(Erik Jacobsen, Threestory Studio. Used with permission.)
DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.
Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.
Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.
“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.”
This tracking capability represents a significant advance for genetics research. And for neuroscientists, it provides a new way to study both the normal brain and brain disorders like epilepsy, autism and intellectual disability.
Walsh and colleagues studied normal brain tissue from a teenage boy who had passed away from other causes. Sampling in more than 30 brain locations, they used deep, highly sensitive, whole-genome sequencing of one neuron at a time – unlike usual methods, which sequence thousands or millions of cells mixed together and simply read out an average.
The blue and green boxes indicate different degrees of mosaicism (based on proportion of cells affected) in the left half of this teen’s normal brain. The blue shaded area indicates that retrotransposon mutation #1 (blue boxes) is limited to a focal area in the middle frontal gyrus. The empty boxes indicate areas where mutation #1 was not detected. (Courtesy Gilad Evrony, PhD, Boston Children’s Hospital)
Next, using technology developed by Alice (Eunjung) Lee in the lab of Peter Park, PhD, at Harvard Medical School’s Center for Biomedical Informatics, they zeroed in on inserted bits of DNA caused by retrotransposons, one type of mutation that can arise as the brain develops. These essentially served as markers that allowed cell lineages to be traced.
“Our findings are intriguing because they suggest that every normal brain may in fact be a mosaic patchwork of focal somatic mutations, though in normal individuals most are likely silent or harmless,” says Gilad Evrony, PhD, in the Walsh Lab.
This model illustrates the origins of two somatic retrotransposon mutations during prenatal development and their subsequent dissemination in the brain. Insertion #2 (in green) occurred soon after conception; #1 (in blue) happened sometime later during brain development. The ‘pie slices’ show a closeup of the layers of the cerebral cortex. Later in development, additional somatic mutations occurred inside insertions #1 and #2, creating new, smaller sublineages of cells. (Courtesy Gilad Evrony, PhD)
A parallel study from Walsh’s lab in 2014 used single-neuron sequencing to find copy number variants – a different type of mutation affecting the number of copies of chromosomes or chromosome fragments. It, too, found the mutations to be present in normal brains as well as neurologically diseased brains.
Walsh and others speculate that some somatic brain mutations might play a role in autism, epilepsy, schizophrenia and other unsolved neuropsychiatric diseases whose causes are mostly still a mystery.
“It is possible that a whole new class of brain disorders may exist that has not been previously recognized,” says Evrony. “In such disorders, a somatic mutation may subtly affect only one small part of the brain involved in a specific ability, for example language, while sparing the rest of the brain.”
Read more:
- Tracking subtle brain mutations, systematically
- Deep sequencing finds hidden causes of brain disorders
