# The Evolution of Gene Regulation and Human Disease

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $449,854

## Abstract

PROJECT SUMMARY
The long-term mission of my lab is to accurately model the effects of DNA sequence differences between indi-
viduals on phenotypes relevant to disease and human evolution. Genetic variants that modify gene regulation
are major contributors to both evolutionary divergence between species and differences in risk for disease
among humans. However, due to the complexity of gene regulatory programs and the evolutionary histories
that shaped patterns of genetic variation, interpreting the implications of an individual’s genome sequence re-
mains challenging. This is a major roadblock to understanding the functional evolution of human-specific biolo-
gy and mapping the genetic causes of disease.
We integrate machine learning, large-scale functional genomics data, and ancient DNA to address this chal-
lenge. The previous R35 funding enabled us with the flexibility to seize opportunities to make significant dis-
coveries including: DNA sequence-based machine learning methods for predicting gene regulatory activity
within and between species; demonstrating that selection against introgressed Neanderthal variation was the
dominant trend across >400 traits, discovering the Neanderthal introgression introduced functional alleles lost
in the out-of-Africa bottleneck; and developing a model for the functional evolution of gene regulatory elements.
The previous R35 was the core source of support for work that led to 32 manuscripts, 26 of which my group led
or co-led.
Given our success in the previous grant period, my lab is uniquely well positioned with this renewal to build on
our previous work to address fundamental questions in the following areas:
 1. Developing powerful new machine learning methods that enable accurate prediction of individual-level
 molecular phenotypes, like gene expression, from DNA sequence.
 2. Reconstructing molecular phenotypes of ancient humans and archaic hominins from their genomes to
 test hypotheses evolutionary transitions.
 3. Leveraging new experimental technologies to dissect the functional drivers of cis vs. trans gene regula-
 tory divergence between species.
 4. Interpreting non-protein-coding mutations identified in patient genomes to inform treatment and preven-
 tative care.
Our work will produce much-needed methods for understanding the effects of genetic variant in gene regulato-
ry regions and identifying mutations responsible for differences in disease risk between human populations.
The renewal of our R35 will enable us to continue making significant contributions to these essential basic sci-
ence and clinical challenges.

## Key facts

- **NIH application ID:** 10842760
- **Project number:** 2R35GM127087-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John Anthony Capra
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,854
- **Award type:** 2
- **Project period:** 2018-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842760

## Citation

> US National Institutes of Health, RePORTER application 10842760, The Evolution of Gene Regulation and Human Disease (2R35GM127087-07). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10842760. Licensed CC0.

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