# Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2024 · $534,228

## Abstract

Abstract:
Understanding the genetic basis of gene regulation is key to understanding the evolutionary processes that have shaped
specific traits in humans and non-human apes. In turn, identifying and characterizing the genetic variants that lead to
inter-individual responses to different exposures is critical to gain insight into gene by environment interactions and
associated phenotypic consequences. By elucidating the genetic variation that underlies regulatory differences between
species, and the genetic variation that is associated with individual differences in response to environmental cues, we
can gain a better understanding of the evolutionary processes that led to human-specific traits, as well as the genetic
basis of complex traits and diseases. The challenge is that to carry out this work in humans and other apes, one must
rely on in vitro systems.
During the first term of the MIRA award, my lab focused on understanding the molecular mechanisms that underlie
the evolution of gene expression, such as natural selection, the influence of epigenetic marks, and the effects of gene
duplication. We developed and broadly shared a comparative panel of iPSCs from humans and chimpanzees, and we
established a new approach for iPSC differentiation (we call it ‘guided differentiation’), which makes it feasible for us
to study gene regulation across a broad range of cell types and contexts. We used these systems to study the impact of
variation in gene regulatory networks on complex diseases and the role of gene regulation in the generation of
phenotypic diversity. We explored the roles of gene expression in human diseases, such as cancer and neurological
disorders, and developed methods for analyzing comparative single-cell gene expression data.
In the next term of this award, we propose to continue to study similar broad areas. We will sharpen our focus on gene
by environment interactions and develop a better understanding of the genetic variation that leads to regulatory
variation in response to different exposures. We will employ a dynamic eQTL mapping approach to offer additional
insight into the genetic basis for disease. We will also explore the role of epigenetic mechanisms, such as DNA
methylation, histone modifications, and non-coding RNAs, in mediating gene by environment interactions. We will
use the comparative iPSC panel to explore the relative impact and evolutionary consequences of changes in cis and
trans regulatory mechanisms in dozens of different tissues and cell types and continue to share the panel and derivative
cultures with the community. Finally, we will take advantage of improved single-cell technologies to characterize the
dispersion and robustness associated with single-cell gene regulation and identify genetic mechanisms that underlie
the regulation of gene regulatory noise.

## Key facts

- **NIH application ID:** 10759898
- **Project number:** 2R35GM131726-06
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Yoav Gilad
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $534,228
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10759898

## Citation

> US National Institutes of Health, RePORTER application 10759898, Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species (2R35GM131726-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10759898. Licensed CC0.

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