# Modeling uniquely human developmental gene regulatory networks using humanized mice

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $568,105

## Abstract

Physical adaptation is a hallmark of human evolution. Morphological changes in our limbs allowed us to make
and use sophisticated tools and to walk upright, and the expansion of the human cortex is the origin of our
advanced cognitive abilities. These traits are ultimately encoded in genetic changes that arose during human
evolution, and which acted to alter molecular and cellular processes during development. The goal of this
ongoing research project, which began in 2010, is to determine where in the genome those changes reside and
to understand their biological functions. Our efforts focus on two classes of gene regulatory elements that may
encode novel functions in humans. The first are Human Accelerated Regions (HARs), many of which encode
transcriptional enhancers that are highly conserved across species but show multiple human-specific sequence
changes. The second class of elements are Human Gain Enhancers (HGEs), which are transcriptional
enhancers that show increased activity in developing human tissues based on comparisons of epigenetic marks
associated with enhancer activity in human, rhesus macaque and mouse. These discoveries reveal that changes
in developmental gene regulation played a central role in the evolution of uniquely human morphology and
provide the means to experimentally model the evolution of human development. In this funding cycle, we will
use humanized mouse models to study the biological function of HACNS1, which we identified as the first
known HAR to encode human-specific regulatory activity. HACNS1 maintains its human-specific activity in
the developing mouse limb and alters the expression of the nearby transcription factor Gbx2 in the
developing embryo. We hypothesize that HACNS1 is acting within a larger network of human-specific
regulatory changes that modified development. Using the HACNS1 mouse model and our maps of
human-specific regulatory functions in the limb as entry points, we will identify transcriptional and
regulatory changes downstream of HACNS1 at single-cell resolution, model additional human-specific
regulatory functions that may interact with the regulatory changes driven by HACNS1, and determine
how these changes influence the development of the limb.

## Key facts

- **NIH application ID:** 10359768
- **Project number:** 5R01HD102030-12
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** James P Noonan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $568,105
- **Award type:** 5
- **Project period:** 2020-06-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359768

## Citation

> US National Institutes of Health, RePORTER application 10359768, Modeling uniquely human developmental gene regulatory networks using humanized mice (5R01HD102030-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359768. Licensed CC0.

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