# Role of human-specific haplotype diversity on cell fate commitment

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $382,090

## Abstract

Project summary
The primary focus of research in my laboratory centers on unraveling the causal relationship
between common genetic variants in humans and susceptibility to complex diseases. We aim to
understand how single nucleotide polymorphisms (SNPs), often residing in the non-coding portion
of the genome, influence cellular physiology, the determination of cell fate, and the alterations in
cell state. We employ a unique human-specific genetic framework, utilizing induced pluripotent
stem cells (iPSCs) and genome editing techniques to investigate non-coding regions of the
genome whose functions are not yet defined. SNPs frequently exhibit correlations with
neighboring variants, forming clusters known as haplotypes through a phenomenon called linkage
disequilibrium. Haplotypes are shared within the same ancestral group and exhibit significant
variations across different genetic ancestries. This genomic diversity translates into varying
degrees of correlation between genetic variants and the risk of developing complex diseases
across diverse ancestries. While this genomic diversity is deeply rooted in human evolutionary
history, our understanding of its functional implications at the cellular level remains incomplete.
The elucidation of haplotypes function and the effect of their diversity are crucial to uncover
unexplored biological processes impacted by the non-coding genome and for enhancing the
accuracy of predicting complex disease risk within different populations. In this proposal, we
outline a research strategy to investigate human-specific haplotype diversity and its cellular
consequences across diverse cell types. Our overarching goal is to determine the physiological
significance of haplotype diversity in cell fate determination and the maintenance of cell states,
shedding light on haplotype functionality and its role in disease susceptibility. By examining the
impact of ancestrally diverse haplotypes at the cellular level, this proposal aims to identify critical
factors contributing to ethnicity-based disease risk and cell-type-specific vulnerabilities. We will
employ human iPSCs obtained from diverse ancestral backgrounds, induce differentiation into
various cell types, perform haplotype editing, and utilize a wide range of assays to evaluate how
diversity at specific genomic loci influences cell fate determination and the maintenance of cell
states in response to various stimuli. The tools we develop will serve as a versatile platform for
investigating non-coding genetic risk factors in various complex diseases, expediting the
translation of functional genomics findings into advancements in human health.

## Key facts

- **NIH application ID:** 10940265
- **Project number:** 1R35GM155127-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Valentina Lo Sardo
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,090
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940265

## Citation

> US National Institutes of Health, RePORTER application 10940265, Role of human-specific haplotype diversity on cell fate commitment (1R35GM155127-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10940265. Licensed CC0.

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