CAMBRIDGE, U.K.—For those in the United States and some other countries, the notion of a spelling bee competition is familiar. But what if the stakes were higher than just losing a spelling competition? What if the stakes were your memories, personality and more? What if the “bee” were “dee” instead, as in D—for dementia.
And perhaps for DNA as well.
Because, according to work led by researchers at the University of Cambridge, many cases of dementia may arise from non-inherited DNA ‘spelling mistakes’ rather than genes passed on by one’s biological parents. According to the university, only a small proportion of cases of dementia are thought to be inherited, with the cause of the vast majority being unknown—at least, perhaps unknown until now. Because if the work recently published by the researchers in the journal Nature Communications (under the title “High prevalence of focal and multi-focal somatic genetic variants in the human brain”) is right, the explanation for most cases of dementia might instead be spontaneous errors in our DNA that arise as cells divide and replicate, rather than genetic inheritance.
Also, the findings suggest that for many people with neurodegenerative diseases—such as Alzheimer’s disease and Parkinson’s disease—the roots of their condition will trace back to their time as an embryo developing in the womb.
As the abstract for the paper notes: “Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.”
Putting it in simpler terms, the university notes that in common neurodegenerative diseases, toxic proteins build up in the brain, destroying brain cells and damaging brain regions, which leads to symptoms including personality changes, memory loss and loss of control. Only around one in 20 patients has a family history of dementia.
A team of researchers led by Prof. Patrick Chinnery from the Medical Research Council (MRC) Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the University of Cambridge hypothesized that clusters of brain cells containing spontaneous genetic errors could lead to the production of misfolded proteins with the potential to spread throughout the brain, eventually leading to neurodegenerative disease.
“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,” said Chinnery. “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?”
To test their hypothesis, the researchers examined 173 tissue samples from the Newcastle Brain Tissue Resource, part of the MRC’s UK Brain Banks Network. The samples came from 54 individual brains: 14 healthy individuals, 20 patients with Alzheimer’s and 20 patients with Lewy body dementia, a common type of dementia estimated to affect more than 100,000 people in the United Kingdom.
The team used a new technique that allowed them to sequence 102 genes in the brain cells more than 5,000 times. These included genes known to cause or predispose to common neurodegenerative diseases. They found ‘somatic mutations’ (spontaneous, rather than inherited, errors in DNA) in 27 out of the 54 brains, including both healthy and diseased brains.
Together, these findings suggest that the mutations would have arisen during the developmental phase—when the brain is still growing and changing while the embryo is growing in the womb.
Combining their results with mathematical modeling, their findings suggest that ‘islands’ of brain cells containing these potentially important mutations are likely to be common in the general population.
“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,” explained Chinnery. “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. Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”
Chinnery noted that further research is needed to confirm whether the mutations are more common in patients with dementia. It is, of course, too soon to predict whether this research might aid diagnosis or treatment, but the university says that the research “endorses the approach of pharmaceutical companies who are trying to develop new treatments for rare genetic forms of neurodegenerative diseases.”
But if dementia tends to be very specific to an individual’s genetics, what might this mean for research into broadly applicable cures for Alzheimer’s disease and other dementias? As Chinnery noted, though, the news might not be all bad on that front: “The question is: how relevant are these treatments going to be for the ‘common-or-garden’ variety without a family history? Our data suggests the same genetic mechanisms could be responsible in non-inherited forms of these diseases, so these patients may benefit from the treatments being developed for the rare genetic forms.”
SOURCE: University of Cambridge