# Chromosome structural variants in meiosis

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $402,384

## Abstract

Project Summary
Accurate chromosome segregation during meiosis is ensured by using recombination to create crossovers
(COs) between homologous chromosomes. Recombination is initiated by a DNA double-stranded break (DSB)
that can be repaired either as a CO or a noncrossover (NCO), but how any given DSB is slated for CO or NCO
repair has remained enigmatic despite a detailed understanding of the genetic networks involved. In the
current proposal, we describe our approach for addressing how the CO/NCO decision is made and how
genome-wide CO patterning mechanisms act locally at a DSB to influence repair outcome. We will use
chromosome structural variants as a system for manipulating DSB repair outcome in Drosophila melanogaster.
We recently showed29 that heterozygous inversions suppress COs locally outside the inversion breakpoint by
altering repair outcome in favor of NCOs and that they simultaneously trigger a genome-wide increase in COs
by altering repair outcome in favor of COs. We are building two research areas based on these results. First,
we are exploring how heterozygous inversions shuttle DSB repair away from a CO repair outcome by carrying
out a genetic analysis of recombination in these zones of suppression. This genetic analysis has two parts, a
candidate gene approach to look for genes that change the distribution of COs and NCOs near inversion
breakpoints, and a molecular genetic analysis of recombination events to determine which recombination
pathways are used. We will take a complementary approach to these studies and use Hi-C and super-
resolution imaging to ask if there are local chromosome structure and/or synaptonemal complex changes at
the inversion breakpoint. Our second research area will ask how heterozygous inversions trigger a genome-
wide increase in COs. To determine the mechanisms that mediate this increase, we will cytologically assay the
kinetics of CO formation in heterozygous inversions, determine if normal CO patterning mechanisms are
bypassed in order to facilitate the increase in COs, and determine which recombination pathways are used to
form the increased COs. In sum, we will leverage our understanding of how heterozygous inversions influence
the CO/NCO decision into general models that address how meiotic recombination and crossover patterning
intersect to create the final recombination landscape. Furthermore, these experiments will elucidate how
structural variants lead to chromosome aneuploidy and subsequent infertility in the human population.

## Key facts

- **NIH application ID:** 10026482
- **Project number:** 1R35GM137834-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kimberly Nicole Crown
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,384
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026482

## Citation

> US National Institutes of Health, RePORTER application 10026482, Chromosome structural variants in meiosis (1R35GM137834-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026482. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*