

Genetic Secret to AIDS Immunity Found - MikeCapone
http://www.technologyreview.com/biomedicine/26682/?p1=A3

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bhickey
I spent the past year sharing office space with Paul's lab, so this result
doesn't really surprise me. I dislike the title that Technology Review is
running, but that shouldn't detract from this.

The major histocompatibility complex sits on chromosome 6. Our best disease
associations for HIV and autoimmune disease show up here. There are a number
of published associations outside of this region, but nothing as blazing hot
as the signal in the MHC. There's an ongoing debate in the field about
'missing variance' -- we can estimate the heritability of diseases haven't
found enough variation in the genetic soup to explain the heritability.

(I'm afraid I need to run out the door, I'll do my best to answer questions on
this work or similar studies.)

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carbocation
There are some groups within the Broad Institute that I think have the tools
to more or less resolve the question of the missing heritability (genetic
variance), and I'm sure you know these folks too. This work isn't published
yet, so sadly we can't really talk about their answer.

~~~
bhickey
I don't believe I'm privy to any secrets, but I'll do my best not to leak
information.

My complaint is with additive models of liability. [In brief compute an
independent relative risk for each SNP. To compute the risk of disease, take
the log sum of the relative risks.] I haven't seen a model that can take into
account epistatic effects.

~~~
carbocation
But heritability expressly excludes non-additive factors so I don't think that
should be a problem. I agree that non-additivity affects the overall variance.

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rflrob
I haven't read through the whole paper yet (behind a paywall (I think... I'm
at a university that subscribes, so I have access) here:
[http://www.sciencemag.org/cgi/content/abstract/science.11952...](http://www.sciencemag.org/cgi/content/abstract/science.1195271)),
but table 1 is somewhat telling: there is no single mutation that's found in
all controllers, and not in progressors. Instead, there's a collection of SNPs
that controllers have more often than progressors, but not all controllers
have any given SNP.

~~~
carbocation
You're almost never going to get perfect genetic discrimination in all-or-
nothing fashion.

The final figure is very interesting: the key SNPs that affect controller
status are located near one another in 3-space in the HLA-B binding groove at
a key site for antigen presentation. The fact that the genetics are all
pointing to specific parts of the molecule in 3-space is extremely helpful.

