Allen Discovery Center uncovers the role of accumulating mutations in the brain
January 18, 2018
Researchers at the Allen Discovery Center at Boston Children’s Hospital and Harvard University have published a technical tour-de-force that may help explain neurodegeneration and everyday “senior moments,” thanks to single-neuron whole-genome sequencing. The work is published in the journal Science.
“It’s been an age-old question as to whether DNA mutations can accumulate in neurons and whether they are responsible for the loss of function that the brain undergoes as we get older,” says Christopher A. Walsh, M.D., Ph.D., Allen Discovery Center leader and chief of the Division of Genetics and Genomics at Boston Children’s Hospital. “It hasn’t been possible to answer this question before, because we couldn’t sequence the genome of a single cell, and each mutation accumulated is unique to each cell.”
Mutations can take place not just in parent-to-child inheritance, but also in individual cells in the course of regular cell division. These mutations, called somatic mutations, have historically been much harder to study. By replicating the DNA many times over, the research team was able to observe somatic mutations in individual cells at extremely high resolution, even picking up on single nucleotide changes.
Researchers tested DNA from 161 individual neurons, taken from 15 neurologically normal people of different ages and nine people with Cockayne syndrome or xeroderma pigmentosum: two genetic disorders that cause premature aging and early brain degeneration. The samples came from two parts of the brain associated with cognition and memory, the prefrontal cortex and dentate gyrus of hippocampus.
Taken together, the analysis shows a higher accumulation of mutations in neurons in the brains of people with one of the two disorders, when compared to neurologically normal patients. Interestingly, researchers found that mutations occur not just in dividing cells, but also in cells that never divide, and that people with disorders causing early brain degeneration acquire mutations in their neurons at a faster rate.