Spontaneous mutations that occur in DNA before birth — part of cell division and reproduction in the growing brain — can predispose a person to neurodegenerative diseases in adulthood and may be more common than thought, a research team led by the University of Cambridge suggests.
The study, “High prevalence of focal and multi-focal somatic genetic variants in the human brain,” was published in Nature Communications.
The causes of neurodegenerative diseases are essentially unknown. Most are sporadic — meaning they simply appear in a person — although hereditary cases are known and well-documented.
Clinical presentation of hereditary forms is frequently like the sporadic types, suggesting that common biological processes underlie both forms of neurodegenerative diseases.
“As the global population ages, we’re seeing increasing numbers of people affected by diseases such as Alzheimer’s, yet we still don’t understand enough about the majority of these cases,” Patrick Chinnery, the study’s lead author, said in a press release.
“Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?” added Chinnery, who is also with the Medical Research Council (MRC) Mitochondrial Biology Unit and a professor in the Department of Clinical Neurosciences at Cambridge.
Chinnery’s team hypothesized that spontaneous mutations within specific clusters of brain cells could contribute to the misfolded protein synthesis found in neurodegenerative diseases, and that such molecular phenomenon could have the potential to spread throughout the brain as a person aged.
Investigators used frozen brains acquired from the Newcastle Brain Tissue Resource, part of MRC’s U.K. Brain Banks Network. Among the 54 brains examined, 20 were from people with Alzheimer’s, 20 with those Lewy body dementia, and 14 who had no family history of any neurodegenerative disorder and showed features consistent with normal aging (samples in this group were from healthy people age 65 and older).
A total of 173 brain tissue samples were examined.
Using a novel sequencing technique, the researchers sequenced — more than 5,000 times — 102 genes known to cause or put a person at risk of a neurodegenerative disease. Around 611,285 cells were sequenced.
The team reported 39 somatic mutations in 27 of the 54 examined brains, including both healthy (control) and diseased samples.
Somatic mutations are spontaneous genetic mutations (i.e., errors in DNA) acquired by a cell and occurring after conception. As cell division progresses during embryonic development, mutated cells will continue to be produced until the body that harbors those cells dies. But these somatic mutations cannot be passed to offspring because they do not occur in germ cell DNA, which are the cells that create sperm or egg.
Eighteen spontaneous mutations (56.4% of the total 39 detected “genetic errors”) were present in only one brain region — although in many cells there, while 17 others (43.6% of 39 mutations) occurred in more than one brain region.
Because the single region mutations occurred in numerous cells, it is highly probable that such DNA errors happened during embryo development, the scientists said.
Researchers then used a simplified mathematical model of neurodevelopment to help them understand their data. They inferred a mutation rate, simulated brain development using their model, and found that each individual tended to have 100,000 to 1 million disease-related mutated cells, suggesting that these mutations occur often in the general population.
Frame-shift mutations, i.e., an insertion or deletion of genetic material into the DNA sequence, in cell proliferation and differentiation disorder genes were detected in 40% of samples taken from people with Lewy body dementia, in comparison to 7% in those from the control group.
“These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history,” Chinnery said. “These mutations likely form when our brain develops before birth — in other words, they are sat there waiting to cause problems when we are older.
“Our discovery may also explain why no two cases of Alzheimer’s or Parkinson’s are the same,” he added. “Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”