# Uncovering the origin of hypermutability in adult brains

> **NIH MH R01** · MAYO CLINIC ROCHESTER · 2026 · $844,959

## Abstract

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.

## Key facts

- **NIH application ID:** 11234312
- **Project number:** 5R01MH131623-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** ALEXEJ  ABYZOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** MH
- **Fiscal year:** 2026
- **Award amount:** $844,959
- **Award type:** 5
- **Project period:** 2023-11-15T00:00:00 → 2028-10-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11234312

## Citation

> US National Institutes of Health, RePORTER application 11234312, Uncovering the origin of hypermutability in adult brains (5R01MH131623-03). Retrieved via AI Analytics 2026-05-18 from https://api.ai-analytics.org/grant/nih/11234312. Licensed CC0.

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