# Origins of Brain Somatic Mosaicism in Developmental Brain Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $312,481

## Abstract

Abstract
Brain somatic mosaicism (BSM) refers to the accumulation of mutations within any of the billions of cells in
the human brain, which can occur from embryogenesis through adulthood. The extent, impact and
mechanisms of BSM on brain disease remain poorly understood. Prior work from the Brain Somatic
Mosaicism Network (BSMN), on which the PI served, made critical breakthroughs in reliability of mosaicism
detection, but also raised new questions, including the degree to which BSM exists in the healthy brain, and
the mechanisms by which BSM mutations explain disease.
 Focal cortical dysplasia (FCD) is associated with substantial neuropsychiatric disability, and is the
most common cause of intractable epilepsy in childhood. Neuropsychiatric features are seen in 15-59% of
patients 5-7, and neuropathologically shows disrupted neurogenesis, migration, differentiation, and altered
neural excitability. We and others previously identified mosaic mutations in the mTOR pathway in a minority
of FCD cases, but most cases remain unsolved, and fundamental mechanisms are lacking.
 We hypothesize that: 1] FCD mutations are similar to neutral somatic mutations in their patterns and
distributions, dictated by developmental processes, but differ in their functional effect. 2] BSM patterns, allelic
fractions (AFs) and allele sharing between cells can reconstruct cellular lineages and migratory histories. 3]
Study of FCD resected tissue can uncover novel causes of disease that would not be tolerated if present in
every cell. 4] BSM modeling in mouse can unravel disrupted signaling networks of complex mosaic mutations.
 Our preliminary data shows: 1] From a post-mortem control cadaver, we validated 259 somatic
variants using 300X genome sequencing, and started to use these variants as ‘barcodes’ to reconstruct
lineage histories. 2] Deep sequencing from 314 FCD patient brain resections identified 12 new candidate
genes, highlighting signaling and synaptic dysfunction, and a novel ‘two-hit’ disease mechanisms. 3] We
established in utero mouse electroporation models to assess putative FCD variants as gain or loss of function,
and to assess effects of ‘single-hit’ and ‘two-hit’ mutations.
 We propose three aims: 1] From control cadavers, we will reconstruct cell lineage across anatomical
domains using BSM as barcodes. 2] With this lineage information, we will study the origins of BSM
mutations in FCD, by recruiting new patients, performing both targeted and unbiased sequencing, and
identifying novel causes. 3] We will functionally validate putative deleterious alleles in animal models for
both ‘single-hit’ and ‘two-hit’ causes. The goal is to achieve a mechanistic understanding of the
extent of BSM in control individuals, to reconstruct neural lineages and to identify novel mechanisms in
developmental brain disease.

## Key facts

- **NIH application ID:** 10466904
- **Project number:** 5R01MH124890-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOSEPH G GLEESON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $312,481
- **Award type:** 5
- **Project period:** 2021-08-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466904

## Citation

> US National Institutes of Health, RePORTER application 10466904, Origins of Brain Somatic Mosaicism in Developmental Brain Disease (5R01MH124890-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466904. Licensed CC0.

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