You Contain Multitudes: Somatic Mutation and Genomic Diversity in Human Brain
Christopher A. Walsh, M.D., Ph.D.
Bullard Professor of Pediatrics and Neurology
Harvard Medical School
Christopher Walsh is Bullard Professor of Pediatrics and Neurology at Harvard Medical School, Chief of the Division of Genetics at Boston Children's Hospital, and an Investigator of the Howard Hughes Medical Institute. He completed his M.D. and Ph.D. degrees at the University of Chicago. After a neurology residency and chief residency at Massachusetts General Hospital, he completed a research fellowship in genetics at Harvard Medical School. Dr. Walsh has studied patterns of neural stem cell division, cell fate choices, and cell migrations in the developing cerebral cortex, and has pioneered the analysis of human genetic diseases that disrupt the cerebral cortex. Among his awards are a Jacob Javits Neuroscience Investigator Award from the NINDS, the Dreifuss-Penry Award from the American Academy of Neurology, the Derek Denny-Brown Award from the American Neurological Association, the Wilder Penfield Award of the Middle Eastern Medical Assembly, and the Research Award from the American Epilepsy Society.
Although it had long been assumed that the genomes of all neurons are identical, recent work shows that every cell division causes mutations even during normal development, and that postmitotic neurons continue to accumulate mutations throughout life even in the absence of cell division. Recent studies implicate clonal somatic mutations in some brain malformations, other pediatric focal epilepsy and adult temporal lobe epilepsy, and some cases of autism spectrum disorders and schizophrenia. These mosaic causes of neuropsychiatric disease illuminate mutations that are different than those that create risk for these diseases when present in all cells, suggesting they may be important for understanding the mechanisms of these conditions. Reading out functionally silent developmental mutations reveals a post-mortem, forensic cell lineage map that records the cell divisions that generate each person, and differences in the ways that different humans develop.
Sequencing the DNA genome from a single neuron reveals a universe of genomic diversity, with transposon insertion, copy number variants, and hundreds of single nucleotide variants (SNV) distinguishing the genome of one neuron from another. Surprisingly, neurons accumulate about 20 mutations per year in human brain, with more than a thousand such mutations present in old age, even though neurons do not undergo cell division. SNV accumulate faster in rare genetic disorders associated with precocious neurodegeneration, and in more common forms of degeneration as well such as Alzheimer’s disease, suggesting that this age-related mutation is likely relevant to many forms of age-related neurodegeneration.
1] Defining somatic mutations, present in some cells of the body but not in the germ cells.
2] Describing roles of somatic mutations in neurological disorders that are not associated with cancer
3] Describing changes to the genomes of single brain cells with age.
This page was last updated on Thursday, February 15, 2024