Focus

Chromosome abnormalities are the most common genetic cause of mental retardation. Furthermore, over 50% of all human pregnancy loss is attributable to chromosome imbalance in the fetus, making chromosome ab normalities the leading cause of reproductive failure. One of the primary aims of this laboratory is the use of cytogenetic and molecular techniques to study the origin and etiology of human chromosome abnormalities, with the aim being to uncover basic mechanisms responsible for the errors.

For example, we have had a long-term interest in studying the origin of human trisomies, using material from spontaneous abortions. Our results indicate that, regardless of the chromosome involved or the age of the women, non-disjunction at maternal meiosis I is the most common source of trisomy. Recently, we have identified an important molecular correlate of these errors, as we have observed alterations in the frequency and location of cross-overs in meioses leading to trisomies 16 and 21. Present efforts are aimed at determining if this pattern extends to trisomies involving other chromosomes, and if recombination is depressed globally in trisomy-generating meioses.

In other studies, we have been combining immunofluorescence with fluorescence in situ hybridization to investigate recombination in the human male, utilizing material from human testicular biopsies. This approach is being used to characterize the distribution of crossing-over in the human male, and to investigate the role of recombination abnormalities in male infertility. This approach allows us to address questions which, until recently, have been intractable; e.g., the possibilities that chromosome abnormalities increase with paternal age, that variation in chromosome regions important in mediating chromosome pairing/recombination or chromosome segregation affect non-disjunction levels, and that there is significant inter-individual variation in non-disjunction frequencies.

Homologous recombination is an essential part of the meiotic process, as it is not only responsible for generating genetic diversity, but is also a key player in the proper segregation of chromosomes during the first meiotic division. Studies in yeast, flies and humans indicate that situations in which recombination is abolished or otherwise altered lead to increased spontaneous nondisjunction, therefore the identification of factors that control or alter frequencies of recombination may play a crucial role in our understanding of chromosome segregation and germ cell aneuploidy. Studies in lower organisms have demonstrated that various local and global contributors act in the placement of meiotic crossovers, including gene organization, chromatin configuration, and chromosome domains. Cis-acting factors involved in the control of mammalian meiotic recombination have not been elucidated to date. We are currently using several mouse models to help discern some of the cis-acting factors, such as position effects and sequence characteristics, which affect recombination. These models include mice with mutations that disrupt meiosis (specifically the process of recombination) to determine how changes in genome-wide recombination levels affect the location of exchanges, and mice homozygous for chromosome rearrangements that may influence activity at recombination hotspots. We hope that these studies will provide insight into the processes that determine where and how often recombination events occur throughout the genome, at the same time providing mouse models of human nondisjunction.