
Every neuron potentially has a different genome than those it's connected to - molecule
https://www.scientificamerican.com/article/scientists-surprised-to-find-no-two-neurons-are-genetically-alike/
======
jboggan
Coming from a bioinformatics background this is really, really surprising to
me. I knew there was always a chance of individual cells diverging from the
shared genome but we always considered that a hallmark of cancerous, abnormal
growth.

Thinking that you could have a trillion unique variations of the genome
significantly ups the computational complexity of simulating an organism by a
frightful order of magnitude. We are so much further from understanding
biological systems than we ever thought.

That's been the main lesson from the modern era of sequencing, genomics, and
bioinformatics - we haven't learned nearly as much as we have unlearned.

~~~
daveguy
Agreed. That's like orders of magnitude orders of magnitude.

Definitely surprising, although in one of those hindsight realizations --
c.elegans has a specific consistent function for each cell and each cell under
normal development.

If 300+ cells of a worm can be that well orchestrated, of course slightly more
complex creatures could. Evolution is a series of slight successes.

What if the cells of the brain have their own genome because each one of the
billions of cells has a near specific specialized function.

Could cellular function be that precise? Each micron of tissue the result of
specific evolutionary pressures?

~~~
mirimir
I suspect that it's much like the immune system. For example, antibody
diversity is "generated by DNA rearrangements during B-cell development".[0]
And:[1]

> In another parallel with the immune system, cadherin-related neuronal
> receptors (CNRs) are diversified synaptic proteins. The CNR genes belong to
> protocadherin (Pcdh) gene clusters. Genomic organizations of CNR/Pcdh genes
> are similar to that of the Ig and TCR genes. Somatic mutations in and
> combinatorial gene regulation of CNR/Pcdh transcripts during neurogenesis
> have been reported.

So as with evolution, more-or-less random variation generates diversity in the
developing nervous system. And then there's selection.

0)
[https://www.ncbi.nlm.nih.gov/books/NBK27140/](https://www.ncbi.nlm.nih.gov/books/NBK27140/)

1)
[https://www.ncbi.nlm.nih.gov/pubmed/12558794](https://www.ncbi.nlm.nih.gov/pubmed/12558794)

------
Real_S
No two cells are ever genetically identical. Within a common hyper-mutable
region, tandem repeats, the mutation rate is 10^-3 to 10^-5. There are over
10^5 tandem repeats in the genome, and therefore at least one mutation is
expected for every cell division. Many other types of hyper-mutable regions
exist in the human genome.

In this research they only examine one form of genetic variation, SNPs. These
findings only reflect a small proportion of the somatic variation present in
the body.

There is no real surprise in these results, but the data may nevertheless be
useful!

~~~
zeotroph
(while most here understands CPU RAM RAII DRY etc., you might want to mentions
that SNP means "single nucleotide polymorphism", which are mutations where
just a single base pair differs.)

------
reubenswartz
"A primary cause of somatic mutations has to do with errors during the DNA
replication that occurs when cells divide—neural progenitor cells undergo tens
of billions of cell divisions during brain development, proliferating rapidly
to produce the 80 billion neurons in a mature brain."

Certainly there must be tens of billions of cell divisions to create all the
neurons, but each neural progenitor cell would only divide 30-40 times, right?

I'm not surprised that there are mutations, but the number of mutations is
remarkable to me, and seems like yet another evolutionary check on brain size
that I hadn't considered (energy use, difficulty of birth, and difficulty of
childhood being the more obvious ones).

~~~
nonbel
>"Certainly there must be tens of billions of cell divisions to create all the
neurons, but each neural progenitor cell would only divide 30-40 times,
right?"

Surprisingly to most, this is not a mainstream opinion:
[https://www.ncbi.nlm.nih.gov/pubmed/25459141](https://www.ncbi.nlm.nih.gov/pubmed/25459141)

I would guess the main reason is that it leads to major problems with the
current model of cancer.

~~~
reubenswartz
Thanks for the link. Very interesting stuff.

Also worth noting that there's a difference between mutation and cancer,
although of course they're related. Just as mice and people get cancer at
similar rates, so do elephants, which have many more cell divisions, but have
more elaborate anticancer mechanisms (presumably because elephants lacking
them died of cancer).

~~~
nonbel
If you give humans 2^53 divisions (as in that paper) and elephants have ~100x
the mass of humans, as a rough estimate they would require 2^60 divisions. So
about 7 more divisions per stem cell to live as long as the usual human (they
usually don't live that long).

~~~
nonbel
Instead of "per stem cell" that should be 7 more divisions from the zygote.

~~~
reubenswartz
For some of the cells, like neurons, that to a first approximation don't
divide in adulthood, this seems true. But for things like blood cells that are
constantly getting turned over, it seems like there would be a lot more
opportunities for bad mutations in a larger creature (although as your link
suggests, there seems to be some fairly strong defense against this).

------
deepsun
Well, DNA is kind of Big Data. And everyone who worked with Big Data knows
that there will always be all kinds of inconsistencies and errors.

Personally, I was always skeptical that all non-sex human cells share the same
DNA, it's just statistically unbelievable that billions of cells each having
billions of DNA pairs would have then equal. I expected something like 1% of
cells to have mutations.

Now they say that it's 100% for neurons. Exact 100% number is also pretty
sketchy from statistical standpoint.

~~~
matt4077
Nobody ever said that all cells share 100% of DNA in the sense you're
implying. It's obvious that DNA undergoes dynamic processes, some of which
will result in lasting differences. The accumulation of errors is the basic
mechanism for cancer, which has been recognised for decades.

But it was previously thought that such differences were detrimental to
function (and health). There were some mechanisms for modifying cells' DNA,
collectively known as "epigenetics", but these were reversible, at least in
principle.

This adds another dimension of complexity, which biology already had plenty
of. My favourite is the double- or triple-coding DNA: because DNA is read in
triplets, there are three possible reading frames. Some organisms have evolved
DNA that produces entirely different, but independently useful proteins on two
or even all three reading frames of the same DNA. Talk about efficiency...

~~~
patall
Do you have any links for the last paragraph? I know that there can be two
gene encoded in reverse in bacteria but have no knowledge of any frame-shifted
translations?

About the second paragraph: well, it was not really thought that differences
are always detrimental to health, and there is quite a number of variant
prioritization tools out there that try to find those variants that are causal
compared to all the silent/no-effect mutations (mostly for comparing humans
but also somatic).

------
jcims
Sometimes I wonder how so much complexity and co-dependency has evolved on
earth in such little time. Most estimates I've read say that we're likely
within an order of magnitude of 100 trillion generations deep from the
universal common ancestor at this point. That sounds like a lot, but not
really. If you took 30 four sided die, you'd have to roll them a million
trillion times to have a good shot at getting any specific permutation.

How many 'die rolls' does it take to get a selective feature to emerge in an
organism? If you do a google image search for 'camouflage bugs', you'll find
some brain-bending examples. There's clearly a selective advantage for some of
those 'configurations', but how many generations would it take for each
genetic mutation required to make a lichen katydid or an orchid mantis to
converge?

~~~
kahoon
> There's clearly a selective advantage for some of those 'configurations',
> but how many generations would it take for each genetic mutation required to
> make a lichen katydid or an orchid mantis to converge?

If you pose the question like that with the posteriori knowledge in mind, then
yes, these configurations are highly improbable. I think another question that
could be asked is: How many generations would it take for some mutations to
produce some camouflage effect in some of the millions of existing species?
Surely some mutations​ that produce camouflage effects will happen.

~~~
mikekchar
Some changes can happen really quickly too. If you look at breeders of fancy
pigeons or fish, they can do incredible things in a relatively small number of
generations. Of course, breeders are generally much more selective than
nature, but it gives you a lower bound on what is possible.

------
abecedarius
Wait, the headline says no two alike, while the body text seems to go no
further than that every cell is potentially different. What is it? If the
somatic mutation rate is >1/neuron, that's a real surprise to me, but if it's
"there's plenty of mosaicism and it makes a real difference", then not.

~~~
dang
Good catch. We've changed the title above to a representative phrase from (I
think) the paragraph you're referring to.

~~~
abecedarius
OTOH Real_S comments that the rate is indeed >1\. So huh, I learned something.

------
apathy
[https://www.nature.com/articles/ncomms12484](https://www.nature.com/articles/ncomms12484)

the more closely you look, the more obvious it becomes that this is the rule
rather than the exception. I would be somewhat surprised if children have
functional mutations rampant between neurons, and I suspect that some fraction
of this is artifactual. But I have no doubt (does anyone?) that some degree of
somatic mosaicism is the rule. About the only cells that tend to hang around
much longer than neurons are blood stem cells, and as soon as you look closely
at those, it's all but unavoidable.

~~~
apathy
God damn it, that Science paper is piss weak even for a Science paper. It's
yet another consortium advertisement. Meanwhile mapping of somatic mutations
in blood progenitors has been happening for a decade.

~~~
patall
This exactly. Somatic variants are one of the most common things around.

I always wonder why HN will almost never upvote a general informatics research
article instead of a good review and with other fields of research it is the
other way around where a review would be much better suited.

------
tropo
Isn't this old news? The reason is vaguely similar to the DNA modification
that happens in the immune system: recognition of self. In this case, the goal
is to avoid loopback connections. Nerve cells that touch themselves are bad.
By DNA modification, the cells get different surface protein and are thus able
to avoid connecting to themselves.

------
failrate
I wonder if this is involved in storing information in the brain.

~~~
zeotroph
Neurons practically never die, so the DNA itself will not directly reflect
what a decades old braincell stores, though some mutations might influence how
or if at all a certain neuron stores something. But since these mutations are
random they are closer to defects (the article draws a connection to
psychiatric diseases) than features.

But DNA can also be _methylated_ , which is something that also happens in
neurons and might be involved with actual memory.

And if you ever want to digitize a brain, then you might have to grab the DNA
of 100 billion neurons as well, and there straightforward mutations are easier
than just a somewhat transient methyl group here and there.

------
RangerScience
Main paper:

[http://science.sciencemag.org/content/356/6336/eaal1641/tab-...](http://science.sciencemag.org/content/356/6336/eaal1641/tab-
pdf)

Unfortunately, looks like you have to register ("free"?) and sign-in to
download the full text.

Other papers linked in article:

[http://www.cell.com/neuron/fulltext/S0896-6273(16)00097-0](http://www.cell.com/neuron/fulltext/S0896-6273\(16\)00097-0)

[http://www.cell.com/neuron/fulltext/S0896-6273(12)00273-5](http://www.cell.com/neuron/fulltext/S0896-6273\(12\)00273-5)

[http://science.sciencemag.org/content/350/6256/94/tab-
pdf](http://science.sciencemag.org/content/350/6256/94/tab-pdf)

------
skosuri
Every single microprocessor in every computer is unique in its own way (small
errors in production). It doesn't mean we can't compute with them, nor that
the variation is useful or relevant.

~~~
dvt
This is an incredibly reductive analogy. The whole point of the article is
that the neuronal variation _does_ seem to be relevant.

~~~
skosuri
It seems to exist. Not clear there is a lot of evidence it's relevant. If you
sequence a tissue that has cancer or some other disease that causes increased
cell division, you will see more somatic variation. Not sure why this is
particularly surprising or interesting. It's been known for a while now. If
somatic variation was important for brain development or function (like it is
in the adaptive immune system), that indeed would be super surprising, but
that's not what I'm seeing here.

~~~
mirimir
A key aspect of CNS development is massive overproduction of neurons, and then
selection for useful ones. The idea that somatic variation plays a role there
is not novel.

[https://scholar.google.com/scholar?q=development+somatic+var...](https://scholar.google.com/scholar?q=development+somatic+variation+neuron)

------
lngnmn
No meaningful parts (which encodes proteins and gene regulation) are
different, however. Nature does not work that way.

Comparison of two genomes as two billions-bases-long strings is meaningless
and yields nonsense due to waste and introns. Genome isn't a uniform string in
the first place.

Nothing to see here, except hipster's self-praise and want for attention.

------
danjoc
I was told in science classes that all of a person's cells shared the same
DNA. Now I learn, nobody ever actually tested to see if that was true. This is
why people don't trust you, science.

~~~
leeoniya
i always wondered how differentiated cells can have _completely_ identical DNA
and still know which proteins to fold based on their specialized function.
different types of cells even look very different!

~~~
khedoros1
I think that a one-word answer would be "epigenetics". Sections of genes are
turned on and off by various chemical processes, so that the genes that are
actively transcribed into proteins can change without the underlying DNA
changing.

There was a brief mention of it at the bottom of the article.

