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Mutations in neurons accumulate as we age; may explain normal cognitive decline & neurodegeneration

Single-cell whole-genome analysis shows steady increase in mutations over time, some implicating oxidative damage

Boston Children's Hospital

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IMAGE: This graph of all 161 neurons in the dataset, sampled at different ages, shows the quantity and type of mutations they carry. From left to right, by ascending age in... view more 

Credit: Reprinted with permission from MA Lodato et al., Science Dec. 7, 2017, DOI: 10.1101/221960

Scientists have wondered whether somatic (non-inherited) mutations play a role in aging and brain degeneration, but until recently there was no good technology to test this idea. A study published online today in Science, led by researchers from Boston Children's Hospital and Harvard Medical School, used whole-genome sequencing of individual neurons and found strong evidence that brain mutations accumulate as we age. They also found that mutations accumulate at a higher rate in people with genetic premature aging disorders causing early brain degeneration.

"It's been an age-old question as to whether DNA mutations can accumulate in neurons -- which usually don't divide -- and whether they are responsible for the loss of function that the brain undergoes as we get older," says Christopher A. Walsh, MD, PhD, chief of the Division of Genetics and Genomics at Boston Children's and co-senior author on the paper. "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."

Testing neurons one by one

The research team tested DNA from 161 single neurons, taken from postmortem samples from the NIH NeuroBioBank. They came from 15 neurologically normal people of different ages (4 months to 82 years) and nine people with one of two accelerated aging and early-onset neurodegenerative disorders: Cockayne syndrome and xeroderma pigmentosum.

Using the latest experimental and data analysis techniques, the team was able to detect mutations as small as single-letter changes in each neuron's genetic code. Each cell had to have its genome amplified -- by generating a multitude of copies -- before its DNA sequence could be determined, and a large amount of data had to be analyzed.

"Because many experimental artifacts arise during the single-cell experiments, a new computational method that can distinguish true mutations from the experimental noise was critical to the success of the project," says Peter J. Park, PhD, of Harvard Medical School's Department of Biomedical Informatics (DBMI), the paper's other co-senior author.

The neurons tested came from two areas of the brain implicated in age-related cognitive decline: the prefrontal cortex (the part of the brain most highly developed in humans) and the dentate gyrus of the hippocampus (a focal point in age-related degenerative conditions like Alzheimer's).

In neurons from neurologically normal people, the number of genetic mutations increased with age in both brain areas. However, mutations accumulated at a higher rate in the dentate gyrus. The researchers think this may be because the neurons have the ability to divide, unlike their counterparts in the prefrontal cortex.

In neurons from people with Cockayne syndrome and xeroderma pigmentosum, there was an increase in mutations in the prefrontal cortex over time -- more than two-fold compared to the normal rate. Additionally, the researchers found that the portions of the genome that neurons used the most accumulated mutations at the highest rate, with help from collaborators at WuXi NextCODE.

The aging genome

The researchers coined the term "genosenium" -- combining the concepts of genome and senescence/senility -- to capture the idea of gradual and inevitable accumulation of mutations contributing to brain aging.

The mutations themselves fell into three categories. "We were able to take all the mutations we found and use mathematical techniques to deconstruct them into different types of DNA changes," says Michael Lodato, PhD, one of six co-first authors on the paper. "It's like hearing an orchestra and teasing out the different instruments."

One category of "clocklike" mutations was strictly aging-related, accumulating like clockwork in both brain areas, and independent of disease status. Another type did not correlate with age, except in the dentate gyrus, where mutation numbers in dividing neurons did increase over time.

A parallel with cancer?

The third type was associated with oxidative damage to DNA and faulty DNA repair; it increased with age and was seen in high numbers in Cockayne syndrome and xeroderma pigmentosum neurons, and to a lesser extent in normal neurons.

"This last finding convinced me I need more anti-oxidants," quips Walsh, who is also a Howard Hughes Medical Institute Investigator and the Bullard Professor of Pediatrics at Harvard Medical School. "Overall, it raises a question as to whether neurodegenerative diseases are like cancer, relating ultimately to DNA mutation."

The researchers are now turning their sights on other neurodegenerative disorders. "The technology we used can be applied to any degenerative disease of the brain," says Walsh.

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Michael Lodato, Rachel Rodin and Michael Coulter of Boston Children's and Craig Bohrson, Alison Barton and Minseok Kwon of Harvard Medical School's DBMI were all co-first authors on the study. Other coauthors were: Maxwell Sherman, Carl Vitzthum and Lovelace Luquette of HMS DBMI; Chandri Yandava, Pengwei Yang and Thomas Chittenden of the WuXi NextCODE Advanced Artificial Intelligence Research Laboratory; and Nicole Hatem, Steven Ryu and Mollie Woodworth of Boston Children's.

The study was supported by the National Institutes of Health (K99 AG054749 01, F30 MH102909, 1S10RR028832-01, T32HG002295, U01MH106883, P50MH106933, R01 NS032457, U01 MH106883), the Harvard/MIT MD-PHD program, the Stuart H.Q. and Victoria Quan Fellowship in Neurobiology, the Allen Discovery Center program through The Paul G. Allen Frontiers Group and the Howard Hughes Medical Institute.

About Boston Children's Hospital

Boston Children's Hospital, the primary pediatric teaching affiliate of Harvard Medical School, is home to the world's largest research enterprise based at a pediatric medical center. Its discoveries have benefited both children and adults since 1869. Today, more than 2,630 scientists, including nine members of the National Academy of Sciences, 17 members of the National Academy of Medicine and 11 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Vector and Thriving blogs and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.

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