Errors during meiotic cell division are a leading cause of mental retardation and pregnancy loss in our species. The vast majority of human meiotic errors are maternal in origin and the rate of errors is strongly influenced by age. While the mechanism(s) of error and the way in which age influences chromosome segregation remain unknown, recent studies have demonstrated that the number and placement of meiotic recombination events profoundly influences chromosome segregation. In the past several years our understanding of the molecular events involved in meiotic recombination has increased dramatically, yet we remain largely ignorant of the factors that control recombination levels and placement in mammals. The studies outlined in this application are predicated on the assumption that recombination is influenced by the interplay of prophase events involved in the establishment of cohesion between sister chromatids, the formation of the synaptonemal complex between homologs, and the repair of DNA double stand breaks. Accordingly, we propose three sets of interrelated studies, one to define the key events in prophase of mammalian female meiosis and to assess the impact of """"""""normal""""""""genetic variation on these processes;one using mutational analysis to examine the effect of """"""""abnormal"""""""" variation on these events;and one to examine the downstream effects of perturbations in prophase. This approach, using the meiotic """"""""reagents"""""""" developed during the initial funding period, will allow us to test specific hypotheses about the role of cohesion, DMA sequence, and the synaptonemal complex in the establishment of meiotic exchanges. The combined data from these studies will allow us to understand the control of recombination In mammals and how the events of prophase influence meiotic chromosome segregation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037502-10
Application #
7628669
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Taymans, Susan
Project Start
2000-02-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$282,539
Indirect Cost
Name
Washington State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Melin, Vanessa E; Potineni, Haritha; Hunt, Patricia et al. (2014) Exposure to common quaternary ammonium disinfectants decreases fertility in mice. Reprod Toxicol 50:163-70
Murdoch, Brenda; Owen, Nichole; Stevense, Michelle et al. (2013) Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior. PLoS Genet 9:e1003241
Nagaoka, So Iha; Hodges, Craig A; Albertini, David F et al. (2011) Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr Biol 21:651-7
Hassold, T; Hansen, T; Hunt, P et al. (2009) Cytological studies of recombination in rhesus males. Cytogenet Genome Res 124:132-8
Hassold, Terry; Hunt, Patricia (2009) Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 21:703-8
Hunt, Patricia A; Hassold, Terry J (2008) Human female meiosis: what makes a good egg go bad? Trends Genet 24:86-93
Hunt, Patricia A; Jackson, Jodi M; Horan, Sonia et al. (2008) The mouse A/HeJ Y chromosome: another good Y gone bad. Chromosome Res 16:623-36
Hassold, Terry; Hall, Heather; Hunt, Patricia (2007) The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 16 Spec No. 2:R203-8
Johnson, Mark T; Freeman, Edward A; Gardner, David K et al. (2007) Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo. Biol Reprod 77:2-8
Cherry, Sheila M; Adelman, Carrie A; Theunissen, Jan W et al. (2007) The Mre11 complex influences DNA repair, synapsis, and crossing over in murine meiosis. Curr Biol 17:373-8

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