
A Single Neuron May Cary Up to 1000 Genetic Mutations - ghosh
http://neurosciencenews.com/single-neuron-genetic-mutations-2813/
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deepnet
The authors are answering questions about this paper on reddit. (5 Oct)

"tl;dr Mutations are happening in your neurons every day! We looked at
individual neurons to find out how many.

We will be back at 2 pm ET (11 am PT, 6 pm UTC) to answer your questions, ask
us anything!"

[https://www.reddit.com/r/science/comments/3nkdj5/science_ama...](https://www.reddit.com/r/science/comments/3nkdj5/science_ama_series_we_are_mollie_woodworth_and/)

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Mieroels
I think a lot of the mutations can be attributed to infidelities of single
cell sequecing. The amplification of DNA that has to be done has a tendency to
incorparate errors. If you start with a single copy of DNA then an copy error
early in amplification will look like a mutation. The neuron data is compared
to non-single cell sequencing of heart cells.

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daemonk
They actually did something kinda clever. They were able to calculate/model a
false positive rate by looking at the homozygosity of the X chromosome. Since
the samples were male, there should only be one X, so any heterozygosity would
have to be errors.

Not saying this is an absolute correct way of going about this (no one really
knows), but it shows they did at least thought about this issue.

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bd
Assuming those mutations have effects on neurons functions (and not e.g. just
remnants from ontogenesis) seems this should make future "immortality" tech
much more difficult (post-cryonics resurrections, brain uploads, etc).

Not enough to scan brain connectivity info, neuron types and per-person
genome, you will now also need per-neuron genomes to truly capture and
reproduce a brain.

Not that we were anywhere close to any sorts of brain uploading, but this news
just made it orders of magnitude more difficult.

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Houshalter
If these mutations are random they can probably be ignored. They likely have
no effect or negative effects. Your brain might actually improve a lot by
removing them.

If they aren't random and there is some purpose or information encoded in
them, then you have a good point. I think that's unlikely though.

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russdill
Clearly you haven't worked on an old buggy codebase. Sure that function has a
bug, but the rest of the codebase has adapted to it and worked around it. If
the function suddenly doesn't have a bug, dozens of other functions will fail
in new and strange ways.

The brain would work in a very similar way. If a neuron has a mutation that
effects it's function, surrounding neurons would adapt to that.

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logfromblammo
Having worked in such codebases, the only difference that _should be_
happening is that a lot of that old, redundant code inserted to work around
the bug would no longer be visited.

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daemonk
I wonder if this is related to neurite repulsion. In Drosophla, the DSCAM gene
is alternatively spliced to provide an "expression signature" for each neuron
so they can maintain neurite repulsion. Maybe these point mutations are
providing a similar function?

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cLeEOGPw
Is that related to the fact that neurons have much longer lifespan than most
of other cells in human body? How many mutations connective tissue cells have
for example? Hard to say whether 1000 is much or not without knowing about
other parts.

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philgoetz
Probably. On the other hand, cells which have a shorter lifespan might have
more mutations, since some mutations are introduced during replication--
several per genome per replication, I think? On the other other hand, if
they're produced from stem cells, that would keep the mutations down.

It probably also is related to the fact that neurons use a lot of energy and
have a lot of mitochondria. Energy requires oxidative phosphorylation in the
mitochondria, which produces a lot of free radicals, which damage DNA.

Yet, 1700 (the number they reported is 1700, not 1000) is about typical. Many
cancer cells have been sequenced; typical findings are that about 100 genes in
cancer cells have acquired mutations, about 10 of which contribute to the
cancer. Genes comprise about 1% of DNA; this suggests that the typical somatic
cell has 1000 to 10,000 acquired mutations. (1000 assuming that all 90
mutations past the 10 that caused the cancer happened after the tissue went
cancerous; 10,000 assuming they all happened earlier. Though that linear
interpolation is a bad estimate, because genes and intergenic DNA mutate at
different rates, owing to transcription and chromatin.)

However, if they sequenced just the exome (the expressed genes) rather than
the entire genome, then 1000 is 10x typical. I can't tell, since their paper
is paywall-protected.

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philgoetz
Given that this was whole-genome sequencing, is 1700 mutations higher than
other tissues? The paper doesn't appear to say that.

If they were claiming that this were an unusually high mutation rate, I'd
wonder why everyone doesn't die of brain cancer. If other tissue had N
mutations per genome, and cancer typically takes 10 mutations to create, in
the absence of compensatory mechanisms, the ratio of brain cancer to other
cancers should be about (1700 choose 10) / 50 * (N choose 10). If N were, say,
100, that number would be so large that not one person would ever had
developed any cancer other than brain cancer.

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krazemon
I like thinking that the mistake 'Cary' in the title of this article was a
meta-commentary on the nature of genetic mutations.

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philgoetz
Are you sure you're not counting mitochondrial DNA mutations? A single neuron
has about 1000 mitochondria, and would easily have tens of thousands of unique
mitochondrial mutations.

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philgoetz
It says "~1700 mutations per neuron", not "up to 1000 mutations".

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DiabloD3
Why do I feel like this makes a cure for Autism just that much harder?

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Terr_
... Well don't leave us hanging: Why _do_ you feel that way?

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DiabloD3
Because when you have a disease or disorder or whatever, and you see research
being done on the organ that contains said disease or disorder, and said
research is both expensive and very awesome, yet does not look like it is
leading to a cure or an effective treatment, science just slowly gets ruined
for you, and you eventually lose hope.

