Brain cells’ DNA differs

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Brain cells’ DNA differs

Postby wolfhnd on October 2nd, 2015, 12:25 am 

Somatic mutation in single human neurons tracks developmental and transcriptional history

"Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function."

http://www.sciencemag.org/content/350/6256/94

How does this matter?
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Re: Brain cells’ DNA differs

Postby Dave_C on December 6th, 2015, 10:09 am 

Hi wolfhnd,
What exactly is the importance of somatic mutation? I found this definition on Google, but maybe I just don't have the right background to grasp what's important about this...
Somatic mutation, genetic alteration acquired by a cell that can be passed to the progeny of the mutated cell in the course of cell division. Somatic mutations differ from germ line mutations, which are inherited genetic alterations that occur in the germ cells (i.e., sperm and eggs).

I take it, neuron DNA is being altered / mutated during our lifespan. But I would assume DNA in other parts of our body undergoes similar mutations. Would that be a bad assumption? Is the rate of mutation in our neurons significantly different somehow? What is it about the mutations in our neurons that differs from the liver for example?
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Re: Brain cells’ DNA differs

Postby wolfhnd on December 6th, 2015, 11:36 am 

“This work is a proof of principle that if we had unlimited resources, we could actually decode the whole pattern of development of the human brain,” says co-senior investigator Christopher Walsh, MD, PhD, the HMS Bullard Professor of Pediatrics and Neurology and chief of the Division of Genetics and Genomics at Boston Children’s. “These mutations are durable memory for where a cell came from and what it has been up to. I believe this method will also tell us a lot about healthy and unhealthy aging as well as what makes our brains different from those of other animals.”

http://vector.childrenshospital.org/201 ... s-history/

Our brain cells apparently have a lot of genetic variation

“Understanding that some mutations can occur late in development and only be present in the brain has important implications for clinical genetic testing, as studying the blood will miss the somatic mutations present only in brain,”

http://vector.childrenshospital.org/201 ... in-autism/
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Re: Brain cells’ DNA differs

Postby Dave_C on December 6th, 2015, 12:20 pm 

Ok, thanks. But is this type of mutation abnormal for cells in the body? Do we see it in liver or muscle or blood cells or others?

Why is it that neurons are being focused in on?

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Dave.
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Re: Brain cells’ DNA differs

Postby wolfhnd on December 6th, 2015, 3:02 pm 

Differentiated neurons do not divide but the mechanisms that initiates division has been cooped by neurons for other purposes presumably synaptic plasticity, learning and memory. Those same mechanisms are linked to cell death when specific stresses are experience. Understanding these processes that appear unique to neurons could help understand diseases such as Alzheimer.
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Re: Brain cells’ DNA differs

Postby Dave_C on December 6th, 2015, 4:13 pm 

wolfhnd » December 6th, 2015, 2:02 pm wrote:Differentiated neurons do not divide but the mechanisms that initiates division has been [copied?] by neurons for other purposes presumably synaptic plasticity, learning and memory.

I'd like to play that back to you. Tell me if I'm misunderstanding because it strikes me as fascinating if this is true...

Neurons that have "differentiated" (from a stem cell) do not divide or reproduce, but the molecular mechanisms that perform cell division are used by neurons for 'other purposes' having to do with learning and memory among other things. I presume then these molecular mechanisms responsible for cell division are the ones which modify the DNA.

Did I get that right?
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Re: Brain cells’ DNA differs

Postby BioWizard on December 10th, 2015, 10:26 pm 

Dave_C » 06 Dec 2015 03:13 pm wrote:
wolfhnd » December 6th, 2015, 2:02 pm wrote:Differentiated neurons do not divide but the mechanisms that initiates division has been [copied?] by neurons for other purposes presumably synaptic plasticity, learning and memory.

I'd like to play that back to you. Tell me if I'm misunderstanding because it strikes me as fascinating if this is true...

Neurons that have "differentiated" (from a stem cell) do not divide or reproduce, but the molecular mechanisms that perform cell division are used by neurons for 'other purposes' having to do with learning and memory among other things.


The cell has a finite number of genes. These genes operate in functional networks, frequently serving more than one conceptual function at a time, at different times, or in different cell types. It's a lot like having a set of legos that you can put together in different ways to make different functional structures. Your body does a lot of that to create many different cell types from the same starting DNA.


I presume then these molecular mechanisms responsible for cell division are the ones which modify the DNA.

Did I get that right?


It doesn't have to be an all or none, yes or no. Components of cell division machinery may be involved in modifying DNA.

But the point here was something different. That after neurons stop dividing, they can start to use gene products that are sometimes involved in controlling cell division for controlling other types of cellular processes.

The reason these mutations appear isn't dependent on that phenomenon. It's just a random "damage" event that sticks and can be used to date cellular events. Similar to how you can date events in your life with respect to a time when you acquired a scar.
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Re: Brain cells’ DNA differs

Postby BioWizard on December 10th, 2015, 10:33 pm 

wolfhnd » 01 Oct 2015 11:25 pm wrote:How does this matter?


If it's sufficiently frequent and robustly analyzable (I didn't read the paper), it could be a useful tool for understanding/mapping brain cell lineage and development. It'd be akin to constructing phylogenetic trees of species based on the similarities in their genomes. The power of this approach is that it does not require a priori definitions of cell types and their distinguishing markers (which biologists tend to have a very hard time agreeing on - probably because cell types fall on a continuum rather than discrete classes).
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Re: Brain cells’ DNA differs

Postby neuro on December 11th, 2015, 12:50 pm 

bravo BioWiz.
I was going to say something very similar:
The interest of neuronal mutation is not so much in the fact that neurons are different from one another (if the mutation were relevant, the neuron would presumably die or be unable to properly differentiate, migrate to its proper site, make and receive appropriate connections).
The interest is exactly in locating neurons that bear the same set of somatic mutations because this would tell you they come from one and the same precursor.

The point about mechanisms used for cell replication that neurons can "recycle" to control other processes can be looked at this way: cell cycle (proliferation) is controlled by a precisely orchestrated regulation of many proteins and enzymes, in such a way that gene expression, biochemical reactions, structural features, organization of the nucleus, of chromosomes and of the cytoskeleton all contribute to have the cell orderly proceed through all the complex steps of a cellular replication. None of these regulated proteins and enzymes would be able - per se - to produce cell replication; but each of these proteins / enzymes (and the biochemical effects of their presence and/or activation) may perform regulatory functions on one or the other pathways of cellular activity, which turn out useful under specific circumstances, independently of cell cycling and proliferation.

A completely different story regards the possibility of semi-stable or even stable modification of genes and chromatin (epigenetic modifications, methylation and acetylation of DNA bases and/or of proteins that are associated to DNA and control its accessibility and activity). These may tell another kind of story of the neuron, as they may be influenced by neural activity and therefore by experience: experience leaves a track in the epigenetic picture (and overall gene expression pattern, and structure and connectivity) of each neuron. This is a "functional" story. The other story, told by somatic mutations, is instead a "genealogical" story of each neuron.
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Re: Brain cells’ DNA differs

Postby wolfhnd on December 11th, 2015, 9:34 pm 

neuro » Fri Dec 11, 2015 4:50 pm wrote:bravo BioWiz.
I was going to say something very similar:
The interest of neuronal mutation is not so much in the fact that neurons are different from one another (if the mutation were relevant, the neuron would presumably die or be unable to properly differentiate, migrate to its proper site, make and receive appropriate connections).
The interest is exactly in locating neurons that bear the same set of somatic mutations because this would tell you they come from one and the same precursor.

The point about mechanisms used for cell replication that neurons can "recycle" to control other processes can be looked at this way: cell cycle (proliferation) is controlled by a precisely orchestrated regulation of many proteins and enzymes, in such a way that gene expression, biochemical reactions, structural features, organization of the nucleus, of chromosomes and of the cytoskeleton all contribute to have the cell orderly proceed through all the complex steps of a cellular replication. None of these regulated proteins and enzymes would be able - per se - to produce cell replication; but each of these proteins / enzymes (and the biochemical effects of their presence and/or activation) may perform regulatory functions on one or the other pathways of cellular activity, which turn out useful under specific circumstances, independently of cell cycling and proliferation.

A completely different story regards the possibility of semi-stable or even stable modification of genes and chromatin (epigenetic modifications, methylation and acetylation of DNA bases and/or of proteins that are associated to DNA and control its accessibility and activity). These may tell another kind of story of the neuron, as they may be influenced by neural activity and therefore by experience: experience leaves a track in the epigenetic picture (and overall gene expression pattern, and structure and connectivity) of each neuron. This is a "functional" story. The other story, told by somatic mutations, is instead a "genealogical" story of each neuron.


Why is the genealogy important outside of disease, if we know the function of cells then how they arrived at that function seems irrelevant?
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Re: Brain cells’ DNA differs

Postby BioWizard on December 12th, 2015, 12:15 pm 

wolfhnd » 11 Dec 2015 08:34 pm wrote:Why is the genealogy important outside of disease, if we know the function of cells then how they arrived at that function seems irrelevant?


Aren't these two sentences contradictory? How can you rationally address disease if you don't understand it? Cell function is a "function" of a cell's genetics, epigenetics, and experiencial history.

Not to mention that most scientific research has not been immediatelly applicable, and history tells us that immediate applicability is a poor measure of the long term applicational impact of any type of research. But I guess that's a different discussion.
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