Talk Title: "Somatic mutation and genomic diversity in the human cerebral cortex.”

Abstract: The role of ‘somatic’ mutations--arising during brain development--in human disease, is not known, nor is the potential role of genomic variation between neurons as a source of normal neuronal diversity.  Hemimegalencephaly and focal cortical dysplasia are two developmental brain disorders that affect part but not all of the cortex, causing intractable epilepsy that requires surgical resection.  Direct analysis of resected brain tissue reveals causative somatic mutations that activate mTOR: activation of AKT3 by mutation or duplication, activating mutation in PIK3CA, PIK3R, and mTOR itself, as well as loss of function of DEPDC5 and TSC2, which encode negative regulators of mTOR.  Preliminary data also shows that somatic mosaic mutations also represent a fraction of the deleterious mutations identified in postmortem ASD brain.

In parallel experiments we have used methods to isolate single neuronal nuclei from human postmortem brain, and amplify and sequence the genomes of single neurons. We have used single cell WGS to study LINE element retrotransposition, CNV, and SNV in single cerebral cortical neurons. Our data suggest that typical neurons from normal brain have many somatic mosaic mutations and that clonal genetic mutations in human brain represent a durable record of the brain’s development.  It remains to be determined what role somatic mutation might contribute to other complex neuropsychiatric diseases.

Supported by the NIMH, NINDS, and HHMI.