Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage divisions of the mammalian embryo are non-disjunction-prone.

Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian non-disjunction. In part, this reflects the fact that, unlike lower organisms, segregation 'impaired' chromosomes are virtually non-existent in mammals. To address this issue, we have studied the mouse Y chromosome on the BALB/cWt ('Wt') inbred background, a system in which loss of the Y chromosome in gonadal tissue has been linked to hermaphroditism. Our results indicate that the Wt Y chromosome is stably transmitted during meiotic cell divisions, but non-disjoins at an extremely high frequency in mitosis. Surprisingly, the non-disjunction events are largely restricted to the earliest cleavage divisions, indicating that there is a temporal 'window' during which the Wt Y chromosome is susceptible to non-disjunction. The non-disjunction phenotype has both cis and trans components: the Wt Y chromosome malsegregates on a variety of genetic backgrounds, demonstrating an intrinsic defect; however, the incidence of non-disjunction is significantly influenced by strain background, indicating the existence of modifying loci and thus providing evidence for a genetic effect on mammalian non-disjunction. These studies suggest that the earliest cell divisions in mammals are non-disjunction-prone, an interpretation which provides an explanation for the high rate of chromosome mosaicism observed in studies of in vitro fertilization (IVF)-derived human preimplantation embryos. Further, our observations raise the possibility that the IVF setting adversely affects chromosome segregation and suggest that genetic quality be an important consideration in any attempt to improve or modify in vitro procedures for use on human eggs and embryos.