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Research Overview

Dr. Walsh’s research focuses on the development, evolution, and function of the human cerebral cortex, including analysis of human genetic diseases that disrupt the structure and function of the cortex. His laboratory has identified genetic causes for more than two-dozen brain diseases of children, associated with autism, intellectual disability, seizures, and cerebral palsy, and has discovered that some of these disease genes were targets of the evolutionary processes that shaped the human brain. Recent work has focused on somatic mutations in the brain, which are present in some brain cells, but not shared by all brain cells, because they occur after fertilization, during the mitotic divisions that generate the brain. The lab has developed methods for analyzing the entire genome of single cells, and has applied that to the systematic analysis of the extent to which the genome of one neuron differs from that of another neuron.

Laboratory Projects

  1. Genetics of brain malformations: We have active ongoing gene discovery projects to identify recessive mutations affecting human brain development, as well as somatic mutations in brain tissue resected to control epilepsy.

  2. Genetics of autism spectrum disorders: We are studying recessive mutations associated with autism spectrum disorders, especially noncoding mutations. We are also studying DNA directly isolated from postmortem autism brains to study somatic mutation in autism brain.

  3. Cell lineage in the human brain: Every time a cell divides, 10-100 somatic mutations occur, so that these somatic mutations represent a permanent record of the cell divisions that give rise to each human brain. We are using single cell, whole genome sequencing to develop a “rough draft” of the cell lineage of the human brain, and would like to examine changes in this development that occur in diseases with abnormal brain development.

  4. Single cell analysis of human brain development: We are interested to study degenerative diseases to determine which ones show increased rates of somatic mutation, which may help us understand the mechanism of neuronal degeneration. We are also profiling mRNA in single brain progenitor cells.

To read more about our work, click here to visit our lab website.

Research Background

Christopher A. Walsh is Bullard Professor of Pediatrics and Neurology at Harvard Medical School, Chief of the Division of Genetics and Genomics at Boston Children's Hospital, and an Investigator of the Howard Hughes Medical Institute. Dr. Walsh completed MD and PhD degrees at the University of Chicago, neurology residency at Massachusetts General Hospital, and postdoctoral training at Harvard in Genetics. He has held the Bullard Professorship since 1999 and joined Children’s Hospital as Chief of Genetics in 2006. His lab’s work has been recognized by a Jacob Javits Award from the NINDS, the Dreifuss-Penry Award from the American Academy of Neurology, the Derek Denny-Brown and the Jacoby Awards from the American Neurological Association, the American Epilepsy Society’s Research Award, the Krieg Award from the Cajal Club, and the Wilder Penfield Award from the Middle Eastern Medical Assembly. He is an elected member of the American Neurological Association, the American Association of Physicians, the National Academy of Medicine (formerly the Institute of Medicine), and the American Association for the Advancement of Sciences.

Selected Publications

  1. Bae* BI, Tietjen* I, et al. Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science 2014 Feb 14; 343(6172):764-8. PMID: 24531968
  2. Jamuar SS, et al. Somatic mutations in cerebral cortical malformations. New Engl. Jour. Med. Aug 21, 2014; 371(8):733-43. PMID: 25140959. Johnson* MB, Wang* PP, et al. Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nature Neurosci. 2015 May;18(5):637-46. doi: 10.1038/nn.3980. PMID: 25734491
  3. Lodato* M, Woodworth* M, Lee* S et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015 Oct 2 350 (6256): 94-98. PMID: 2643012

Publications