Five Points Lecture: Christopher A. Walsh, MD, PhD
Where: New York Genome Center
101 Sixth Ave.
646-977-7000 Price: Free
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Talk Title: “One Brain, Many Genomes: Somatic Mutation and Genomic Diversity in the Human Cerebral Cortex”
The role of ‘somatic’ mutations—those arising during prenatal development–in human disease is not well understood, nor do we understand the potential role of genomic variation as a source of normal neuronal diversity. Analysis of blood DNA with high coverage panel sequencing suggests that >25% of undiagnosed patients with brain malformations show causative mosaic mutations in known genes. Hemimegalencephaly (HME) and Focal Cortical Dysplasia (FCD) represent epileptic brain malformations caused by mosaic mutations resulting in mTOR pathway activation, but the mutation is typically present in only a minority of cells (1-30%) within the brain lesion and undetectable in blood DNA. These data show that mosaic mutations causing disease can occur either before, or after, separation of neural tissue from non-neural tissue.
Similarly, analysis of standard whole exome sequence of patients with autism spectrum disorders (ASD) with a new calling algorithm shows that 5-10% have mosaic mutations detectable in blood. Analysis of postmortem ASD brains shows that about 10% of likely causative mutations are mosaic in brain, sometimes unevenly distributed between brain regions. Such somatic mutations have the potential to create a mosaic brain that could underlie other neuropsychiatric diseases, though this remains untested.
In parallel experiments analysis of single human neurons, using single cell whole genome amplification and sequencing, reveals that somatic LINE element insertions can be found in up to half of the neurons in normal cerebral cortex; large CNV are also frequent; and hundreds to thousands of SNV occur in each single cerebral cortical neuron. Clonal somatic SNV represent a permanent lineage map of the human brain of quite high density, revealing unique patterns of clonal structure in human brain. On the other hand, nonclonal somatic mutations appear to be driven by transcriptional damage, and occur at even higher rates in rare genetic syndromes associated with precocious neuronal degeneration.
Supported by the NIMH, NINDS, and HHMI.Buy tickets/get more info now