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So Huntington's chorea is a late-onset inherited disorder
with symptoms gradually worsening and leading to
dementia.
It's one of a family of diseases caused by an expansion in
the number of tandem three-nucleotide repeats - in this
case
cytosine-adenine-guanine; CAG, in the coding sequence
of the huntingtin
gene (in which it encodes a string of glutamine residues).
The normal range of repeats is about 10 to 35; the high
end of that is at risk and definitely by over 40 there is a
strong
tendency to develop the disease. Additional repeats over
that leads to an earlier
onset.
So essentially this locus is 'fragile', being susceptible to
mutation. Why is this so?
This sort of repeat is unstable, and can expand or
contract during replication. This explains the risk. But
why does the repeat
exist?
Well, it's been proposed that having more repeats (up to
about 40) has a positive effect on intelligence (link), so
there is some
selection for the 'at risk' state.
However, I suggest that the existence of the repeat as
such is simply a result of the evolution of the site by
mutation - the
beneficial effect is actually due to the string of
glutamines.
So. Let us assume that at some point in the future scar-
less genetic engineering in humans becomes possible.
This looks like it
might actually be feasible, and may eventually be
low-risk and accepted enough to be commonplace.
There are actually two codons which encode glutamine;
CAG and CAA. It's highly likely that CAA could be
substituted for some
of the CAG codons without impacting function, and this
should
reduce mutation.
I don't claim to know enough to specify the best way to
avoid repeat expansion or slippage. Maybe it is
alternation, maybe it is
a semi-random distribution of the two. Furthermore-
it is, I believe, likely that the requirement for glutamine
isn't completely stringent and other amino acids could
also be
substituted at least a fraction of the sites - Aspartic acid
is in
the 'highly conserved' category and has two codons: GAC
and GAT - judicious use of these could further disrupt
mispairing.
Experimentation in animal models could determine this.
Therefore it may be possible to 'fix' this fragile locus to
more reliably retain the most beneficial length while
avoiding the risk
of disease in descendants.
Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence
https://www.ncbi.nl...rticles/PMC6013750/
scientific paper. [Loris, May 10 2019]
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This could be attempted (sort of) now or in a few years
using CRISPR. It would be an easy fix for a human oocyte; it
would also be fixable in a whole person, but treating a large
enough proportion of the relevant cells (or all cells) would
be difficult. My own company is also working on an editing
technology that could do this. |
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I wouldn't trust the purported link between repeat number
and intelligence - it's probably spurious. And I agree,
replacing some CAG codons with CAA would prevent triplet
expansion and probably have no adverse consequences. |
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//This could be attempted (sort of) now or in a few years using CRISPR.// |
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CRISPR isn't fit for this purpose yet. Too many off-target mutations.
And yes, the germ-line is the ideal point of action. |
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//I wouldn't trust the purported link between repeat number and intelligence - it's probably spurious// |
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It might be, but please refer back to the cautious language in which I couched the statement.
It doesn't really matter. Presumably function requires at least a short run of glutamine (if not, trim to one; problem solved!),
so we really just need a massive trial to determine the optimum number, and then nail that down in the genome. |
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What's really needed is some very fast
memory editor so people wouldn't remember
they lent money to me. |
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Weird, I'm sure I had fiver..must be here
somewhere |
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// My own company is also working on an editing technology that could do this. // |
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"My own company has bought one of those nifty high-speed drill thingies in the weekly discount sale at Lidl and we are looking round for something to try it on." |
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// Too many off-target mutations. And yes, the germ-line is the ideal point of action. // |
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<Obligatory Blade Runner Reference> |
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"We've already tried it. Ethyl methane sulfonate is an alkylating agent and a potent mutagen." |
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//Too many off-target mutations.// Exactly. I am waiting
for it to kill a few people. |
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// germ-line is the ideal point of action// Yes and no. The
people who are most upset about Huntington's are people
who are already multicellular. Genome editing needs to
work for grown-ups. |
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//weekly discount sale at Lidl// Harrumf. If you get
Huntington's, don't come running to me. |
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//The people who are most upset about Huntington's are people who are already multicellular.// |
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I suppose that's true, but I was thinking in terms of my proposed preventative treatment.
If you're trying to expunge the progression of Huntingdon's chorea in an adult's brain, you presumably 'just' need to trim out
excess repeats in the appropriate cells. Trying to prevent those repeats from ever expanding again over multiple
generations is unnecessary complexity in somatic tissue. |
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Life would be so much simpler if we were all single-
celled organisms. |
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Well we used to be, but then some wise-guy eukaryote said
"Listen! I have an idea ..." |
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