Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Crossovers direct the accurate segregation of meiotic chromosomes. Several decades of effort has led to a detailed model outlining the mechanism of meiotic recombination. This is based almost entirely on research done with a single model organism, the budding yeast S. cerevisiae. We recently tested key features of this model in the metazoan Drosophila melanogaster. To do this, we knocked out both canonical (long- patch) and short-patch mismatch repair, the first time this has been done in a metazoan. Our results suggested a new model, one that has some fundamental differences from the budding yeast model.
In Aim 1 we test key predictions of our model. To do this, we examine genome-wide meiotic recombination in the absence of mismatch repair. We will sequence maternally haploid embryos and also maternally haploid embryos that are disomic for one major chromosome, which is essentially half-tetrad analysis. We've also made recent discoveries that open up a new avenue to understanding how crossover position is controlled. We found that the Bloom syndrome helicase (BLM) and a complex we call the meiotic-MCM (mei-MCM) complex are both required for normal crossover positioning;in mutants, crossovers are distributed randomly along a chromosome arm and even occur on chromosome 4, which normally has no meiotic crossovers. We hypothesize that BLM controls choice of repair pathway;we test this hypothesis in Aim 3. We found that the mei-MCM complex is physically required for normal crossover regulation, but this does not require ATPase activity (this activity is essential for making crossovers, just not for distributing them).
In Aim 3 we continue to elucidate functions of the mei-MCM complex in crossover control, including blocking crossover near the centromere and on chromosome 4. Results from these experiments will shed new light on meiotic recombination mechanisms and provide novel insights into regulation of crossover placement.

Public Health Relevance

Genetic exchange between homologous chromosomes is essential to ensure that they segregate accurately in meiosis, the specialized cell division that gives rise to eggs and sperm. Errors in recombination can lead to aneuploidy, which is the most common cause of birth defects and miscarriage. We are using the fruit fly as a model organism to understand mechanisms and regulation of these processes in animals.

National Institute of Health (NIH)
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Molecular Genetics B Study Section (MGB)
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Janes, Daniel E
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Kuo, H Kenny; McMahan, Susan; Rota, Christopher M et al. (2014) Drosophila FANCM helicase prevents spontaneous mitotic crossovers generated by the MUS81 and SLX1 nucleases. Genetics 198:935-45
Crown, K Nicole; McMahan, Susan; Sekelsky, Jeff (2014) Eliminating both canonical and short-patch mismatch repair in Drosophila melanogaster suggests a new meiotic recombination model. PLoS Genet 10:e1004583
LaFave, Matthew C; Andersen, Sabrina L; Stoffregen, Eric P et al. (2014) Sources and structures of mitotic crossovers that arise when BLM helicase is absent in Drosophila. Genetics 196:107-18
Kohl, Kathryn P; Sekelsky, Jeff (2013) Meiotic and mitotic recombination in meiosis. Genetics 194:327-34
Lake, Cathleen M; Holsclaw, Julie Korda; Bellendir, Stephanie P et al. (2013) The development of a monoclonal antibody recognizing the Drosophila melanogaster phosphorylated histone H2A variant (ýý-H2AV). G3 (Bethesda) 3:1539-43
McMahan, Susan; Kohl, Kathryn P; Sekelsky, Jeff (2013) Variation in meiotic recombination frequencies between allelic transgenes inserted at different sites in the Drosophila melanogaster genome. G3 (Bethesda) 3:1419-27
Crown, K Nicole; Sekelsky, Jeff (2013) Targeted gene replacement in Drosophila goes the distance. Genetics 193:377-81
LaFave, Matthew C; Sekelsky, Jeff (2011) Transcription initiation from within P elements generates hypomorphic mutations in Drosophila melanogaster. Genetics 188:749-52
Andersen, Sabrina L; Sekelsky, Jeff (2010) Meiotic versus mitotic recombination: two different routes for double-strand break repair: the different functions of meiotic versus mitotic DSB repair are reflected in different pathway usage and different outcomes. Bioessays 32:1058-66
Mukherjee, Sushmita; LaFave, Matthew C; Sekelsky, Jeff (2009) DNA damage responses in Drosophila nbs mutants with reduced or altered NBS function. DNA Repair (Amst) 8:803-12

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