# Comparative and functional analysis of conservation and rearrangement of topologically associating domains across mammals.

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $717,254

## Abstract

PROJECT SUMMARY
Chromosomal rearrangements are a great source of inter- and intra-specific genetic variation and are major
contributors to human disease. Although position of rearrangement breakpoints can now be mapped at high
resolution, interpreting the evolutionary or clinical implications of these events remains challenging. Depending
on where they occur, rearrangements can disrupt the organization of genomic functional compartments, known
as topologically associating domains (TADs). Within TADs, nearby loci (i.e. promoters and enhancers) interact
frequently with each other, while interactions with loci outside TADs are prevented by TAD boundaries.
Disruption of TAD boundaries can result in ectopic genes regulation, aberrant phenotypes, and genetic
disorders. The functional outcomes of chromosomal rearrangements, therefore, can only be fully understood
when studied in the context of genome topology. To shed light on some of the evolutionary implications of
genome reorganization, we recently studied the gibbon genome, which has experienced rapid and recent
karyotype evolution with respect to human and the other apes. In the gibbon genome, we observed that TADs
remained genetically and epigenetically intact (genomic false-shuffle), because evolutionary breakpoints
overlapped almost exclusively with TAD boundaries. Comparison with human and other mammals shows that
these TAD boundaries are evolutionary conserved, indicating that TAD boundary establishment predated, and
may have even contributed to, occurrence of evolutionary breakage. Motivated by our preliminary findings in
gibbon, we propose to use a broad comparative and functional approach to assay multiple species with
naturally highly rearranged genomes across the Boreoeutheria tree, and characterize the genetic context,
epigenetic state, and evolutionary conservation of their TAD boundaries. We will determine if the false shuffle
is a recurring mechanism of genome evolution and we will identify chromatin states associated with
evolutionary fragility, as these regions and states could be relevant to human disease (Aim 1). Additionally, we
will determine the level of conservation for TAD boundaries across different clades. Overall, the combination of
these annotations will be a valuable resource to aid the interpretation of clinically and/or evolutionarily relevant
rearrangements. We will then use an evolutionary-motivated approach to delete a subset of highly conserved
and clade-specific TAD boundaries using CRISPR/Cas9 in cell lines and mouse, to assess the functional
consequences of their deletion on DNA interaction, chromatin state, and gene expression (Aim 2). Finally, by
analyzing differential gene expression and chromatin conformation between closely related species with
structurally different genomes, we will evaluate the extent to which chromosomal rearrangements can alter
short- and long-range functional interaction and contribute to differential gene expression (Aim 3). Overall, ...

## Key facts

- **NIH application ID:** 9955287
- **Project number:** 5R01HG010333-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Lucia Carbone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $717,254
- **Award type:** 5
- **Project period:** 2018-09-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955287

## Citation

> US National Institutes of Health, RePORTER application 9955287, Comparative and functional analysis of conservation and rearrangement of topologically associating domains across mammals. (5R01HG010333-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955287. Licensed CC0.

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