The role of sister-chromatid cohesion in heterochromatin-mediated association of achiasmate homologues in Drosophila oocytes

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Intellectual Merit: Meiosis is a specialized type of cell division that is required for the production of eggs and sperm. A physical connection between each pair of homologous chromosomes is necessary for their accurate segregation during the first meiotic division. If this association is not established or maintained, homologues can missegregate resulting in aneuploid gametes and in most cases, inviable offspring. Therefore, analysis of the mechanisms that ensure proper homologue association will yield critical information about sexual reproduction and species propagation. Normally, meiotic recombination in conjunction with sister-chromatid cohesion establishes a physical connection that holds each pair of homologous chromosomes together until anaphase I. However, some organisms utilize an alternative mechanism that ensures the proper segregation of homologue pairs that fail to recombine. In Drosophila melanogaster (fruit fly) oocytes, accurate segregation of non-recombinant homologues depends on heterochromatin near their centromeres. In addition, recent work in the principal investigator's laboratory has uncovered an unexpected link between sister-chromatid cohesion and heterochromatin-mediated pairing of homologues. These data suggest that sister-chromatid cohesion proteins not only maintain the association of recombinant homologues but also play an important role in promoting the physical association of non-recombinant homologues. This project will define the relationship between sister-chromatid cohesion and heterochromatin in promoting accurate segregation of non-recombinant homologues by completing the following three objectives: 1) Test the hypothesis that the cohesin complex promotes heterochromatin-mediated pairing of non-recombinant homologues; 2) Explore the role of the cohesin regulator WAPL in promoting the association of non-recombinant homologues; 3) Test the hypothesis that the heterochromatin protein HP1 promotes the accurate segregation of non-recombinant homologues.Broader Impacts: Accurate chromosome segregation during meiosis is essential for sexual reproduction. This research will expand the understanding of this fundamental biological process by elucidating the mechanisms that ensure proper segregation of non-recombinant chromosomes during female meiosis in Drosophila melanogaster. Given that centromere pairing plays a role in the faithful segregation of non-recombinant chromosomes in both fission and budding yeast and that sister-chromatid cohesion is evolutionarily conserved, these results may also yield valuable information about homologue association and the segregation of non-recombinant chromosomes in other organisms. In addition, this project will integrate research and education at both the undergraduate and graduate levels. Students will be involved in all aspects of the research involved including experimental design, execution and data analysis. The methodology used for each of the objectives lends itself easily to the full participation of undergraduates at both the technical and intellectual level. Both undergraduates and graduate students will attend weekly lab meetings/journal clubs. Learning to effectively communicate their research and ideas will be an essential part of their training. In the past 11 years, the principal investigator has mentored 22 undergraduates and 5 Ph.D. students. The small size of the research group facilitates interaction of the principal investigator with each member of the lab as well as extensive interaction among members. In addition, mentoring undergraduates represents an important component of graduate student training.