# Causes and functional consequences of chromatin evolution

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2024 · $428,281

## Abstract

PROJECT SUMMARY
DNA packaging into chromatin mediates chromosome segregation, telomere protection, and genome integrity,
among other essential, conserved cellular processes. However, many chromatin proteins are strikingly
unconserved—domains and residues evolve rapidly between even closely related species. This paradox of
conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that some
essential cellular processes require recurrent innovation. The biological significance of this paradox is poorly
understood, and yet aberrant chromatin packaging is a hallmark of cancer, infertility, and aging. We
hypothesize that the pervasive rapid evolution of chromatin proteins is driven by the exceptionally rapid
evolution of DNA repeats, including transposons and DNA satellites. Specifically, we hypothesize that
chromatin proteins and DNA repeats antagonistically coevolve: repetitive DNA evolution imperils essential
chromatin functions, triggering reciprocal evolution of chromatin proteins to restore these essential chromatin
functions. Repeated bouts of DNA repeat evolution and chromatin protein adaptation result in exquisitely
coevolved, species-specific components of the genome. To probe this model of antagonistic coevolution, we
conduct evolution-guided functional analysis: we swap into a focal genome a diverged chromatin protein from a
closely related species, generating an "evolutionary mismatch" between the contemporary DNA repeats of one
species and a contemporary chromatin protein of another species. Upon swapping a diverged version of a
transposon-silencing protein into Drosophila melanogaster, we triggered transposon hyper-proliferation and a
consequent loss of genome integrity. Upon swapping a diverged version of a DNA satellite-associated protein
into D. melanogaster, we similarly triggered a profound loss of genome integrity but through a distinct pathway.
Having successfully defined the genome components engaged in antagonistic coevolution during the current
funding period, we are now poised to unravel the molecular mechanisms by which DNA repeats imperil
essential chromatin biology and the molecular mechanisms by which chromatin proteins mitigate these threats.
Leveraging our two established systems, we will probe the evolutionary and functional diversification of two
vital chromatin-mediated pathways shaped by coevolution: 1) the regulation of chromatin accessibility at
genomic regions vulnerable to transposon insertions and 2) the resolution of DNA entanglements enriched in
DNA satellite arrays. Our published and preliminary data also propel our investigations of how antagonistic
coevolution reverberates beyond the two embattled parties, triggering secondary coevolutionary dynamics that
preserve protein:protein interactions among multiple host chromatin proteins. Using transgenics, cell biology,
biochemistry, and classical genetics, we will elucidate the otherwise invisible hazards of DNA repeat evolu...

## Key facts

- **NIH application ID:** 10756451
- **Project number:** 5R35GM124684-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Mia Tauna Levine
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $428,281
- **Award type:** 5
- **Project period:** 2017-09-11 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756451

## Citation

> US National Institutes of Health, RePORTER application 10756451, Causes and functional consequences of chromatin evolution (5R35GM124684-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10756451. Licensed CC0.

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