Washington: A single neuron in a normal adult brain may carry more than a thousand genetic mutations some of which can lead to disease, new research has found. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. “We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated,” said Christopher Walsh, a Howard Hughes Medical Institute (HHMI) investigator at Boston Children’s Hospital.
It’s not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease. But by tracing the distribution of mutations among cells, Walsh and his colleagues are already learning new information about how the human brain develops.
“The genome of a single neuron is like an archaeological record of that cell,” said Walsh, who led the research. “We can read its lineage in the pattern of shared mutations. We now know that if we examined enough cells in enough brains, we could deconstruct the whole pattern of development of the human brain,” said Walsh.
In the study, scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. The scientists also sequenced DNA that they isolated from cells in each individual’s heart.
Walsh’s group teamed up with Peter Park, a computational biologist at Harvard Medical School, and Semin Lee, a postdoctoral fellow in Park’s group. What they found was that every neuron’s genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell.
Based on the types and locations of the mutations they found in the neurons, the scientists concluded that most DNA damage had occurred during the unwinding and copying process. While most of the mutations in the neurons were unique, a small percentage did turn up in more than one cell. That signalled that those mutations had originated when future brain cells were still dividing, a process that is complete before birth.
Those early mutations were passed on as cells divided and migrated, and the scientists were able to use them to reconstruct a partial history of the brain’s development. The scientists also found that a particular neuron might be more closely related to a cell in the heart than to a neighbouring neuron.
The scientists say intermingling cells with different developmental origins might protect the brain from the effects of early-arising, potentially harmful mutations.
Although most of the mutations the scientists catalogued were harmless, they did encounter mutations that disrupted genes that, when impaired throughout the brain, can cause disease. The finding was published in the journal Science.