# Studying the function of human genetic variation in the light of 3D genome organization

> **NIH NIH R35** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2024 · $494,100

## Abstract

Abstract
The search for causal genetic variants associated with specific diseases among many variants identified by
genome-wide association studies (GWAS) has been rejuvenated several times by the increase in throughput,
resolution and the number/modality of experimental techniques that are broadly available. Advances in capturing
cell-type-specific physical proximity among genomic regions also added a new dimension for this search by
revealing the importance of 3D genome organization in interpreting the role of genetic variants in gene regulation.
A number of combinations of these different techniques have proven useful in identifying a number of causal
variants but many major challenges remain in our goal towards creating complete maps of genotype-phenotype
associations for complex diseases. Our recent focus has been to address an important gap in the current
knowledge of how genetic variants may impact 3D genome organization with or without a measurable impact on
gene expression of the cell state/type that is available for molecular characterization. We have identified a
number of genetic variants that associate with read coverage, strengths of specific loops and/or overall
connectivity of large genomic regions. Leveraging our expertise in computational analysis and the newly
established experimental component of our lab, we will address a number of questions emerging from our recent
findings within the next five years. We will first define and characterize the role of genetic variants, which we
found to be associated with specific chromatin loops and/or overall connectivity of regions harboring regulatory
elements in specific human immune cell types. Next, we will perform long read-based assays and develop
accompanying analysis methods to resolve allele-specificity and connection modality of multi-way interactions
involving regulatory elements. Throughout the project period, we will continue developing computational methods
for integrative, comparative and high-resolution analysis of conformation capture data. As we have done before,
our methods development will be in alignment with biological questions we are trying to answer but with flexibility
and generalizability in mind for their broad utility by other researchers.

## Key facts

- **NIH application ID:** 10852845
- **Project number:** 5R35GM128938-07
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Ferhat Ay
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $494,100
- **Award type:** 5
- **Project period:** 2018-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852845

## Citation

> US National Institutes of Health, RePORTER application 10852845, Studying the function of human genetic variation in the light of 3D genome organization (5R35GM128938-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852845. Licensed CC0.

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