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Updated: Feb 10, 2026

Characterizing Mutational Load and Clonal Composition of Human Blood
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Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy.

Sattar Khoshkhoo1,2,3, Mingyun Bae2,4, Yilan Wang2,5

  • 1Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA.

Biorxiv : the Preprint Server for Biology
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Somatic variants in Ras-MAPK pathway genes are common in mesial temporal lobe epilepsy (MTLE), a frequent focal epilepsy. These acquired genetic changes in the hippocampus influence epilepsy risk and surgical outcomes.

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Area of Science:

  • Neuroscience
  • Genetics
  • Epilepsy Research

Background:

  • Mesial (medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy.
  • Drug-resistant MTLE is treated with anterior temporal lobe resection, often revealing hippocampal sclerosis (HS).
  • While germline genetics play a minor role, somatic variants in Ras-MAPK pathway genes are suspected contributors to MTLE.

Purpose of the Study:

  • To investigate the prevalence, clinical relevance, and biological mechanisms of somatic Ras-MAPK variants in MTLE.
  • To determine if somatic variants are enriched in MTLE surgical specimens compared to controls.
  • To explore the association between somatic variant burden and surgical outcomes in MTLE.

Main Methods:

  • Targeted duplex sequencing of hippocampal DNA from 462 MTLE surgical resections and controls.
  • Analysis of somatic variants in Ras-MAPK pathway genes, including novel genes.
  • Single-nucleus RNA sequencing and functional validation of identified variants in cellular models.

Main Results:

  • Over 40% of MTLE specimens showed activating Ras-MAPK variants in known and novel genes, with significant enrichment versus controls.
  • Eight Ras-MAPK genes exhibited positive clonal selection in MTLE.
  • Increased somatic variant burden correlated with worse surgical outcomes and was linked to older seizure onset and HS pathology.

Conclusions:

  • Somatic Ras-MAPK variants are prevalent in MTLE and may arise early in development.
  • These variants are enriched in specific hippocampal cell types and influence gene expression, potentially driving hyperexcitability.
  • Acquired risk factors and somatic Ras-MAPK variants may interact through clonal competition to increase epilepsy risk.