# An Ancient Neural Enhancer that has Rapidly Evolved in the Human Lineage

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $704,922

## Abstract

The distinctive features of humanity—our intelligence, creativity, language, as well as our ecological and
demographic success—are thought to be the result of evolutionary changes elicited by several non-mutually
exclusive genetic mechanisms. One means by which this may be achieved is through the action of ancient DNA
sequence that have undergone rapid evolution specifically in the human lineage. These sequences—called
human accelerated regions (HARs)—have since been shown to be almost exclusively non-coding sequences.
Of HARs that have been evaluated functionally, 30 to 50% are transcriptional enhancers. It has been
hypothesized that rapid evolution of these HAR enhancers in the human lineage has driven changes in gene
expression that ultimately yielded useful human-specific traits. In support, a handful of HAR enhancers have
been shown to regulate neighboring genes in a temporal and/or spatial-specific manner. However, to date, none
of the identified >3000 HARs have been definitively shown to confer human-specific traits. This application is
focused on one particular HAR—called “HAR123”—that has characteristics that we believe make it a strong
candidate to confer human-specific traits. HAR123 is a neural enhancer highly conserved in mammals and
marsupials, but has undergone rapid evolution specifically in the human lineage. HAR123 strongly promotes
the generation of human neural progenitor cells (NPCs). In support of human HAR123 having human-specific
functions, we found—through single-cell RNA-sequencing (scRNAseq) analysis—that human HAR123 drives
cellular and molecular events that differ from those elicited by chimpanzee HAR123. To examine its function in
vivo, we deleted HAR123 in mice and found that this causes a specific defect in cognitive flexibility, as determined
by two independent behavioral tests. Together, these data lead to our central hypothesis that HAR123 is an
ancient neural enhancer that has acquired new properties in the human lineage, leading to changes in gene
expression that impact NPC generation and, ultimately, cognitive flexibility. In this application, we propose to
address this central hypothesis. Towards this goal, we will elucidate the cellular and molecular functions of
mouse, chimpanzee, and human HAR123. Aim 1: to decipher the roles of HAR123 in human neural cells,
including NPCs, with a focus on how HAR123 acts as an enhancer. We will investigate how human HAR123
differs—at both the cellular and molecular level—from chimpanzee HAR123 in its impact on NPC genesis and
neural development. Our planned studies are designed to elucidate the selective forces that have acted on
HAR123 during primate evolution. Aim 2: to elucidate the neural roles of HAR123 in vivo. In this Aim, we will
investigate the cellular and molecular mechanisms underlying the intriguing cognitive flexibility defect we have
defined in HAR123-KO mice. Through behavioral, cellular, and molecular analyses of human and chimp
HAR123 knock-in mice, we ...

## Key facts

- **NIH application ID:** 10944852
- **Project number:** 1R01MH137503-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Kun Tan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $704,922
- **Award type:** 1
- **Project period:** 2024-08-09 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944852

## Citation

> US National Institutes of Health, RePORTER application 10944852, An Ancient Neural Enhancer that has Rapidly Evolved in the Human Lineage (1R01MH137503-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10944852. Licensed CC0.

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