Somatic Mutations and Cell Lineage in the Human Brain

Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism.

In this study we use whole genome, RNA, and ATAC sequencing of single cells and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the  human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain through cell type-specific analyses.

• Study Design:
  • Case-Control
• Study Type:
  • Case Set
  • Case-Control
• Total number of consented subjects: 24
• Subject Sample Telemetry Report (SSTR)

Our current single neuron whole genome sequencing protocol requires that we use frozen brains, however, we are not able to produce high quality sequencing data from neurons isolated from all frozen brains. Thus, the first criterion was that we could obtain high quality WGS from single neurons isolated from the brain. For control samples, we used brains from individuals of different ages and sexes. There were a limited number of frozen brains for individuals who had Cockayne syndrome or Xeroderma pigmentosum, so we used what was available.

Version 1 of this study included whole genome sequencing data of 161 neurons from the prefrontal cortex or dentate gyrus and 20 bulk tissue samples from the brain, heart, or liver from 24 subjects, including 15 neurotypical subjects, 6 subjects with Cockayne syndrome, and 3 subjects with Xeroderma pigmentosum.

Version 2 of this study adds additional data from a few of the neurotypical subjects that were part of the original release. This includes deeper genome sequencing of select brain regions from 3 subjects as well as genome sequencing from additional tissues (heart, liver, and spleen), and single cell RNA and ATAC sequencing of prefrontal cortical brain tissue in one subject.

• Primary Phenotype: Cockayne Syndrome
• Xeroderma Pigmentosum

• Principal Investigator
  • Christopher A. Walsh, MD, PhD. Boston Children's Hospital, Boston, MA, USA.
  • Peter J. Park, PhD. Harvard Medical School, Boston, MA, USA.
• Funding Sources
  • R01NS032457. National Institutes of Health, Bethesda, MD, USA.
  • U01MH106883. National Institutes of Health, Bethesda, MD, USA.
  • HHMI. Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, USA.