1. sa smith
  2. ERVs and Multiple Sclerosis, #5

ERVs and Multiple Sclerosis, #5

By sa smith on September 18, 2012.

This is not overly helpful information for MS patients, but its still good news:

No additional copies of HERV-Fc1 in the germ line of multiple sclerosis patients.

Previous research has indicated that there are endogenous retroviruses that are disregulated and leading to detectable production of ERV proteins in MS patients.  They found the bugger involved-- an ERV they named HERV-Fc1. We do not know whether this protein is causing MS, or just a side-effect we might (might not) be able to capitalize on for diagnostic purposes, or whether its a bit of both.

But with all of this previous research on ERVs and MS, we all missed a huge elephant in the room-- Contrary to what Creationists like to say, ERVs are junk DNA.  They are junk, and thats a good thing.  Of the many reasons we are glad that 8% of your genome arent active, replication competent retroviruses is that retroviruses cause cancer.

If MS patients have HERV-Fc1 bopping around, its possible that there are other ERVs disregulated.  Even if infectious viruses arent being made, some ERVs might be making mRNA that gets turned into reverse transcriptase and integrase, that can turn other ERV mRNA into DNA and pop it back into the genome.  There could be all kinds of genetic instability goin on.  Genetic instability, insertional mutagenesis, its just a fancy way of saying CANCER.

One way to look for this is to count the number of ERVs per cell.  This isnt exactly practical, so these folks looked for increased copies of HERV-Fc1 in MS patients.  If wayward ERV expression is leading to genomic instability, there would be more-than-expected numbers of HERV-Fc1 in MS samples.  And, they would find copies of HERV-Fc1 in unexpected locations-- not only in the germline, 'normal' location.

Well, there are not more copies of HERV-Fc1 in the cells of MS patients vs healthy controls.  Just the normal 2:1 ratio between men and women (HERV-Fc1 is found on the X chromosome).

This doesnt directly help MS patients at all, but its still good news-- The relationship between ERVs and MS is still murky, but at least the ERVs probably arent also causing cancer in MS patients.  Yaaaaaaay...

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I'm not overtly surprised; its been established since I was a grad student (no comment on when that was - lets just say it was a while ago) that HERV's are often transcribed under inflammatory conditions. Nothing magical about it - many retroviral regulatory regions have their transcription induced by endogenous inflammation and cell-stress transcription factors (for example, the pro-inflammatory factor NFkB can induce transcription of several HIV-1 genes). That a HERV was transcribed during MS is far from surprising, as MS involves inflammation; I'm more surprised that only one was transcribed HERV ID'd.

I'm actually surprised this field isn't moving forward faster - there are several huge MS family cohorts, including genomic samples, out there - many open to any researcher willing to submit a proposal. It should be "trivial" (in quotes, because it would be trivial compared to starting from scratch) to screen those for common HERV elements, copy numbers, etc, to see what is actually going on.

In fact, this has been sort-of done, through a few GWAS studies - no HERVs popped up:
http://wattle.well.ox.ac.uk/wtccc2/external/ms/
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0036…

Bryan

Wow, if I didn't know better I'd swear english was my fifth or sixth language. This:
I’m more surprised that only one was transcribed HERV ID’d

Should have been:
I'm more surprised that only one transcribed HERV was ID'd

That there is only one ERV locus causing trouble is the key to this puzzle. If we were dealing with some kind of global disregulation, some issue with inflammation or alterations in epigenetics, you would think more would be active.

But apparently its just the one, and this paper supports that (if more were active, you would get increases in copy numbers, in novel locations in the genome).

I really dont have a clue as to what is really going on, here.

ERV can you explain your statement above concerning 'junk' DNA?
"But with all of this previous research on ERVs and MS, we all missed a huge elephant in the room– Contrary to what Creationists like to say, ERVs are junk DNA. They are junk, and thats a good thing. Of the many reasons we are glad that 8% of your genome arent active, replication competent retroviruses is that retroviruses cause cancer."
In reference to the culmination of the scientific Encode Project.
http://www.eurekalert.org/pub_releases/2012-09/embl-fff083112.php
ENCODE scraps the junk

Link to the results of the Lipkin Study results in case you want to close out your XMRV group *wipes tear from eye*. It had a good run.

http://mbio.asm.org/content/3/5/e00266-12

"A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus"

By Poodle Stomper (not verified) on 18 Sep 2012 #permalink

Jane: The popular press is overstating the case. The root of the misunderstanding is ENCODE's definition of "functional" DNA:

a discrete genome segment that encodes a defined product (for example, protein or non-coding RNA) or displays a reproducible biochemical signature (for example, protein binding, or a specific chromatin structure).

That's actually a really really broad definition. Stuff can be totally useless in every meaningful sense and still meet that definition. Hence the 80%.

By Corkscrew (not verified) on 18 Sep 2012 #permalink

@Bryan

Remember the blog "ERVs and Multiple Sclerosis #4" that Abbie wrote about back in April? That group did describe an increase in the copy number of another ERV, HERV-W, in MS patients ("In quantitative real-time PCR for both RNA expression and DNA copy number, 40% of MS patients were increased relative to healthy controls, whereas 4% of the blood donors were increased"). I found this difficult to believe as I could not see a plausible mechanism for this apart from active replication with all the resulting problems (and you tried to explain that to me).

So, I am further confused - or does the XMRV explanation apply to the HERV-W results: "It's all contamination"...? I just guess as we all share almost the same HERV copies in our genomes even a blinded study performed by different persons at different sites may still be prone to contamination.

Anyway, they had it successfully published.

OWE

@Corkscrew
Thanks, maybe ERV can write a post on the Encode project and how it will effect future research. :)

OWE,

I don't think we can say anything about contamination or other issues at this point. It is odd that two studies came to the exact opposite result, but as I recall, the paper that found copy number variations did have some of the controls we'd expect to avoid contamination issues (multiple sites, etc).

I was dubious of the HERV link then, and I remain dubious now. We don't see evidence of HERV antigen reactivity in MS; that alone eliminates the most likely mechanisms (HERV = auto-antigen).

ERV can combine with other retroviruses, they are hardly junk DNA. ERV are also expressed in all neuroimune disease and infections.