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Uncovering the origin of hypermutability in adult brains

Award Number: R01MH131623
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/15/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Uncovering the origin of hypermutability in adult brains - Abstract Genomic variants in an individual may be either inherited (i.e., transmitted through the germline) or generated by mutagenesis in post-zygotic cells. Widespread genomic mosaicism in somatic cells of phenotypically normal individuals is now well established. In certain cases, it is known that mutations have causative role in diseases and contribute to neuropsychiatric disorders. But generally, little is known about to what extent natural mosaicism influences an individual’s susceptibility to disease. In our recent study we discovered a phenomenon of hypermutability in adult brains. Hypermutability was not related to diagnosis but increased with age, reaching at least 3% population frequency (95% confidence interval) for brains over 40 years old. The phenomenon of hypermutability could have implications for a number of conditions. Since it correlates with aging, it could be important for age-related neurodegenerative diseases; or, as it involves mutations in cancer-related genes, it may be related to predisposition for brain cancer. Alternatively, hypermutability may reflect imbalances (expansion/contraction) between cell lineages in the developing brain. We have three hypotheses explaining hypermutability. The goal of the proposed study is to firmly establish the origin(s) of hypermutability. To conduct the study, we will first expand the set of hypermutable brains (Aim 1). The ultimate judgement about the origins will be made from the regional distribution and frequency of mutations in the brains (Aim 2), the cell type(s) carrying the mutations (Aim 3), and proving (or disproving) that mutations in the hypermutable brains arose from a clonally expanded cell lineage (Aim 4). Proving the hypothesized origins of hypermutability will be a fundamental contribution to understanding brain development and aging in humans and will lay the foundation for future studies of the underlying mechanisms.


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 = $844,959 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Mental Health Research Grants	000	3	12/10/2025	NON-COMPETING CONTINUATION	$844,959
														Subtotal = $844,959

Issue Date FY: 2025 ( Subtotal = $848,578 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Mental Health Research Grants	001	2	9/23/2025	NON-COMPETING CONTINUATION	$127,286
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Mental Health Research Grants	000	2	11/19/2024	NON-COMPETING CONTINUATION	$721,292
														Subtotal = $848,578

Issue Date FY: 2024 ( Subtotal = $901,382 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Mental Health Research Grants	001	1	5/14/2024	NEW	$87,069
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Mental Health Research Grants	000	1	11/15/2023	NEW	$814,313
														Subtotal = $901,382

Grand Total All Awards = $2,594,919

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Uncovering the origin of hypermutability in adult brains

Award Number: R01MH131623

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/15/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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