Chromosome abnormalities due to meiotic errors are a leading cause of birth defects and spontaneous abortions in humans. The long-term objective of this work is to elucidate the mechanisms of meiotic pairing and to understand how these mechanisms help to ensure the fidelity of chromosome transmission from one generation to the next. While the events of meiosis are well conserved across species, their execution accommodates nuclear volumes and genome sizes that vary by several orders of magnitude.
Our aims address the hypothesis that the 3D configurations of chromosomes are discrete, dynamic, and governed in space and time to accommodate the changing nuclear structure/function requirements throughout the course of meiotic prophase. This proposal builds on our recent discovery that a 125 amino acid region of the yeast nucleoporin Nup2 is required for proper chromosome segregation in meiosis, independent of its role in transport. We will determine how this meiotic autonomous region (MAR) functions in carrying out this role using a variety of genetic and structure-based approaches. We also introduce zebrafish as a new genetic model organism to study meiotic chromosome dynamics during oogenesis and spermatogenesis. Our finding so far suggest that zebrafish may an excellent model for human male meiosis. Adult zebrafish produce gametes throughout life, progeny number in the hundreds and embryos develop outside the body. We will determine the spatial and temporal program of homolog pairing, DNA double-strand break formation and synapsis as it relates to the canonical meiosis program in other species. Finally, we will apply a three-dimensional live-cell imaging pipeline we created for budding yeast to measure interaction kinetics between homologous and ectopic chromosomal loci in the two zebrafish sexes. Our results will lead to an understanding of how environmental hazards increase the occurrence of chromosome-based birth defects and inherited disease.
Human reproductive health can be compromised both genetically or by exposure to myriad compounds found in prescription drugs, food containers and toxic waste products found in the environment. This work is significant because it will identify genetic and biochemical pathways that may be direct targets of these insults during gametogenesis. A detailed understanding of these pathways will aid in identifying the underlying causes of human infertility and birth defects by exposure to environmental contaminants.
