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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD021341-30
Application #
8699225
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Parisi, Melissa
Project Start
1988-01-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
30
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164
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
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
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
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
Gerona, Roy R; Woodruff, Tracey J; Dickenson, Carrie A et al. (2013) Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population. Environ Sci Technol 47:12477-85

Showing the most recent 10 out of 16 publications