Mitochondrial ERVs

EMAIL!

Dear ERV–

Hope you don’t mind a real question instead of the stupid stuff teh idiots usually send you.

This morning we had a lecture by Salvatore DiMauro, M.D. from columbia university (he is neurolog/neuromuscular mainly mitochondrial diseases) about mitochondrial diseases.

Any evidence for ERV’s in the mitochondrial genome?

Cool question!

Short answer– No. Mitochondria have a different kind of integrated virus…

Long answer– There are two ways mitochondria could get an ERV.

Retrovirus infected bacteria was the original endosymbiont 1.7-2 billion years ago– Not likely. We dont have any evidence retroviruses have/do infect bacteria.

Retrovirus infected mitochondria post endosymbiosis– Not likely. A ‘naked’ retrovirus that has infected a cell has no way of getting into a mitochondria. Especially the kind of retroviruses that tend to form ERVs– They need the nuclear envelope to dissolve to gain access to nuclear DNA. Their cDNA would have a lot of trouble crossing mitochondrial membranes, if it was even misdirected towards the mitochondria instead of the nucleus in the first place. And, while there is some suggestion that plant mitochondria can take up double-stranded DNA, what they are capable of sucking up is a fraction of the size of the smallest retrovirus.

But this doesnt mean mitochondrial genomes are virus-free! Mitochondria werent always a part of us. They used to be bacteria. And bacteria have PHAGE!!

You know how human genomes can commandeer ERV proteins and promoters for stuff? Mitochondria have done the same thing… with phage genes! Phages are DNA viruses that infect bacteria. But they insert, permanently, into genomes like retroviruses. So bits and pieces of phage genome in an endosymbiont 1.7-2 billion years ago have turned into mitochondrial genes!

Awesome question!

Comments

#1 Ranson
July 30, 2009

I’ve got a buddy that’s very interested in phages. I’ve got to send him this…
#2 AZSkeptic
July 30, 2009

Wow!! Science and a nod to Doc Horrible. What a good way to start the morning off right…
#3 Barklikeadog
July 30, 2009

Ohh! You’re very good, Abbie!
#4 Paulino
July 30, 2009

My mind still boggles about this whole endogenous viri thing. What a marvelous research field it must me.

Why don’t you put up a section on the left column (<–over there) with a selection of your older posts for your interested readers?

Thanx!
#5 Sili
July 30, 2009

What? No “phag” jokes?

AND FOR FUCK’S SAKE! “VIRI” IS NOT A WORD! IT’S FUCKING NOT A BLOODY WORD! NOR IS “VIRII”!

ARRRRGLE! RAARRRRGLE! BLARRRRGLE!!
#6 Cain
July 30, 2009

Wait…so your first point means retrovirus didn’t exist before eukaryotic cells evolved? That’s pretty freakin cool.
#7 Jason Thibeault
July 30, 2009

This is so damned cool. Wow.
#8 The Chimp's Raging Id
July 30, 2009

So much win here, I’m not sure where to begin. Thanks as always, Abbie, for the gud science learnin!

OT: May I ask for your take on ?
#9 The Chimp's Raging Id
July 30, 2009

Typing fail. The missing last word was “this.”

And the article I was trying to link to was this:
http://www.newscientist.com/article/mg20327194.500-brain-cells-show-surprise-immunity-to-hiv.html
#10 Scott Fanetti
July 30, 2009

Paulino,

Virus is a mass noun – where the word refers to an uncountable mass of subcomponents. Rice, water, furniture, etc. These are not count nouns that are usually subject to modification to make a plural form.

Viri and Virri are neologisms – that I think could eventually make it into the common vernacular – but they have much more competition with the term viruses. The latin -us rule for plurality applies to many things but not to virus.

Sili,

ferfucksake – don’t yell. Educate. I am sure Paulino would have been more happy to understand why a particular construction is wrong than to be berated by a pedantic git.
cheers.
#11 Paulino
July 30, 2009

@Sili

Ok, got it, but virus/vira/viruses(blergh) is such an uncommon case… Still viri IS fucking a bloody word, it just doesn’t mean what I meant.
#12 jxc100
July 30, 2009

Abbie, really interesting. But phages are MUCH more than “DNA viruses that infect bacteria”. MS2 is ssRNA, phiX174 is ssDNA and the first DNA-based genome to be sequenced (Sanger in 1977) and has recently been assembly entirely synthetically (Venter and colleagues, 2003), M13 is a ssDNA filamentous phage, and phi6 is a dsRNA phage that is somewhat reovirus-like. Think of anything – phage probably did it first!
#13 Paper Hand
July 31, 2009

“Viri” is the plural of “vir”, man. “Virus” was a fourth declension noun in Latin, which means the Latin plural is “virus”.
#14 Sili
July 31, 2009

Sorry. I guess I’ve just seen it once to often.

Even to the point of forgetting how to decline “vir”.

Mea culpa, mea maxima culpa.

I’m trying to cut back on the language rage.
#15 Stephen Wells
July 31, 2009

And for bonus points, the u in the plural virus is long and the u in the singular is short, no? (da mihi veniam…)
#16 Jason Dick
July 31, 2009

I don’t know what it is, but the word “phage” just sounds so much more menacing than “virus”…
#17 stogoe
July 31, 2009

Screw it, I’m using ‘virii’ as much as I want. As a neologiphile, I’m doing what I can to improve this crappy language we call English.

PS – I’m also using Octopi, just to spite you.
#18 phantomreader42
July 31, 2009

Jason Dick:

I don’t know what it is, but the word “phage” just sounds so much more menacing than “virus”…

Yes, “phage” is a menacing word. It doesn’t take much license to translate it as “devourer”. It’s derived from the Greek for “to eat”.
#19 Sili
July 31, 2009

ARRRRGLE! RAARRRRGLE! BLARRRRGLE!!
#20 justawriter
July 31, 2009

Hmmm… that means there is proof that viruses predate eukaryotes. I believe I once read something hypothesizing that viruses were much younger than the other main branches of life. If there is no other explanation for how that DNA got into the mitochondria, that pretty much consigns the “young virus” theory to the wastebin of history.
#21 hiphop
July 31, 2009

Yes, “phage” is a menacing word. It doesn’t take much license to translate it as “devourer”. It’s derived
#22 eddie
August 1, 2009

Yes, phage is from the greek phagw – I eat. Also phageis – you eat, phagei – they eat and with plural forms phagoume, phagete and phagouv.
I’m afraid my latin is not that good.
#23 jim
August 1, 2009

@20
If there is no other explanation for how that DNA got into the mitochondria, that pretty much consigns the “young virus” theory to the wastebin of history.

The observation is that there is a series of T-odd phage genes’ products are now functioning within the mitochondria of most modern eukaryotes. There is strong support to the theory that the phage genes replaced the mitochondrial-ancestor versions of the genes, but the question is “when?”.

This paper proposed that this occurred at or very near the time of the endosymbiosis between mitochondria and their hosts. But the authors have not reconciled how a very “primative looking” mitochondrial genome of the protist R. americana encodes alpha-proteobacteria-like versions of these genes (not the phage versions). If the phage was there at the very beginning, how did [at least] one lineage loose it while all others maintained it?

This paper is an interesting theory, but not a clincher for their own hypothesis. So is probably not a death blow to the young virus theory, either.
#24 Prometheus
August 3, 2009

“Yes, phage is from the greek phagw – I eat. Also phageis – you eat, phagei – they eat and with plural forms phagoume, phagete and phagouv.
I’m afraid my latin is not that good.”

Vorare to devour, is the corresponding Latin word.
#25 Timothy Chase
August 8, 2009

There is something else which mitochondria and chloroplasts have: type II introns. These are also found in bacteria and archaea. And while most type II introns found in organelles lack open reading frames those that are found in bacteria do not, and appear to function as mobile retroelements.

Please see for example:

“Dai and Zimmerly (2002a) suggested that whereas organellar group II introns function as introns without the need for protein-assisted mobility, bacterial group II introns act mainly as retroelements, requiring the encoded-protein for their spread by either homing or ectopic transposition, which will explain the lack of ORF-less introns in Bacteria.”

Minireview: Bacteria and Archaea Group II introns: additional mobile genetic elements in the environment
Nicolas Toro
Environmental Microbiology (2003) 5(3), 143-151

Based upon phylogenetic analysis of their reverse transcriptases, group II introns (found in bacteria) and LINEs (non-LTR retrotransposons found in our own genome) appear to be fairly closely related, whereas both appear to be only more distantly related to LTR-retrotransposons.

Please see for example:

“For example, when comparing sequences from retroviruses and non-LTR retrotransposable elements only the domains we have labelled 4, 5 and 6 were identically aligned by the two methods. When comparing the group introns and retroviruses only domains 5 and 6 are identically aligned by the two methods.”

Origin and evolution of retroelements based upon their reverse transcriptase sequences
Yue Xiong and Thomas H.Eickbush
The EMBO Journal vol.9 no.10 pp.3353-3362, 1990
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=552073&blobtype=pdf

*

It would likewise appear that LTR-retrotransposons arose chimerically from the fusion of group II introns and a DNA transposon.

Please see:

“We propose that the origin of the LTR retrotransposons was the fusion of a DNA-mediated transposon and a non-LTR retrotransposon. Although this model is highly speculative, it is the only simple model that can explain the sudden origin of the two-step mechanism used by LTR retrotransposons in the absence of obvious eubacterial precursors. Based on the similarity of the IN of LTR retrotransposons and the transposases of DNA transposons,Capy et al. (1998) have also recently postulated that one likely origin of the LTR retrotransposons was by a DNA-mediated transposon acquiring RT activity.”

Late, Chimeric Origin of LTR Retrotransposable Elements and Retroviruses
Harmit S. Malik and Thomas H. Eickbush
Genome Res. 2001 11: 1187-1197
http://genome.cshlp.org/content/11/7/1187.full.pdf

Then of course retroviruses are essentially LTR-retrotransposons that have acquired ENV-genes responsible for the viral capsid.

*

But where did group II introns arise from?

Well, it appears that their reverse transcriptase is related to that of the Mauriceville retroplasmid:

“The characteristics of the mRP RT suggest that it may be related to the progenitors of retroviral and other types of RTs (38). Amino acid sequence comparisons indicate that the mRP RT belongs to the same class as those encoded by the non-long terminal repeat (non-LTR) family of retroelements, a diverse group that includes the abundant human long interspersed nuclear elements (11, 42)….”

The Mauriceville Retroplasmid Reverse Transcriptase Initiates cDNA Synthesis De Novo at the 3′ End of tRNAs
Chia-Chien Chiang and Alan M. Lambowitz
Molecular and Cellular Biology, Vol. 17, No. 8, p. 4526–4535, Aug. 1997
http://mcb.asm.org/cgi/reprint/17/8/4526.pdf

In this article we can see that the mainstream view has been that LTR-retrotransposons and retroviruses are derived from ancient group II introns for some time:

“Within this group, the mRP belongs to a separate subclass, along with group II introns and bacterial retrons, all members of which are found in bacteria or in organelles, mitochondria and chloroplasts, that evolved from endosymbiotic bacteria (11). These retroelements are believed to have evolved in prokaryotes and likely include the early ancestors of retroviruses and other retroelements….”

ibid.

But the reverse transcriptase of the Mauriceville retroplasmid appears more primitive:

“Biochemical analysis showed that the mRP RT has the remarkable ability to initiate cDNA synthesis de novo (38). This de novo initiation occurs opposite the penultimate C residue (position C-2) of the 3′ CCA of the mRP transcript (38), the same position used for initiation of negative-strand RNA synthesis by phage Qβ and plant viral RNA-dependent RNA polymerases (4, 29)…. The ability of the mRP RT to recognize a 3′ tRNA-like structure and initiate cDNA synthesis de novo suggests that the mRP RT might be related to primitive RTs that evolved from RNA-dependent RNA polymerases (38).”

ibid.
#26 Stephen Bahl
August 9, 2009

I didn’t know there was phage DNA in mitochondrial DNA. Is there also phage DNA in any of the nuclear-encoded mitochondrial genes?
#27 jim
August 9, 2009

To Stephen Bahl,

It depends on who’s mitochondria you look at. MtDNA content is so diverse that it is really hard to make general comments on it. Most of the diversity seems to be in “protists”, of which we have sampled too few.

Keeping the comment to animals, all of the phage DNA is in the nucleus, and imported to the mitochondria as a protein. The fungi I am aware of are the same as animals. Not sure of the origin of all plant mitogenes. Describing the protists would require it’s own blog.
#28 Stephen Bahl
August 9, 2009

Thank you, Jim. I guess I forgot that mitochondria vary so much.

Cue me insisting to people that I’m “part bacteriophage” in 3, 2, 1…
#29 qbsmd
August 10, 2009

Two followup questions:
1. Why don’t bacteria get retroviruses? Is it because they are missing something a virus needs to use? Or is it something that could be used to make vaccines?

2. I’ve heard of genes moving from mitochondria to the nucleus. How does that work, and why can’t it happen in reverse, with either an existing ERV or a ‘naked’ retrovirus?
#30 jim
August 11, 2009

To qbsmd

I’ll take a stab at #2, from a functional perspective only. There are a number of evolutionary arguments as well for the one-way transmission.

Mitochondria can leak DNA or RNA outwards by many different methods, and a small amount of this is not necessarily lethal to the cell. They are (at least in yeast and in cell culture) fusing and diving frequently. They can be lysed or broken open. They can leak their contents. So the nucleic acids can get into a living, functional cell. If they make it to the nucleus, there is a chance of incorporation (DNA) or some weird reverse transcription and insertion (for the RNA).

In the other direction, disruption of the nucleus seems to signal the end of the cell along with its’ organelles, so DNA is not getting out and into living mitos. In the off chance this happens, the mitos don’t survive and pass on the change. Other than tRNAs in some odd species*, DNA and RNA is not imported into the mitochondria. (The mitochondrial disease field has been trying this for a very long time, with no real success). So no mechanism to introduce the “foreign” DNA. There are two double-membranes and a proton gradient to overcome. There is a specific set of proteins to facilitate protein import, but normally not one for nucleic acid import*.

It is all a fascinating dynamic that this post is not really doing justice to.

* Except in some strange protists mitos. As I implied in a post above, if you look deep enough in the protists, you will find an exception to almost every rule.