Studies of human trisomies indicate a remarkable relationship between abnormal meiotic recombination and subsequent nondisjunction at maternal meiosis I or II. Specifically, failure to recombine or recombination events located either too near to or too far from the centromere have been linked to the origin of human trisomies. It should be possible to identify these abnormal crossover configurations by using immunofluorescence methodology to directly examine the meiotic recombination process in the human female. Accordingly, we initiated studies of crossover-associated proteins (e.g., MLH1) in human fetal oocytes to analyze their number and distribution on nondisjunction-prone human chromosomes and, more generally, to characterize genome-wide levels of recombination in the human female. Our analyses indicate that the number of MLH1 foci is lower than predicted from genetic linkage analysis, but its localization pattern conforms to that expected for a crossover-associated protein. In studies of individual chromosomes, our observations provide evidence for the presence of “vulnerable” crossover configurations in the fetal oocyte, consistent with the idea that these are subsequently translated into nondisjunctional events in the adult oocyte.
One of the defining events in the formation of eggs and sperm is meiotic recombination, a process in which DNA is exchanged between “partner” chromosomes. If this process is perturbed, chromosomes often go astray during meiotic division, resulting in eggs or sperm with too many or too few chromosomes. In humans, the resulting embryos are almost always abnormal and are a major source of miscarriages or congenital birth defects (e.g., Down syndrome). Over the past decade, techniques have become available that make possible the examination of meiotic recombination “as it happens” in the human egg, and this has allowed us to define the properties of this process. In the present study, we used this methodology to characterize meiotic recombination in human fetal oocytes and to ask whether we could identify abnormal recombination patterns. Such patterns were, indeed, observed for each chromosome we studied, although different abnormalities were observed among the individual chromosomes. Thus, factors operating before birth influence the likelihood of chromosome misdivision in the adult oocyte, although those that make chromosome 21 misdivide (leading to Down syndrome) may not be the same as those that make other chromosomes misdivide.