# Genome organization, evolutionary structural variation, and gene regulation in immunity

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $549,702

## Abstract

Abstract: The activities of innate and adaptive immune cells need to be precisely coordinated for an effective
immune response to a wide-range of pathogens. There are many similarities between immune responses in
different species, but each species also has adapted to combat unique pathogenic insults. Mechanistically,
structural variation in the genome between species plays a prominent role in the acquisition (or loss) of
regulatory events involved in defining the functional activity of immune cells. Structural variation refers to
genome rearrangements such as translocations, insertions, amplifications, and inversions. Structural variation
in the genome between species has the potential to substantially alter the placement of genes and regulatory
elements, including splitting apart clusters of genes with similar functions, relocating genes to different
chromosomes, and changing the orientation of loci. The functional consequences for changes in the genome
between species are based on how each change affects the regulatory events responsible for controlling gene
expression. Therefore, it is important to define how structural variation between species affects regulatory
principles to improve our ability to relate findings from mechanistic and preclinical studies in model organisms
to the regulation of the human immune response. In this application, we will define how structural variation
between the mouse and human genomes influences the regulatory events involved in controlling genes that
are differentially expressed in mouse and human immune cells. We will determine how structural variation
between the mouse and human genomes affects the 1) topology of the genome, 2) regulatory events that
position topological domain boundaries, 3) enhancer landscape available to genes, and 4) long-range
enhancer-promoter interactions for genes with differences in expression between mouse and human immune
cells. We will test the functional consequences for divergent regulatory events between mouse and human
immune cells, with a focus on defining the regulatory events contributing to differences in the LPS-inducible
expression of Nos2 (encodes inducible nitric oxide synthase; iNOS) in mouse and human macrophages, and
we will use this to build a mouse model reflecting human expression. The mouse is one of the most widely
used preclinical models of the human immune response, and the studies in our proposal will aid in
understanding how structural variation between the genomes of model organisms and the human genome
contribute to species acquiring different cell-type and stimulation-dependent gene expression patterns and
functions. It will also make it possible to predict how mechanisms defined in mice translate to human as well as
build mouse models that better reflect human immune responses for pre-clinical studies.

## Key facts

- **NIH application ID:** 10662147
- **Project number:** 1R01AI172067-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Amy Susan Weinmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $549,702
- **Award type:** 1
- **Project period:** 2023-01-26 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662147

## Citation

> US National Institutes of Health, RePORTER application 10662147, Genome organization, evolutionary structural variation, and gene regulation in immunity (1R01AI172067-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10662147. Licensed CC0.

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