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The regulatory landscape of segmentally duplicated genes: Implications for human evolution and disease

Award Number: R00GM155552
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The regulatory landscape of segmentally duplicated genes: Implications for human evolution and disease - This project seeks to comprehensively understand how gene regulatory elements within rapidly evolving areas of the human genome, segmental duplications, influence human evolution and disease. Despite their potential significance, these regions have historically been challenging to study due to technical limitations. The specific aims of this project are: 1. Characterize segmental duplications across the human population by constructing a pangenome graph using thousands of high-quality genome assemblies. 2. Establish a statistical and computational methodology for mapping regulatory DNA within SDs using long-read chromatin fiber sequencing (Fiber-seq). 3. Identify conserved regulatory and genomic elements within segmental duplication loci by mapping genetic and epigenetic haplotypes into the pangenome graph. 4. Uncover the regulatory fate of multi-copy gene families by analyzing segmental duplication para logs with Fiber-seq across tissues, determining if these para logs have undergone changes in regulatory function. Research Design and Methods: In this work, I will create a comprehensive SD pangenome graph by integrating thousands of long-read haplotypes from multiple consortia, which will significantly enhance our understanding of human variation within SDs. Next, I will use long-read Fiber-seq in conjunction with the development of a machine-learning framework to detect regulatory elements within SDs and use that information to impute the results of other short-read epigenetic assays. My approach will also involve a conservation analysis that prioritizes SD genes and regulatory elements. I will introduce a novel 'loss-of-paralog intolerance' (pLPI) score to rank these genes based on their conservation levels across populations. Additionally, the regulatory trajectories of SD genes will be determined using Fiber-seq conducted on a range of human tissues. This will help me identify distinct patterns such as neofunctionalization, subfunctionalization, or pseudofunctionalization. This investigative approach will deliver an in-depth understanding of the regulatory mechanisms in SDs using cutting-edge genomic tools. The insights gained have the potential to highlight human-specific regulatory adaptations and could pave the way for discovering new therapeutic avenues in personalized medicine.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $248,965 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	3	1/9/2026	EXTENSION WITH OR WITHOUT FUNDS	$248,965
														Subtotal = $248,965

Grand Total All Awards = $248,965

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The regulatory landscape of segmentally duplicated genes: Implications for human evolution and disease

Award Number: R00GM155552

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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