# Causes and consequences of intra-genomic coevolution

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $122,747

## Abstract

PROJECT SUMMARY
Essential chromosome biology such as chromosome segregation and the preservation of genome integrity are
conserved across the tree of life. Paradoxically, many proteins that support these chromosome functions are
unconserved—domains and residues evolve rapidly between even closely related species. A leading resolution
to this paradox posits that essential, chromosomal proteins evolve rapidly to keep pace with chromosomal
regions enriched with tandemly repeating DNA sequences prone to frequent changes in array size and
composition across short stretches of evolutionary time. This turnover of repetitive DNA imperils chromosome
functions, triggering adaptive evolution of chromosomal proteins to restore these functions. This conceptual
model of intra-genomic coevolution was proposed two decades ago, and yet the DNA repeats, the chromosomal
proteins, and the vital chromosome biology sculpted by intra-genomic coevolution are largely uncharacterized.
To experimental test this model, I generate an “evolutionary mismatch” between contemporary DNA repeats in
Drosophila melanogaster and a fast-evolving chromosomal proteins from its closely related sister species D.
simulans. To generate these mismatches, I leverage CRISPR/Cas9-mediated editing to swap native
chromosomal proteins from D. melanogaster with diverged versions from D. simulans. Using this approach, my
recent work demonstrates an incompatibility specifically between the D. simulans allele of the ovary-enriched
chromosomal protein, MH, and the D. melanogaster-specific 359bp repeats. My findings revealed that
DNA:protein coevolution is required to preserve genome integrity in the female germline. This system is now
uniquely poised to reveal the chromosome biology and evolutionary consequences sculpted by coevolution.
Here I integrate evolutionary, cell biology, and biochemistry approaches to investigate the chromosome biology
preserved by 359bp:MH coevolution. I also probe how 359bp:MH coevolution reverberates beyond the
DNA:protein interface, triggering a secondary coevolutionary process that may result in an interspecies hybrid
incompatibility. Finally, I explore the pervasiveness and the consequences of evolutionary innovation at the
dynamic MH gene family across the Drosophila phylogeny.

## Key facts

- **NIH application ID:** 10873127
- **Project number:** 5K99GM149943-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Cara Brand
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $122,747
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873127

## Citation

> US National Institutes of Health, RePORTER application 10873127, Causes and consequences of intra-genomic coevolution (5K99GM149943-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10873127. Licensed CC0.

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