Christopher Walsh

Our lab is well suited to participate in this project on somatic mutation across human tissues, because of our longstanding interest in 1] somatic mutation in human brain, 2] cell lineage in human brain, and 3] innovative genomic technologies. Previous and ongoing work from our lab studies genetic disorders of human cerebral cortical development associated with epilepsy, intellectual disability, and other learning disorders. Mutations in these essential genes disrupt the normal development and function of the human brain and cause Mendelian pediatric brain diseases, manifesting as autism and epilepsy, as well as intellectual disability and other learning disorders. We have identified more than three-dozen human disease genes over the course of 20 years. Recent work from our lab has pioneered the analysis of clonal somatic mutations as causes of disease, and we have revealed roles for somatic mutations in pediatric focal epilepsy, adult temporal lobe epilepsy, autism spectrum disorders, and schizophrenia. We have also analyzed rates of occurrence of somatic mutations in normal brain cells, and revealed the ongoing accumulation of somatic mutations with age in single human neurons, even though these cells do not divide in adulthood. We most recently described additional increases in neuronal somatic mutations in neurons from Alzheimer disease brain and other neurodegenerative disorders.

Our work on single cell genomics has resulted in an expansion of our research into brain aging and degenerative diseases, as exemplified by recognition of the lab with the Pignolo Award for Aging Research from the Univ. of Pennsylvania in 2018. Before becoming Chief of the Division of Genetics and Genomics at BCH, I served as Director of the Harvard-MIT MD-PhD training program for three years, and have been active on many committees and as an advisor for this program for 20 years. I have been involved in post-doctoral training of over 50 MDs, PhDs, and MD/PhDs and more than 20 pre-doctoral students. Most of these trainees continue to be involved in medical research after leaving my lab, many starting their own labs. I am enthusiastic to continue in my role as a mentor to clinical and research trainees.

Ongoing Laboratory Projects

1. Howard Hughes Medical Institute (HHMI)
   Walsh (PI)
   10/01/02-10/31/31
   HHMI Investigator in patient-oriented research; The major goals of this project are to describe syndromes in which the development of the human brain is abnormal, and determine the genetic basis of these syndromes.
2. R01NS035129 (NIH/NINDS)
   Walsh (PI)
   07/01/20-02/28/25
   Human epilepsy genetics: neuronal migration disorders; The major goals of this project are to map and clone autosomal recessive neuronal migration disorders.
    
3. R01NS032457 (NIH/NINDS)
   Walsh (PI)
   07/01/20-06/30/25
   Cell Identity Determination In Human Brain: Somatic mutation and cell lineage; The goal of this study is to use somatic mutations to trace normal cell lineage in the human cerebral cortex.
    
4. R01AG070921 (NIH/NIA)
   Walsh (PI)
   04/01/21-03/31/26
   Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain; The major goal of this grant is to determine the rates and signatures of somatic variants in single neurons and single glial cells across the aging and Alzheimer brain.
    
5. Paul Allen Frontiers Group
   Walsh (PI)
   04/01/21-03/31/25
   Center for the Study of Human Brain Evolution; The major goal of this project is to study the evolution of the human brain.
    
6. UG3NS132138 (NIH/NINDS)
   Walsh (PI)
   04/01/23-03/31/25
   Development of an efficient high throughput technique for the identification of high-impact non-coding somatic variants across multiple tissue types.; The major goal of this project is to develop an efficient high throughput technique for the identification of high-impact non-coding somatic variants across multiple tissue types.
    
7. Simons Foundation Autism Research Initiative
   Walsh (PI)
   09/01/22-08/31/25
   Identification of somatic mutations in regulatory regions in autism; The major goal of this grant is to study somatic mutations in autism brain
    
8. John Templeton Foundation
   Walsh (PI)
   09/01/22-8/31/25
   One brain, many genomes: How the genomic individuality of cells defines human individuality The major goals of this project is to better understand how somatic mutations impact the human brain.