Segregation of homologous chromosomes at the first meiotic division is dependent on the placement of genetic exchanges along the length of the chromosomes. In most organisms, including humans, absent or mis-located exchanges dramatically increase the likelihood of nondisjunction. Despite the importance of this process, we remain remarkably ignorant of the mechanisms through which the sites of exchange are chosen and the overall level of recombination is controlled in meiocytes. In the proposed studies we will combine molecular and cytological approaches to investigate the biology of human meiotic recombination. Our studies will focus on the human male, assessing the manner in which homologous chromosomes initiate and complete the process of synapsis and characterizing recombination in normal males. These studies will allow us to test hypotheses about inter-individual and inter-chromosomal variation, the importance of the synaptonemal complex in mediating recombination levels, and the nature of cross-over interference and to ask directly whether some individuals may be predisposed to meiotic nondisjunction. In related studies, we will use the power of mouse genetics to identify the gene(s) that control the level of recombination in mammals. In a final set of studies, we will conduct meiotic studies of infertile men. We will utilize the meiotic data obtained and the clinical findings to categorize these individuals, focusing subsequent mutation detection studies on that subset of infertile male most likely to include individuals with mutations in meiotic genes. The combined data from these studies will not only provide answers to basic questions about meiotic recombination in the human, but may well lead to the identification of the first recombination-dependent causes of human infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042720-05
Application #
7232385
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Taymans, Susan
Project Start
2004-04-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2007
Total Cost
$396,495
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
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Hassold, T; Hansen, T; Hunt, P et al. (2009) Cytological studies of recombination in rhesus males. Cytogenet Genome Res 124:132-8
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
Topping, Daniel; Brown, Petrice; Judis, LuAnn et al. (2006) Synaptic defects at meiosis I and non-obstructive azoospermia. Hum Reprod 21:3171-7
Brown, Petrice W; Judis, Luann; Chan, E Ricky et al. (2005) Meiotic synapsis proceeds from a limited number of subtelomeric sites in the human male. Am J Hum Genet 77:556-66
Lynn, Audrey; Schrump, Stefanie; Cherry, Jonathan et al. (2005) Sex, not genotype, determines recombination levels in mice. Am J Hum Genet 77:670-5