erv

ERVs and ALS #2

sa smith — Fri, 09 Oct 2015 09:00:59 +0000

ERVs and ALS #2

Theyre figuring out what the heck is going on in the saga of ERVs and ALS!

2011:

ERVs and ALS

2015:

Human endogenous retrovirus-K contributes to motor neuron disease

1-- Of the many ERVs in your genome, the ones they found activated in the brains of people with ALS are HERV-Ks, at two positions: one on chromosome 7 and one on chromosome 10. ERVs degrade a lot over time, but they could find transcripts for all the major retroviral proteins, gag, pol, and env.

Why is this important?

At first, they could only find activity from the chromosome 7 locus, only in some patients. HERV-K activity from chromosome 10 is a new one, for me. There might not be only one HERV-K that can wake up and cause ALS.

Also, they only looked for pol before. It seems the previous work was focused on the enzymes of ERVs, including reverse transcriptase, possibly because RT activity has been detected in ALS patients. Theyve even tried giving people with ALS RT-inhibitors. But in this study, they looked for mRNA from all three major retroviral proteins.

2-- The Env protein appears to be the one causing trouble. Again, before scientists were focused on RT. In this study, they looked for the Env protein, and found it in ALS brains. Furthermore, whether they put active HERV-K genomes or only the Env gene into neuronal cells, both were cytotoxic to the cells.

In the absence of any other environmental/physiological/anything, these HERV-K Env proteins are enough, by themselves, to cause neuronal damage.

3-- This knowledge could be translated into an Env-expression based small animal model for ALS. They made a transgenic mouse that would express HERV-K Env in neurons. The prefrontal cortex of these animals was fine. It was the upper and lower motor neurons that died. Mice progressively lost motor function.

ALS. "Your mind is fine, while your body is collapsing around you".

4-- What about TAR DNA binding protein 43? In the previous study, TDP-43 was a confusing issue. It was playing a role in this ERV-ALS story, but they couldnt quite figure out where it fit. But now they know HERV-K Env expression alone is enough to cause neuronal damage/ALS-like disease in mice. Whats up with TDP-43?

Point #2? How they could put HERV-K Env in human neurons and see damage? They tried the same experiment, but but TDP-43 in human neurons. Thats it. Nothing else. Guess what happened?

They saw increased expression of HERV-K Env, and cytotoxicity.

They also found *exactly* where TDP-43 was probably binding in the HERV-K DNA to make these unwanted transcripts-->proteins.

This paper has answered a lot of questions about the relationship between ERVs and ALS (some ALS, not enough patients in this paper to definitively say 'ALL ALS!'), but there is still a lot to do before this translates into any therapies/preventative measures for patients. The main questions for me involve TDP-43, not the ERVs. 1) Why does TDP-43 start snuggling up to ERVs? Whyyyyy? Why would it start doing this?? 2) How the hell can you prevent/stop TDP-43 activating ERVs? Not only do scientists have to figure out how to do it, they then have to figure out how to get this therapy into the CNS. It is *hard* to get any kind of drug in there-- its going to suck.

So, good news/bad news with ERVs and ALS-- Good news is these folks are really starting to figure out what is going on with this disease. Bad news is, its not RT causing trouble, which explains why RT-inhibitors did nothing for ALS patients. RT-inhibitors would have been a nice, already tested/approved drug. TDP-43-Env relationship will need an entirely new approach.

And, repeat after me, folks:

"The vast majority of ERVs are junk. JUNK DNA. This is a good thing. When junk DNA is accidentally reactivated, BAD THINGS HAPPEN. Not magic unicorn rainbow things. BAD THINGS."

sa smith Fri, 10/09/2015 - 05:00

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ERVs

ALS

erv

A question for anyone who knows the answer, from a non-biologist. I am trying to understand, of the 100,000 or 200,000 (I have seen both numbers) fragments of ERVs, or of the ~230 (as of 2005, refc below) full-length ERVs, how many are (1) the result of separate infection events, versus (2) just being duplicates of the first class? Does each infection and its duplicates get classified as a whole new "family"?
Here is the meatiest reference I have found so far. It is ten years old :" Recent evaluation of the human genome sequencing data revealed that about 9% of the human genome is comprised of elements with long terminal repeats (LTRs) (LTR retrotransposons) (36, 43, 84) comprising over 200 families (30). The majority of these LTR elements, however, lack sequence similarity to retroviral genes within their internal region or constitute solitary LTRs. About 40 families identified so far have at least some members that show discernible homology to coding regions of retroviruses, but most of them have not yet been analyzed in depth (47, 74). These families are grouped into three classes based on the sequence homology of their pol regions with the pol genes of exogenous gammaretroviruses, betaretroviruses, and spumaviruses. They comprise around 200,000 entities (36), including about 230 full-length proviruses. " - -
Seifarth. et al., J. Virol. 79 ,341-352 (2005)
http://jvi.asm.org/content/79/1/341.full
Thanks in advance...

@Kurios

Almost certain nobody knows the answer to your first question, it would take a rather tremendous amount of work to get a good estimate, especially for more ancient ERVs; the older they are, the more fragmented they get, and the more difficult to piece together what the original provirus looked like.

For HERV-K HML-2, this analysis has been done, as there aren't that many loci, and they are fairly intact -there are ~100 full length/partial proviruses (10 times that many solo LTRs) and 12 of them are the result of duplications, from maybe 4 unique integrations. See figure 2 of this paper: http://www.retrovirology.com/content/8/1/90

In terms of HERV 'families,' that's a somewhat contentious area, but the answer to your specific question is no. HERV 'families' are not well defined (they certainly do not correspond to viral families, as all retroviruses, endogenous or not, belong to the family Retroviridae), but generally correspond to large-ish, distinct clades of HERVs, most of the time with more than one unique integration. For example, the HERV-K HML-2 clade is sometimes considered a 'family,' sometimes just a sub-group of the larger HERV-K 'family,' which contains, at a minimum, all 10/11 HML clades. Either way, there are shed loads of independent integration events within the group, spread over the course of millions of years of primate evolution.

I should note that, although your question about duplication/vs integration is hard to answer exactly, I can say that there are a *lot* of unique integrations, it's certainly not completely dominated by duplication events. Once a HERV group has completely lost replication competence, you would generally expect the duplication/unique ratio to increase over time, as at that point the only way to increase copy number is duplication.

Also, there's the related question of how many ERV integrations are formed from infection of exogenous viruses vs intracellular retrotransposition, i.e., transcription->reverse transcription->integration, skipping virion budding and cellular entry. That problem has been explored in a bit more detail than the duplication question, see here: http://mbe.oxfordjournals.org/content/22/4/814.full and here: http://www.pnas.org/content/109/19/7385.full

@zmil
Thank you for your prompt and comprehensive replies. I read through the references you provided. Your summaries were very helpful in stating the relevant conclusions. Also, I didn't know the right words to put it in, but what I was actually wondering about was infection of exogenous viruses vs intracellular retrotransposition,, which you addressed in your second reply. Thanks again.

My pleasure.

Opposite Day: When the data in an ERV paper says the opposite of what the authors say

sa smith — Sun, 25 Jan 2015 15:01:52 +0000

Opposite Day: When the data in an ERV paper says the opposite of what the authors say

A paper was recently brought to my attention via a Creationist. It was the usual 'HAHAHA! Oh you silly Creationist! This paper says the opposite of what you think it says!', and I was going to write a blog post along that usual theme.

Fazale Rana, 'Vice President' of 'Research and Apologetics' at Reasons to Believe said on Facebook:

What happens when the best evidence for biological evolution becomes evidence for intelligent deign?

Retroviruses, long thought to be junk DNA, play a role in regulating gene expression in the brain (link to ScienceDaily about the article)

The article has some interesting observations about how expression a few young ERVs is restricted in some brain cells in mice:

TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells

Your genome does not 'want' ERVs to be expressed. Wayward activity can damage DNA, make proteins that disrupt normal processes, aka kill the host organism. So genomes have evolved ways to control ERV expression: Epigenetics.

Epigenetically modify histones to wrap ERV DNA up *tight*, so it cant be expressed.

Epigenetically modify ERV DNA to wrap ERV DNA up *tight*, so it cant be expressed.

These folks demonstrate another protein, Trim28, plays a role in keeping some ERVs silent.

1. If they knock out Trim28 entirely, baby mice die, straight up.

2. When they cut out Trim28 in fetal mice, and look in neuronal progenitor cells, there is increased ERV RNA expression (altering the environment in which the cells grow (culture) can alter epigenetic profiles, thus alter ERV expression-- they compared these to control animals).

3. They think ERV family MMERVK10C is the one causing trouble. When Trim28 is gone, the histones around these ERVs are not in the 'off' position. The DNA around these ERVs is not in the 'off' position.

4. In addition to the ERVs being transcribed, there was also an increase in transcription of 28% of the genes near the ERVs. Not all genes are 'on' in all cell types. Turning unnecessary genes 'on', or increasing/decreasing the expression of 'on' genes, can cause chaos in a cell.

Conclusion? Though Histone/DNA modification USUALLY controls ERVs in somatic cells, in this case (neural progenitor cells), TRIM28 needs to work too. If its not there, stuff gets messed up. Like hardcore messed up.

We have previously demonstrated that deletion of Trim28 in postmitotic forebrain neurons results in complex behavioral changes (Jakobsson et al., 2008). In addition, heterozygous germline deletion of Trim28 has been described to result in abnormal behavioral phenotypes (Whitelaw et al., 2010). In this study, we found that deletion of Trim28 during brain development is lethal (Figure S3). In addition, we also noted that heterozygous deletion of Trim28 during brain development resulted in behavioral changes characterized by hyperactivity (Figure S3). Together, these findings demonstrate that disruption of TRIM28 levels in the mouse brain results in behavioral changes that are similar to impairments found in humans with certain psychiatric disorders.

Many genes (in mice!) are disrupted when TRIM28 is deleted, some ERVs are too. And it is a train-wreck. Dead baby mice. Behavioral changes. Train-wreck. ERVs making noise are assholes. YAY for shutting them up!

Pretty straight forward paper.

I thought a Creationist just read 'junk DNA' 'ERV expression' and was somehow arguing that 1) dead baby mice, 2) abnormal behavior in mice, is evidence for Intelligent Design.

But this Creationist didnt get his idea out of thin air. The authors of this paper also have some strange interpretations of their data.

I think the authors might be somewhat confused-- They seem very excited about the fact that when they got rid of TRIM28, some of the genes around ERVs are over-expressed. We have known for a very, very, very long time that retroviral/ERV promoters can act as promoters for nearby genes. This is, to my knowledge, been universally bad. This is one of the ways retroviruses, and ERVs, can cause cancer and other diseases. Disrupting normal gene expression.

The data in this paper also supports the idea that wayward retroviral promoter activity is bad. When they disrupted control of ERVs, mice *die* or, if control is disrupted later, have behavioral abnormalities.

But the authors speak as if the *opposite* were true.

ScienceDaily--A new study from Lund University in Sweden indicates that inherited viruses that are millions of years old play an important role in building up the complex networks that characterise the human brain.

Researchers have long been aware that endogenous retroviruses constitute around five per cent of our DNA. For many years, they were considered junk DNA of no real use, a side-effect of our evolutionary journey.

In the current study, Johan Jakobsson and his colleagues show that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when. The findings indicate that, over the course of evolution, the viruses took an increasingly firm hold on the steering wheel in our cellular machinery. The reason the viruses are activated specifically in the brain is probably due to the fact that tumours cannot form in nerve cells, unlike in other tissues.

"We have been able to observe that these viruses are activated specifically in the brain cells and have an important regulatory role. We believe that the role of retroviruses can contribute to explaining why brain cells in particular are so dynamic and multifaceted in their function. It may also be the case that the viruses' more or less complex functions in various species can help us to understand why we are so different," says Johan Jakobsson, head of the research team for molecular neurogenetics at Lund University.

Scientific American-- By manipulating mice genetics, researchers found evidence that some endogenous retroviruses gained new roles that are important for brain development in our not-so-distant rodent relatives. “Brain cells are very complex compared to other cells,” says Johan Jakobsson, a researcher at Lund University in Sweden and lead author of the study. “Co-opting endogenous retroviruses allows for much more complexity, especially since they make up so much of the genome.”

Press Release-- "Do viruses make us smarter?"

If, when they *silenced* ERVs, there was death/abnormalities, *that* would support the idea that ERVs play a role in brain development. But that is simply not what they, or anyone else as far as I know, have observed. They observed what we already know: Wayward ERV expression is virtually universally BAD. ERVs=Death. ERVs=Disease.

I literally have no clue where the authors are getting the idea that ERV expression is a good thing. Thats not what their data says. If anything, their data says neural progenetor cells require an extra level of protection from ERVs.

So, its opposite day.

Scientists are saying their data says the opposite of what it says.

And Im looking at scientists, baffled, and telling Creationists "Its not your fault you said something stupid."

sa smith Sun, 01/25/2015 - 10:01

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'HIV infection en route to endogenization: two cases' facepalm

sa smith — Fri, 05 Dec 2014 12:26:08 +0000

'HIV infection en route to endogenization: two cases' *facepalm*

For some reason, pop news became enamored with this paper last month (unfortunately while I was away at a conference):

HIV infection en route to endogenization: two cases

Inexplicable media frenzy--

Scientists find mechanism for spontaneous HIV cure

French scientists find genetic mechanism by which two men were spontaneously cured of HIV.

HIV discovery offers new lead in finding cure

I have a lot of problems with this paper. Starting with the first sentence.

The long-term spontaneous evolution between humans and the human immunodeficiency virus (HIV) is not well characterized.

"Spontaneous evolution"? Wat? Do they mean basic co-evolution of HIV and humans? While the field hasnt 'done everything', co-evolution has been explored, to the point where I have written about it on my blog (which covers only the smallest percentage of HIV papers).

And this paper doesnt improve at all from there. I mean basic stuff like descriptions of reagents used (peptide library. neat. WHICH ONE?) This paper is functionally useless to me.

But because they issued some press release, every pop news outlet from MSN to Al Jazeera was talking about their paper, and now I have to to dispel some flat-out bad science.

1-- Are these two people 'cured' of HIV/AIDS?

No. Nothing in this paper suggests they are. The two patients are long-term non-progressors.

2-- Is HIV becoming an endogenous retrovirus?

No.

Firstly, there are very, very, very few endogenous lentiviruses. There is something about them that is not conducive to endogenization. There are no endogenous SIVs in primate populations that have been co-evolving with their SIVs for much longer than humans ~100 years with HIV (the 'best' we have in that lemur ERV, linked above). In fact pin-pointing exactly how old HIV/SIV viruses are has been extremely difficult because of this, so scientists have had to study the evolution of SIV in geographically/temporally isolated colonies of animals, and study the evolution of primate genomes to extrapolate the age of SIV-like retroviruses:

Paleovirology– HIV-1s ancestors just got older

HIV-1s ancestors just got older-er

Indeed the 'example' they gave in this paper is the retrovirus in the process of endogenization in Koalas, is a gammaretrovirus. Another common example-- MMTV in mice-- is a betatretrovirus. Gammas and betas are the retroviruses that tolerate being endogenized 'the best', and even *then* it is an accident. To people not familiar with retroviurses, theyre all just 'retroviruses', when in reality, they are two entirely different creatures.

There is also nothing, nothing, in this paper that suggests HIV is becoming an ERV. Nothing. Step 1 would be sequencing the genomes of sperm. Is HIV getting into sperm genomes, thus potentially creating an ERV? No idea. They didnt look.

Is there a child born to an HIV+ mother who is 'HIV+', and has 'HIV+' skin cells, liver cells, smooth muscle cells, etc and no immune response to HIV? Cause that would be evidence for endogenization!

But they dont have anything like that.

However, because I want you readers to learn SOMETHING for clicking on this post, Im going to thought-experiment-answer a third question:

3-- Is an HIV ERV a cure for HIV?

Again, this is thought-experiment country, here.

With MMTV, having endogenous MMTVs can protect against infection from exogenous MMTVs. The key here is how. Well, your immune system automatically kills developing immune cells that recognize 'self'. If you have an ERV active at the right place/right time, your immune system will kill any immune cell that recognize the retroviral proteins.

With MMTV, the protein of interest is 'SAg'. Exogenous MMTV needs the immune system to react to SAg to establish infection. But if there is an endogenous MMTV, any immune cell that sees MMTV SAg will be killed. No immune reaction=Protection from exogenous infection.

Maybe.

Because sometimes an endogenous MMTV leaves a mouse *more* susceptible to infection.

Getting back to HIV-- HIV does not have a protein homologous to MMTV SAg, because HIV and MMTV are not the same creature.

I think a likely outcome from an endogenous HIV would be... nothing.

The world-wide HIV quasispecies is so diverse, its likely that one would be exposed to an exogenous HIV that looked nothing like the endogenous HIV (ie, the reason why we have a hard time making an HIV vaccine). An endogenous HIV would look so different from the HIV a person was actually exposed to, that any negative selection of B- and T-cells would likely be pointless.

IF the exogenous and endogenous were similar enough, you would still be infected with HIV, but have fewer CD4+ and CD8+ and B-cells that could be activated to fight that infection. Now, a lot of the 'problems' with HIV/AIDS come from an over-activated immune system, so maybe no reaction would be a good thing? But you are not going to clear an infection by not fighting it, either.

None of this equals endogenous HIV as a cure for HIV.

Even for fun, I cannot think of a pathway from endogenous HIV-->CURE, and there is nothing in this paper to help us make that connection.

sa smith Fri, 12/05/2014 - 07:26

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ERVs vs HIV-- Maybe a bad idea

sa smith — Wed, 24 Sep 2014 11:45:53 +0000

ERVs vs HIV-- Maybe a bad idea

For quite a while, now, there has been a connection between Endogenous Retroviruses and HIV. For some unknown reason, some of the young ERVs in humans, the ones that can still code for a protein here and there, are reactivated in HIV+ patients. Scientists have found ERV RNA in HIV+ patient plasma, and they have even found cytotoxic T-cells that target ERV proteins.

HIVs controlled by HERVs

This lead some scientists to believe that maybe, maybe, ERVs could be a good target for an anti-HIV therapy.

HIV changes a lot. It is really hard to train your immune system to fight it.

ERVs are 'human', now. Which means they are 'self', and attacking them could be bad (it would be a kind of purposeful autoimmunity), but because the ERVs are 'human', they wont mutate much. HIV is a moving target. Targeting the ERV activated by HIV infection could be a non-moving alternative anti-HIV target.

HERVs and HIV-1

Bad news. Targeting ERVs as a 'sneak attack' on HIV is probably a bad idea.

HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) Proviruses In Vivo but Not to Increased Virion Production

The problem is, we dont know exactly how or why ERV RNA/DNA/proteins are being expressed in HIV+ individuals.

If it is something very very specific, something that only happens in a CD4+ T-cell in direct response to that being infected by HIV, that would mean targeting the ERV is a great idea. You could train the HIV+ individuals immune system to 'see' the ERV components in an HIV infected CD4+ T-cell, and BAM! Kill the HIV infected cell!

BUT, if it is something very very broad-- like, over activation of the immune system leads to wide-spread disregulation and expression of ERV RNA/DNA/proteins, that would be targeting ERVs is a terrible idea. If you trained the HIV+ individuals immune system to 'see' ERV components... the immune system could not only target the HIV infected cells, but also other immune cells-- The B-cells the patient needs to fight HIV, the CTL cells the patient needs to fight HIV, the CD4+ T-cells the patient is trying to preserve... and who knows what else.

In this paper, they still havent nailed down *WHY* ERV components are expressed in HIV+ individuals, but they did determine that ERV activation is broad.

... total PBMCs from HIV-infected and uninfected patients were sorted into CD4+ and CD8+ T cell subsets, in addition to B cells and monocytes. These cell types represent the major constituents of PBMCs, although smaller populations, including dendritic cells and NK cells, could potentially represent sources of HML-2 expression. When HML-2 RNA upregulation was assessed in sorted cells, we saw no significant difference in expression in any subset from HIV patients compared to controls, although each subset individually showed a small increase in patients compared to controls, with the greatest difference in monocytes, a cell type that is not a target for HIV infection in vivo (59). The lack of enrichment in the CD4+ T cell population is consistent with HML-2 RNA expression having no clear relationship to HIV replication (Fig. 4), while the lack of enrichment in other cell populations could exemplify the indirect mechanism regulating HML-2 expression in HIV-1-infected patients. The differences in the magnitude of HML-2 transcription in cell subsets could be due to cell-specific transcription factors, methylation patterns, or other epigenetic changes, which are believed to control endogenous retrovirus expression in differentiated tissues (60, 61). Based on these results, it appears that differential expression from multiple cell sources may lead to the 2-fold difference in HML-2 expression in HIV-infected versus control individuals.

There was a slight increase in ERV RNA in each cell type in HIV+ vs controls. The difference between HIV+ and control is all of these little differences adding together, NOT because ERV RNA is expressed in HIV infected CD4+ T-cells.

Based on these observations, it appears that the use of HML-2 expression as a way to target HIV infection carries a significant risk of off-target effects. Our data suggest that HML-2 protein may be expressed in CD8+ T cells and B cells. Thus, targeting HML-2 epitopes may affect these cells and weaken the cytotoxic and humoral arms of an individual's immune response to HIV-1 infection (69).

Damn.

sa smith Wed, 09/24/2014 - 07:45

Tags

How very interesting

awesome blog. i believe it's only when HIV decides to take the plunge and become an ERV, i.e., integrate into our germline, that HIV will spell the beginning of it's end, as we currently know it. i once heard Will Taylor refer to HIV as a "fallen angel". that comment fits well with your blog tagline. i wonder what HIV will create in us if and when it does become an ERV????????

An 81 million year herpes infection: First endogenous herpes virus found!

sa smith — Tue, 24 Jun 2014 08:00:43 +0000

An 81 million year herpes infection: First endogenous herpes virus found!

1-- Herpes viruses are old. They are ooooooold. Like, hundreds of millions of years old. Specifically, about 400 million years old.

2-- Herpes viruses are everywhere. Fish, reptiles, birds, cows, humans, everywhere. And there are lots of different kinds that humans have to deal with-- CMV, EBV, HHV-8, VZV, HSV...

3-- And, though herpes viruses should not be inserted into the genome of their host cell, generally, some herpes viruses can. Its called 'strategic somatic genome integration', and some herpes viruses (and only a small percentage of cells infected with that virus) do insert.

So considering 1), 2), and 3) above, its kinda odd we havent found an *endogenous* herpes virus yet, right? I mean chance + 400 million years = its gotta happen sometime!

A couple things have complicated the hunt for endogenous herpes-- the fact many host organisms 'complete genome' is not really 'complete' and only 'first drafts', and the nature of the herpes genomes. They are complicated. So even people specifically hunting for endogenous non-retroviruses, shy away from herpes. It can be an exercise in futility.

One of my favorite labs dug in and finally found some!

The First Endogenous Herpesvirus, Identified in the Tarsier Genome, and Novel Sequences from Primate Rhadinoviruses and Lymphocryptoviruses

In the genome of this ridiculously cute creature:

http://en.wikipedia.org/wiki/Philippine_tarsier

They found a herpes virus that 'looks' like Human Herpes Virus-6 (HHV-6). And not only did they find the virus, they determined the tarsier genome around the virus (as in, it is not a contaminant/mistake, the virus is *in* the tarsier DNA). And, they confirmed the herpes virus was really there themselves, in a different tarsier.

And, like many ~~specially designed viruses inserted into genomes by our creator~~ viral footprints of evolution in our genome, the endogenous tarsier herpes virus is non functional. Frame-shifts, stop codons, it is no longer the infectious virus it once was. Its just a fossil. In fact some of the characteristics of a HHV-6-like virus were 'mutated beyond recognition'.

Not only did this lab find the first genuine endogenous herpes virus, they did it with 'publicly accessible data and open source software'. They needed a good strategy (looking for HHV-6 like elements) and the will to dig through a lot of garbage. That hard work payed off in them getting exactly what they wanted! Herpes!

:-D

More info:

http://www.paleovirology.org

sa smith Tue, 06/24/2014 - 04:00

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Corals. You forgot corals. LOTS of herpesviruses!!

I still don't understand why our genomes accommodate so much damn dead weight. I mean, sure, we don't have to replicate our genomes as much as bacteria, but you'd think there's be *some* selective pressure to ditch the cruft.

Ed - that sounds really interesting, I knew of the oyster herpesvirus, but not corals! Can you recommend a paper?

This can't be right. It violates the principle of homologous recombinaltion tiniker.

Heh. What a great effort, searching through the data. I love the implied (well, to me, at least) image of species as little islands of waxing / ebbing "stability" in a swirling ocean of mobile, transferable genetic elements.
In my old age, I now have biology envy :\ YOU BASTARDS.

Soooo ... you're sayin' God has herpes?

@Kevin #3
Think of all that "junk" as a backup plan. Kind of like the spare tire you lug around, even though it technically wastes fuel, because you might need it. One day. Or not...
Of course, the other side of that is that a lot of what we used to call junk is stuff we now realize is incredibly important! Who knows what we will learn about the rest of that excess DNA sequence and how it helps us....

Hey, Kevin

Let me first say that i looked up the integration site for the endogenous herpes in these primates. However, the herpesvirus genome is full of enhancers, insulators, transcription factor binding sites and other transcriptional regulatory elements. While the protein coding sequence has degraded over evolutionary time, these regulatory regions may still serve a purpose. There are examples of this for endogenous retroviruses and their LTRs. Other endogenous retroviruses create regulatory long non-coding RNAs that are important for the maintenance of a stem cell phenotype. I believe we are nearing a paradigm shift in biology where we respect these endogenized viruses and stop calling them "junk"

Oops "have not looked up"

@ both Kevins

I think that while some EVEs probably do offer some kind of function, there's probably a lot more that doesn't do anything, which I think is what first Kevin is wondering about. my take on this is that as long as its not *too* harmful, then there won't be enough of a selective pressure to purge something from a genome. This is why much of it just drifts at the neutral rate. However, there is evidence to show that even currently non-functional viral fossils appear to have degraded less than would be expected given the neutral rate and time since integration, therefore suggesting they were once useful to the host. Maybe with more data, we'll be able to answer some of these questions - it would be cool to find out if a host selective advantage was the reason many viruses integrated in the first place!

Oh dear this is a mess: ERVs and Multiple Sclerosis #5

sa smith — Wed, 18 Dec 2013 09:00:07 +0000

Oh dear this is a mess: ERVs and Multiple Sclerosis #5

Okay, I have written a LOT about the connection between wayward ERV activity and Multiple Sclerosis. This is something scientists have been investigating for a long time... but we still do not know exactly what is going on.

It seems the running hypothesis is that 'something'/'somethings' alter the epigenetic profile of individuals DNA, allowing for expression of an endogenous retroviral Envelope protein, especially in the brains of (future) MS patients. These proteins are pro-inflammatory, start causing all sorts of trouble, like MS.

Its gotten to the point where other scientists are trying anti-ERV-Env therapies to fight MS.

But, we still dont *know* this chain of events is what is leading to MS, or that targeting Env expressing cells would stop MS.

Comprehensive Analysis of Human Endogenous Retrovirus Group HERV-W Locus Transcription in Multiple Sclerosis Brain Lesions by High-Throughput Amplicon Sequencing

A lot of the ERV-->MS papers are looking at ERV expression in the blood cells of MS patients. That has *really* bothered me. Why would someones CD8+ T-cells tell you anything about what is going on in their brains?

But, I fully understand that brains are not as easy to study as blood.

In this paper, however, they looked at the brains of MS patients and controls.

There was no difference in ERV expression between MS patients and controls.

:-/

The data was all over. Some MS patients had some ERV expression up, and other ERVs were down. And some ERV expression was up compared to some controls, but equal to other controls. They called it "interindividual variation regarding overall and locus-specific HERV-W transcript levels".

It still might have nothing to do with the ERV Env proteins. The presence of the proteins might be an artifact of the ERV LTR (promoter) activity. Because this paper did note that the LTRs associated with the ERVs associated with MS retain promoter activity in both directions (think of it as a book you can read forwards and backwards), even if they arent perfect LTRs (mutations).

Maybe its not the ERVs in the genome, but the stuff around the ERVs that are being expressed inappropriately that are causing trouble?

:-/

What a mess.

Though we have learned a *lot* about ERVs-->MS, we are still where we were at when I wrote about this in 2009:

Active ERV proteins could be a cause of MS, an effect of the cause of MS, or an effect of a cause that ends up perpetuating MS.

Bonus for those of you familiar with the XMRV fiasco-- In 1997, a paper in PNAS reported they found a novel retrovirus in Multiple Sclerosis patients, MSRV. This current paper says those 'novel retroviral sequences' were really just recombination in sequencing of ERVs. Totally an artifact, not 'real'. Yup...

sa smith Wed, 12/18/2013 - 04:00

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ERVs

erv

Multiple sclerosis

Not to be snarky, but...

Why would someones CD8+ T-cells tell you anything about what is going on in their brains?

CD8+ T cells are the major pathological cell in MS. It is these cells that enter the CNS and kill oligiodendrocytes. And since these cells continually re-circulate, looking at them tells you a hell of a lot of what is going on at the site of immune activity. We (grand 'we', not me specifically) have been IDing active, MS-antigen specific T and B cells in the peripheral blood of MS patients for a good 20 years.

This results is pretty much what any immunologist would have expected. Many immune cells - T cells among them - produce HERVs when activated. As far as I can recall, the first images of HERV VLP's exiting cells were observed in activated T cells.

I suspect that the variability they observed could have been due to sampling errors - if they took pieces of inflammed brain from some patient, but uninflammed regions from others, you would expect to see this sort of heterogenety. This is quite common with immune responses in the brain - they tend to be highly localized (to the point that immune cells for tertiary lymphoid structures - transient "lymph nodes" in the brain). Finding consistent results requires either analysis of large brain volumes, or careful microdissection to include/exclude things like the tertiary lymphoid structures.

"This results is pretty much what any immunologist would have expected. Many immune cells – T cells among them – produce HERVs when activated...."

Indeed, so HERV expression is associated with inflammation. MS is an inflammatory disease. Correlation not causation.

"I suspect that the variability they observed could have been due to sampling errors"

Indeed..or..not errors. Just the inflammatory state of the T-cells in the sample.

One other question, from an interested outsider. HERV-W gag and env are expressed normally in healthy brain tissue, though the levels may or may not be higher in MS related inflammation. Functional necessity had been suggested by the same group for at least the gag in CNS, as with env / syncitin in the placenta? That wouldn't necessarily make anti-ERV Rx dangerous even in the long term - but it would add to the caution about targetting env.

HERV-W gag CNS expression is particularly high in various CNS sites with high and consistently specific levels of local variability. The middle temporal gyrus, not an area renowned for redundancy, for example showing esp. high expression. The authors conclude, 'Our current findings that human tissues harbor patterned and extensive expression of genomic loci containing HERV-W elements, suggests that functionality for such transcripts cannot be ruled out.

Neanderthal and Denisovan retroviruses in YOU!

sa smith — Thu, 21 Nov 2013 09:00:34 +0000

Neanderthal and Denisovan retroviruses in YOU!

Well, some of you! And maybe me!

Last year, scientists combed through Neanderthal and Denisovian DNA sequences (yeah, those exist!) and found fourteen ERVs that were in Neanderthals and/or Denisovians, but NOT humans.

Neandertal and Denisovan retroviruses

SUMMARY:

Modern humans (Homo sapiens) last shared a common ancestor with two types of archaic hominins, Neandertals and Denisovans, roughly 800,000 years ago, and the population leading to modern H. sapiens separated from that leading to Neandertals and Denisovans roughly 400,000 years ago [1,2,3,4]. Genome sequences for these two types of archaic hominins have been reported [1,2]. They were determined by sequencing ancient DNAs using techniques that generated many short sequence reads. Here, we analyzed individual sequence reads used to assemble the published Neandertal and Denisovan genomes for insertions of Human Endogenous Retrovirus K (HERV-K) DNA. Virus–host DNA junctions were identified that defined 14 proviruses where modern humans contain the corresponding, empty, preintegration site. Thus, HERV-K reinfected germ lineage cells of Neandertals and Denisovans multiple times, and these events occurred around the time of or subsequent to the divergence of the archaic hominin lineages from that leading to modern humans. One of the proviruses was shared by Neandertals and Denisovans, which is consistent with the hypothesis that these archaic humans shared a common ancestor more recently than they shared one with the lineage leading to modern humans.

Remember, HERV-K ERVs are usually the 'youngest', thus the most likely to be polymorphic between humans, Neanderthals, and Denisovans. In humans, there was no evidence these 14 Neanderthal/Denisovan ERVs were ever there (not a broken ERV, not a solo LTR, just regular ol DNA sequence).

The conclusion was, was that these Neanderthal and/or Denisovan ERVs must have inserted themselves into their respective genomes after the ancient relatives/human split.

BUT

Speciation isnt a 'clean' break. Its not as if one day there is a human/Neanderthal/Denisovan ancestor, and the next day there are humans and Neanderthals and Denisovans.

Speciation is a time consuming, tangled up mess.

So this new information isnt surprising at all:

Neanderthal and Denisovan retroviruses in modern humans

The human genome project, the human reference genome, does not contain the genomes of all humans. It contains the genomes of a select few humans.

These researchers hunted through the genetic sequences of individuals whos genomes were sequenced for other reasons (a cancer project) and they ended up finding most of the 'absent' ERVs! Not in every patient, but some patients had one, some patients had others, etc.

What does this mean?

With the exception of co-opted ERV loci such as syncytins [5], which could increase in frequency due to positive selection, we assume ERV loci become common by genetic drift, and the average time for a neutral allele to go to fixation is 4Ne generations (where Ne is the effective population size). Given estimates of long-term human generation time and population size [6], this is ∼800,000 years. The population divergence of modern humans from the Denisovan/Neanderthal lineage is more recent, between 170,000 and 700,000 years according to a more recent — and much deeper —sequencing of the above Denisovan fossil [7], so many loci will have persisted at fluctuating frequencies in all three lineages.

It means unless an ERV is really positive (and selected for) or really negative (and selected against), ERVs just drift. They will remain polymorphic in a population until a given number of generations, depending on the size of the population (that is, all humans have the same really old ERVs, these younger ERVs are different between humans).

So some of us have more in common with our Neanderthal and Denisovan ancient cousins than others.

Neato!

sa smith Thu, 11/21/2013 - 04:00

Tags

ERVs

evolution

erv

The implication seems to be that these ERVs found in a minority of modern humans are leftover from several hundreds of thousands of years previously and moving, slowly, towards fixed absence. An alternative hypothesis is that they were later acquired by the interbreeding that has now been pretty well demonstrated to have occurred to a small degree. If the former hypothesis were true, you would expect some of them to be found in Africans, who are more genetically diverse than Eurasians and their descendants; if the latter, you'd expect sub-Saharan Africans not to have any (though perhaps to have others acquired from the recently reported probable interbreeding with archaic humans there).

"fourteen ERVs that were in Neanderthals and/or Denisovians, but NOT humans"

They were humans :-(((

I haven't made the trip to the library to see this paper yet. Can they tell from the haplotype around each insertion whether the ERV was first inserted in modern human or Neandertal/Denisovan? Without this, it seems possible that the insertion could have occurred in either lineage and been transferred during mating ,or even that the insertion occurred before they divergence of the lineages with incomplete lineage sorting determining what we see today.

While I will not pretend to understand everything she is talking about with ERVs, and how a virus can introduce its DNA into ours, as I am not a scientist; It appears many, many Scientists spent a lot of time in a Lab, but perhaps should have taken a one or two Philosophy classes.
You do understand the absurdity of saying that because entity X has attribute 1 , and entity Y has attribute 1; therefore entity Y came from entity X?
I guess a very simple analogy would be "My cat has the common cold, I have the common cold, therefore I came from my cat..." It's equally absurd to say "Cave man x has an attribute of ERV X, I have an attribute of ERV X, therefore I must have came from, am related to, or have any connection what so ever to cave man x." It may or may not be true however, but the like attributes do not prove it.
Possessing like attributes, even when talking about progeny, does nothing to prove causation. Just thought you should know this...
Actually, here's a bit of a challenge for you. Can you give me any example, of anything, anywhere, other than the one you provided, where we would look at two entities and determine that because they have some like attribute, that one caused the other? The emphasis here is that the similarities are the crux that prove the causation.

Hey Matt,
The difference between your examples and what scientists use do determine relatedness (descended from, or sharing common ancestry) is that you are talking about phenotypes - hair colour, proteins, placentas - and these can be produced from different sents of instructions, such as birds and insects both having wings - or you are talking about things that are not passed genetically, like the common cold. What is evaluated in these papers is the DNA - that is, the particular source of a phenotype. The DNA that codes the (very complex) information for a bird's wing is drastically different and easily distinguishable from the sequence that codes for an insect wing, so we know that these two things, although similar in appearance, arose from different sources and are not evidence for genetic relatedness. The ERVs discussed here, when found in ancient Neanderthal and Denisovian, or modern human, DNA, have sequences that are similar enough that we can say with confidence "They are the same in Neanderthals as in modern humans and must have a common origin." Much like the DNA that codes for syncytin (coded by an ERV that is found in placental mammals and is key in us having a placenta), or the various sequences that together give us fingers.

ERVs, from three perspectives

sa smith — Thu, 14 Nov 2013 09:00:00 +0000

ERVs, from three perspectives

I love viruses, and I love ERVs, but I am not the only one :-D

Here are some links to pieces people have written about these lovely pirates, from three different perspectives.

1-- Nicholas Covington at Humes Apprentice (formerly AIG Busted!) is more a philosopher than a scientist, but even as a 'layman', he gets what ERVs are, and their place in evolutionary biology:

Proving Darwin: Fun with Endogenous Retroviruses!

2-- Carl Zimmer is no stranger to viruses. While he is still a 'layman', he has turned a personal fascination into a professional interest in viruses and ERVs. I love his writing on viruses, and this latest piece is no exception:

How Our Minds Went Viral

We have a ton of ERV elements in our genome. Carl writes about a paper where scientists looked at some of the youngest ones (the ones most likely to retain some kind of function) in humans, and specifically looked at the viral promoters to see if any of them had been co-opted for host (human) use.

The Big Differences between humans and our closest ancestors is not necessarily our genes, but the expression levels of those genes. These scientists found one ERV promoter that might have played a role in altering a genes expression in certain parts of the human brain.

It is hard to tell the difference between 'An ERV promoter CAN do X' and 'An ERV promoter DOES do X', and Im not sure whether the scientists are there yet, but its a cool paper nonetheless. I totally missed this paper, so Im glad Carl caught it!

3-- If you want to read ERVs from a professional who is not me, there was a cool little bio piece on Ravinder Kanda a while back that I never got around to linking to. Dr. Kanda is a post-doc in the Zoology department at Oxford, who also got bitten by the ERV bug:

Women in Science: Genome Invaders – Friend or foe?

That department is also home of Aris Katzourakis, someone who has done some super sweet ERV research.

sa smith Thu, 11/14/2013 - 04:00

Tags

ERVs

evolution

erv

"Women in Science: Genome Invaders – Friend or foe?"

Women are getting into science to steal our genomes!11! Protect the purity of your bodily fluids.

Anti-ERV as anti-Multiple Sclerosis... Is this a good idea?

sa smith — Wed, 13 Nov 2013 09:00:01 +0000

Anti-ERV as anti-Multiple Sclerosis... Is this a good idea?

I have written quite a bit about the connection between wayward expression of an ERV, and Multiple Sclerosis.

ERVs and Multiple Sclerosis

ERVs and Multiple Sclerosis, #2

ERVs and Multiple Sclerosis, #3

ERVs and Multiple Sclerosis, #4

ERVs and Multiple Sclerosis, #5

I am very comfortable saying there is a connection between ERV expression and MS. I am not confident in saying 'If we destroy the cells producing this ERV, we will stop MS.'

I totally get that the ERV protein in question, an Env, can be inflammatory in the brain, so knocking that out might stop some inflammation/damage in the brain.

But the cells producing this ERV are not tumors. They are not virally infected cells. If this Env is being expressed because of epigenetic modifications, then targeting the Env cells will not necessarily help. I would think you need to target the environment allowing the development of these cells. If you dont, it seems like all you will do is, for example, kill 5 Env expressing cells, and then 5 more will take its place, over and over. Having a lot of cell death (even controlled, purposeful cell death) going on can be bad for the patient.

Buuuut it seems some people are willing to try an anti-ERV therapy in the form of a therapeutic monoclonal antibody, GNbAC1, in the hopes it will stop MS. Because the ERV they are targeting is not a 'retrovirus' that changes all the time, but a 'retrovirus' that has become a part of us, they can fairly confidently create antibodies that will target the ERV Env protein on the surface of cells. Once this antibody binds to the target cells, the antibodies can either directly lead to death of the cell, or they can recruit effector cells that will kill the Env expressing cell.

They have given various doses of this therapeutic anti-ERV antibody to healthy patients (Phase I clinical trials) and nothing obviously 'bad' happened. And, now they have given the anti-Env antibody in various doses to MS patients, and nothing obviously 'bad' happened (Phase IIa).

The next goal will be to see what kinds of doses they have to give MS patients to see any positive effects (if any dose will lead to positive effects), and then see if anything 'bad' happens at those doses.

I really hope this works out, for the researchers and the patients! I just dont have those hopes up too high. Im not sure if this is the best idea...

sa smith Wed, 11/13/2013 - 04:00

Tags

ERVs

erv

Multiple sclerosis

Seems like this is shutting the barn door after the horse has left, or whatever that saying is. The inflammation leading to MS seems like a plausible etiology, but once the T-cells get going and you actually have symptoms, the cascade seems like it would be hard to stop.

Maybe this in combination with Natilizumab, so you stop the T-cells from getting in, and then block the inflammation so they don't come back?

I dunno about any of this, but here's the latest thing I've read about possible new developments in MS.

'Toxin-Emitting Bacteria May Be Environmental Trigger for MS'
http://www.healthline.com/health-news/ms-bacteria-identified-as-possibl…

Already researched in Denmark 350 RRMS patients and SPMS patients have the Herv FC1 virus another study reveals PPMS patients have the Herv fc 16 virus

How the Appaloosa got its leopard spots

sa smith — Mon, 11 Nov 2013 09:00:23 +0000

How the Appaloosa got its leopard spots

I have no idea how the leopard got its spots, but scientists have figured out how horses got their leopard spots!

Evidence for a Retroviral Insertion in TRPM1 as the Cause of Congenital Stationary Night Blindness and Leopard Complex Spotting in the Horse

Get this!

Scientists have known for a few years that it is mutations within 'transient receptor potential cation channel subfamily M member 1' (TRPM1), that cause leopard spots and sometimes night blindness in horses. It turns out the bugger causing both of these phenotypes is a retrovirus that decided to plop into TRPM1.

The retrovirus did this in an egg or sperm, so it became an endogenous retrovirus. At some point, the two LTRs overlapped and cut out the 'virus' part of the ERV, so there is only a single LTR left. This happens the majority of the time with ERVs, but these solo LTRs are still disruptive.

In this case, the presence of the LTR results in a partially dominant fur/vision phenotype.

ERV-/ERV- horses dont have white patches on their horse butts, and have no vision issues.

ERV+/ERV- horses are white/have white patches on their butts WITH leopard spots, and have no vision issues.

ERV+/ERV+ horses are white/have white patches on their butts with NO leopard spots, and DO have vision issues.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0078…

Random mutations leading to phenotypic diversity!

Though the insertion does cause, what we would call a 'negative' phenotype (reduced night vision), the insertion has been maintained in the horse population for about 17,000 years.

THAT is how the Appaloosa got its spots (and some other breeds) :-D

sa smith Mon, 11/11/2013 - 04:00

Tags

ERVs

evolution

erv

Huh. It'd be interesting to find out how many different species have similar variations. I just recently found out I have something called "multiple lentigines syndrome" -- basically, I'm spotty everywhere, which I knew -- apparently the syndrome can also include eye and heart issues. My eyes are ok (for my age), but turns out I also have an inverted T-wave. Nothing serious though.

Here's the dl on the genetic variation in humans: http://ghr.nlm.nih.gov/condition/multiple-lentigines-syndrome