# How age-dependent alterations in meiotic recombination cause chromosome mis-segregation in sperm

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $394,264

## Abstract

PROJECT SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 9974532
- **Project number:** 5R01HD098129-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Francesca Cole
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,264
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974532

## Citation

> US National Institutes of Health, RePORTER application 9974532, How age-dependent alterations in meiotic recombination cause chromosome mis-segregation in sperm (5R01HD098129-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974532. Licensed CC0.

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