first meiotic division in oocytes. Temporal disturbance of meiotic progression seems likely to underly aneuploidy production in the female mouse, and this could equally be true in women, most especially as they approach the menopause when irregular cyclicity sets in. For human monosomy X, a high proportion of cases show loss of the paternal sex chromosome, and from experimental data giving similar findings in the mouse, it seems likely that the error could arise at the pronuclear stage after sperm entry into the egg, rather than at meiosis in the male. For human point mutations and structural rearrangements, a bias exists towards paternal origins. Errors arising during spermatogonial proliferation in men could contribute point mutations, these accumulating over a lifetime to give paternal age effects. For structural rearrangements, the hypersensitive stage is likely to be the post-meiotic differentiating spermatid, a stage not subject to germinal selection, and one which in Drosophila has been shown to combine high breakability with enhanced repair. Lack of a comparable cell type to the condensing spermatid of the male might be a reason why balanced structural rearrangements are produced rather rarely in females, at least in the mouse.