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A Single Neuron May Cary Up to 1000 Genetic Mutations (neurosciencenews.com)
64 points by ghosh on Oct 5, 2015 | hide | past | web | favorite | 23 comments

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!"


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.

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.

If you look in the second paragraph, they say they used multiple-displacement amplification (MDA). This method reduces the amount of times that any copied DNA is re-amplified, allowing them to significantly reduce the issue you bring up.

[1] https://en.wikipedia.org/wiki/Multiple_displacement_amplific...

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.

> 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.

Is the cup half-full or half-empty? From one perspective, if the known fixed functionality of the brain is implemented in part using DNA mutations, this is good long-term news - after all, if there is one thing you can expect to be kept intact and be recoverable in a vitrified brain, it's the DNA. That makes decoding more difficult, but also makes information-theoretic death less likely.

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.

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.

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.

It is extremely unlikely that the brain encodes information by introducing controlled mutations into DNA. Random mutations would add noise, not information.

It is likely that some mutations affect the efficiency of signal propagation, and encoding might adapt to this, so that equivalent inputs would create more or fewer or "stronger" or "weaker" synapses to generate the same output from the second neuron. But this could be detected functionally, if you could observe the signals and responses of neuron pairs.

Our immune system is also full of somatic hyper-mutated cells.

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?

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.

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.

Says who? Our best evidence says that muscle cells live for our whole life as well, only increasing/decreasing in size in response to exercise. Liver can regenerate but I'm not aware of turnover or a death checkpoint for them. Same with the other solid organs.

We've got lots of cells that are turning over continually, but plenty of long lived structures as well.

Also, if it's related to cell turnover, you would expect cells which replicate through our life to have higher numbers of mutations compared with our initial zygotic state due to the potential for mutation at each point

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.

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

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.

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

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

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

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.

This. Autism is a label with a very wide spectrum. Just because my brain works differently from the other 98% of mankind (1 in 42 boys[1]) does not means I'm sick.

[1] https://www.autismspeaks.org/what-autism/prevalence

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