Despite the importance of maternal meiotic errors to the etiology of human chromosome abnormalities, we know very little about chromosome dynamics during human female meiosis, and remain ignorant of the reasons why the process is so error-prone. Further, we have little understanding of the basis of the sex-specific differences in meiotic error rate or recombination patterns in our species. The studies that comprise this renewal application will directly examine meiosis in human oocytes and spermatocytes. By combining this approach with molecular and quantitative methodologies, we will answer fundamental questions about meiosis in humans. We will examine and compare the way in which homologous chromosomes find and synapse with one another during meiotic prophase in the human female and male and ask how synaptic patterns influence the formation of crossovers. In addition, because the placement of crossovers established during the fetal stages of oogenesis affects chromosome segregation in the adult female, we will combine the data obtained from human studies with studies in the mouse to test different models proposed to explain the relationship between recombination and nondisjunction. Finally, we will examine the contribution of chromatin structure and interference to sex-specific differences in recombination rates. The clinical implications of the basic information obtained from these studies are considerable: Aneuploidy is the most common cause of miscarriage and birth defects in our species. Understanding the mechanics of the meiotic process in humans and sex-specific differences not only provides a crucial first step in the development of therapeutic approaches to prevent or at least minimize errors, but also critical information for the development of systems for producing gametes in vitro to treat human infertility.
Meiosis is a specialized cell division that gives rise to eggs and sperm. Errors in the meiotic process can give rise to infertility or to offspring with developmental defects. Our current understanding of the causes of these meiotic errors is limited, and the studies outlined in this proposal will not only provide basic information on female and male meiosis, but will also will yield insights regarding the origins of these errors.
|Wang, Shunxin; Hassold, Terry; Hunt, Patricia et al. (2017) Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis. Cell 168:977-989.e17|
|Gruhn, Jennifer R; Al-Asmar, Nasser; Fasnacht, Rachael et al. (2016) Correlations between Synaptic Initiation and Meiotic Recombination: A Study of Humans and Mice. Am J Hum Genet 98:102-15|
|Vrooman, Lisa A; Oatley, Jon M; Griswold, Jodi E et al. (2015) Estrogenic exposure alters the spermatogonial stem cells in the developing testis, permanently reducing crossover levels in the adult. PLoS Genet 11:e1004949|
|Rowsey, Ross; Gruhn, Jennifer; Broman, Karl W et al. (2014) Examining variation in recombination levels in the human female: a test of the production-line hypothesis. Am J Hum Genet 95:108-12|
|Vrooman, Lisa A; Nagaoka, So I; Hassold, Terry J et al. (2014) Evidence for paternal age-related alterations in meiotic chromosome dynamics in the mouse. Genetics 196:385-96|
|Baier, Brian; Hunt, Patricia; Broman, Karl W et al. (2014) Variation in genome-wide levels of meiotic recombination is established at the onset of prophase in mammalian males. PLoS Genet 10:e1004125|
|Gruhn, Jennifer R; Rubio, Carmen; Broman, Karl W et al. (2013) Cytological studies of human meiosis: sex-specific differences in recombination originate at, or prior to, establishment of double-strand breaks. PLoS One 8:e85075|
|Rowsey, Ross; Kashevarova, Anna; Murdoch, Brenda et al. (2013) Germline mosaicism does not explain the maternal age effect on trisomy. Am J Med Genet A 161A:2495-503|
|Johnson, Matthew E; Rowsey, Ross A; Shirley, Sofia et al. (2013) A specific family of interspersed repeats (SINEs) facilitates meiotic synapsis in mammals. Mol Cytogenet 6:1|
|Murdoch, Brenda; Owen, Nichole; Stevense, Michelle et al. (2013) Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior. PLoS Genet 9:e1003241|
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