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HEALTH Thousands of Mutations Accumulate in the Human Brain Over a Lifetime
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  1. #1
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    3 Thousands of Mutations Accumulate in the Human Brain Over a Lifetime

    For links see article source.....
    Posted for fair use.....
    https://www.the-scientist.com/?artic...er-a-Lifetime/

    Thousands of Mutations Accumulate in the Human Brain Over a Lifetime

    Single-cell genome analyses reveal the amount of mutations a human brain cell will collect from its fetal beginnings until death.

    By Ruth Williams | December 7, 2017

    Two studies in Science today (December 7)—one that focuses on prenatal development in humans, the other on infancy to old age—provide insights into the extent of DNA sequence errors that the average human brain cell accumulates over a lifetime. Together, they reveal that mutations become more common as fetuses develop, and over a lifetime a person may rack up more than 2,000 mutations per cell.

    “I think these are both very powerful technical papers, and they demonstrate how single-cell sequencing . . . can reliably detect somatic changes in the genomes of human neurons,” says neuroscientist Fred Gage of the Salk Institute in La Jolla who was not involved in either study.

    “What’s cool about [the papers] is that they show two different ways that one can look at somatic mutations in single human neurons . . . and yet they get consistent results,” says neuroscientist Michael McConnell of the University of Virginia School of Medicine.

    Cells of the human body acquire mutations over time, whether because of errors introduced during DNA replication or damage incurred during transcription and other cellular processes. But, until recent technological developments enabled whole genome sequencing from the miniscule quantities of DNA found inside single cells or small clones of the same cell, investigating the nature and extent of such somatic mutations—and the resulting tissue mosaicism—was practically impossible.

    Within the now burgeoning field of somatic mutation analyses, the brain is a particular area of interest. That’s because unlike organs such as the skin and gut where cells are replaced daily, the brain’s neurons, once established in the fetus, for the most part stick around for life. Somatic mutations in these cells, then, could affect brain function, behavior, and the propensity for disease long-term. Indeed, it’s thought that such mutations could influence the development of diseases such as schizophrenia, autism, and Tourette’s, which have unclear etiologies, says Yale School of Medicine’s Flora Vaccarino who authored one of the studies.

    See “Advancing Techniques Reveal the Brain’s Impressive Diversity”

    But before studying pathologies associated with somatic mutations, Vaccarino says, “we wanted to know what is the normality of this phenomenon . . . When does it occur? Are there some stages of development that are more susceptible to somatic mutation? That was the aim of our study.”

    Vaccarino’s team examined the genomes of single cells taken from the post mortem forebrains of three human fetuses (15 weeks, 17.5 weeks, and 21 weeks post conception). Instead of amplifying the genomes of the cells directly for sequencing—which, it has been suggested, might introduce DNA artifacts—her team took advantage of the fetal neuronal cells’ ability to replicate and grew small clones from the individual brain cells to generate enough DNA for sequencing.

    They found that, on average, each cell contained between 200 and 400 single nucleotide variations (SNVs), which were, largely speaking, distributed randomly across the genome. A small percentage of the SNVs were also present in spleen cells, indicating that they occurred prior to the differentiation of mesodermal and neuroectodermal tissues—that is, before embryonic gastrulation.

    By determining the numbers of mutations in the differently aged fetuses, and knowing the average speed of cell divisions, the team was able to calculate the average mutation rate during neurogenesis as 5.1 mutations per cell, per division. Extrapolating their calculations further back in development, they also determined that in the early embryo the mutation rate was 1.3 mutations per cell per division.

    The ramping up of the mutation rate during neurogenesis, says Gage, is not surprising. From an evolutionary point of view, he explains, it makes sense that “protecting the genome at embryonic stages is more imperative than at the later stages of differentiation,” where mutations would affect far fewer cells. But, while that’s a sensible theory, he adds, “that the researchers give evidence of it, is important.”

    The second study looked at single cells from the post mortem brains of 15 people aged four months to 82 years. Because by these ages most neurons have lost their ability to replicate, clonally expanding the cells in culture was not possible. The team therefore extracted DNA directly from each cell and amplified it for sequencing.

    The researchers found that a neuron “starts with around 600 mutations” in an infant, “and the mutations accumulate about one every two weeks, so that by the time a neuron is 80 years old it has about 2,400 or so,” says Christopher Walsh of Harvard Medical School and Boston Children’s Hospital who authored the study. “In general, our numbers pick up right where [Vaccarino’s] leave off,” he says.

    “It’s nice to see the two approaches getting similar answers,” says McConnell. “It’s very good news for folks like me that do single-cell sequencing.”

    The second study also looked at brain cells from two individuals with neurodegeneration caused by defects in DNA repair enzymes, finding them to have roughly 2.5 times more SNVs than age-matched controls.

    “About one percent of the mutations are likely to be functional in the sense that they disrupt a protein,” says Walsh, “so by the time you’re 80 years old there’s about one in a thousand neurons that has had a gene essentially knocked out.” Mutation accumulation could therefore be “a reasonable model for how age-related cognitive decline might come about,” he says.

    Walsh’s team also noted that the types of SNVs varied with age, with those apparently caused by oxidative damage being more prevalent in the elderly. That fits “with previous literature that suggests that one cause of aging in the brain might have to do with oxidative damage,” he says. “So that has me eating a lot of blueberries and drinking a lot of red wine.”

    What remains to be determined, says McConnell, is not only whether these mutations may influence a person’s likelihood of developing certain neurological conditions, but also whether during development these mutations could actually be an important part of establishing essential cellular diversity within the brain. “Studies like these provide important data that will help direct us toward an understanding of the actual functions of somatic mutations,” he says.

    T. Bae et al., “Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis,” Science, doi:10.1126/science.aan8690, 2017.

    M.A. Lodato et al., “Aging and neurodegeneration are associated with increased mutations in single human neurons,” Science, doi:10.1126/science.aao4426, 2017.

    Tags
    somatic mutations, single-cell analysis, neuroscience, neurogenesis, neurodegeneration, mutations, mosaicism, genetics & genomics and developmental biology

  2. #2
    I would HOPE that brains change and grow and "get smarter" over a lifetime. And that people can over-ride their firmware programming to learn healthier habits and deepen good personality traits.

    But I guess they're more interested in the negatives in the situation. Maybe if they looked at how this process is a good thing, first, it would be easier to identify where things go wrong and find non-pharmaceutical ways to address it.

  3. #3
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    Well that might explain what is going on with liberal brains........
    We have done so much, with so little, for so long....We can now do anything, with nothing, forever.

  4. #4
    Quote Originally Posted by Sacajawea View Post
    I would HOPE that brains change and grow and "get smarter" over a lifetime. And that people can over-ride their firmware programming to learn healthier habits and deepen good personality traits.

    But I guess they're more interested in the negatives in the situation. Maybe if they looked at how this process is a good thing, first, it would be easier to identify where things go wrong and find non-pharmaceutical ways to address it.

    Sounds kind of like the old Indian explaining life to his grandson.The story goes something like this:inside of each of us are two wolves,one with a good nature and one who would do evil.The grandson asked,which one wins,the old man tells him ,the one that you feed.

  5. #5
    The researcher said he was eating a lot of blueberries and drinking a lot of red wine.He would do better to leave off the wine and instead add turmeric and a product called Protandim,produced by Lifevantage.This stuff runs circles around ANY thing else to reduce or eliminate oxidative stress.It protects all of the organs in the body and greatly reduces the damage that oxidative stress causes.

  6. #6
    Thousands? Don't we have billions of neurons in the brain? The brain has a lot of redundancy, and the significant issue is connections between the neurons, not so much the numbers of neurons themselves. "Thousands" of mutations shouldn't matter at all. Also, it is my understanding that until recently scientists didn't think that the number of brain cells increased after birth. According to later studies, we do get some more, but it isn't significant, so replication errors shouldn't be a significant source of mutations for brain cells anyway.

    Someone please correct me if I'm wrong, but I wasn't impressed with the article. I don't think the author knows her subject.

  7. #7
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    I read it as thousands of mutations within the same neuron. Maybe thousands in the same DNA chain.

    I could be wrong though.
    Accept certain inalienable truths: Prices will rise. Politicians will philander. You, too, will get old. And when you do, you'll fantasize that when you were young, prices were reasonable, politicians were noble and children respected their elders. - Mary Schmich

    If you find yourself in a fair fight, your tactics suck.

  8. #8
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    Quote Originally Posted by ShadowMan View Post
    Well that might explain what is going on with liberal brains........
    Hate to break it to you, but this article is talking about mutations in the human BRAIN - something that is obviously missing in the North American Liberal. ;-)

  9. #9
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    Quote Originally Posted by fish hook View Post
    Sounds kind of like the old Indian explaining life to his grandson.The story goes something like this:inside of each of us are two wolves fighting ,one with a good nature and one who would do evil.The grandson asked,which one wins,the old man tells him ,the one that you feed.
    Added the missing component.
    "It ain't no secret I didn't get these scars falling over in church."


    The healthy human mind doesn't wake up in the morning thinking this is it's last day on Earth. But I think that's a luxury, not a curse. To know you're close to the end is a kind of freedom. Good time to take... inventory.

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