Errors of chromosome segregation during meiosis are a leading cause of infertility, miscarriage, and birth defects. Faithful segregation requires homologs to become tethered by crossovers, a recombination product that exchanges homolog arms. DNA double-strand breaks are induced during meiosis to provoke recombination. Only a small subset of breaks become crossovers with the remaining repaired as noncrossovers, which are patch-like repairs that facilitate pairing, but cannot connect homologs. Thus, dysregulation of crossovers in favor of noncrossovers can lead to aberrant chromosome segregation. A fundamental question in chromosome and reproductive biology is how cells ensure crossovers between each homolog. In order to design therapies to prevent chromosome mis-segregation in meiosis, an understanding of the molecular underpinnings of meiotic recombination is required. We have developed assays that can distinguish contributions from the major recombination pathways at high resolution in mouse spermatocytes. Using this technology, we found that in juvenile mouse spermatocytes, alternative pathways involving structure-selective endonucleases and complexes that dissolve crossover precursors generate noncrossovers in lieu of crossovers, causing crossover maturation inefficiency. As a result, crossovers are found at lower density leading to chromosome mis-segregation. We found similarly lower crossover density in young human spermatocytes suggesting a root cause for why younger fathers are more likely to have children with Down syndrome. This proposal will investigate 1) when recombination pathways act during meiotic prophase in spermatocytes and oocytes, 2) whether there are temporally regulated expression, localization, or activity changes of enzymes that execute recombination pathways, and 3) in what way are juvenile human spermatocytes like human oocytes. Taken together, the successful execution of the proposed research will provide a comprehensive understanding of why meiotic recombination is altered with age in spermatocytes and how chromosomes mis-segregate as a consequence.

Public Health Relevance

We lack understanding of why chromosomes are more likely to mis-segregate in spermatocytes from younger men and mice. This proposal describes a novel approach to comprehensively determine molecular mechanisms underlying changes in meiotic recombination with age. Successful completion will provide the needed mechanistic insight to design therapeutic intervention to prevent infertility, miscarriages, and birth defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD098129-01
Application #
9710112
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2019-07-15
Project End
2024-06-30
Budget Start
2019-07-15
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Overall Medical
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030