Genome-wide analysis of influenza viral RNA and nucleoprotein association https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx584
Also, I’m super excited for This Week in Immunology! Thanks for all that you do!
Ed Grow writes:
Hi Vincent and the TWiV gang-
On TwiV 447 Pete asks several questions about ERVs, and I’ll try to answer them focusing on HERV biology but drawing on examples from other organisms.
If it were feasible to remove, say, 1 – 5% of the ERV base pairs from a sexually reproducing organism: Would you expect that organism to be able to reproduce with an unmodified partner?
- I think you might be alluding to Drosophila re: hybrid dysgenesis which involves mismatching of autonomous P-element transposon containing males with non-transposon containing females. Resultant progeny from this mating can be non-viable or sterile. So far, I’m not aware of similar systems that give such a dramatic phenotype in humans as hybrid dysgenesis in Drosophila.
- However, you can easily imagine a system conceptually similar to the Mutator system characterized in maize in which a dominant allele called Mu-killer—essentially an inverted duplication of the mutator transposon—leads to organism-wide silencing of dispersed Mutator transposons through the production of dsRNA/siRNAs/RNAi-mediated DNA methylation.
- Therefore, it is of course possible that some ERV sequences are maintained to serve as an inoculation or inhibitor of re-infection or re-colonization of an organism by new ERVs.
- I’m not sure that removing interspersed ERV repeats would affect chromosome pairing and/or recombination during meiosis, so in my opinion, it’s unlikely this would lead to aneuploidy or lethality/infertility. But ERVs are thought to have mediated the expansions of clusters of duplicated and subsequently diverged KRAB-zinc finger genes on human chromosome 19 through illegitimate recombination—so it’s plausible that they served a useful role in expanding this class of genes which in turn serve as an anti-transposon/retrotransposon/ERV defense. This type of accident-turned-benefit seems to be a common in host/pathogen coevolution (see below examples).
- Although not leading to hybrid dysgenesis per se, mice have a system of loci called Fv1-Fv4 (Friend virus susceptibility) which were initially genetically defined as loci that conferred resistance to Murine Leukemia Virus. When positionally cloned and sequenced, these loci were found to encode portions of retroviruses which interfered with infection from exogenous viruses. For instance, Fv-1 encodes a gag fragment that inhibits viral replication and Fv-4 which encodes an envelope fragment thought to lead to resistance through receptor-mediated-interference.
- So the evidence is clear in mice that ERV sequences can be beneficial, and this seminal work really inspired researchers to consider the possibility of beneficial ERVS in humans.
- Not to be too self-serving, but here are some recent examples in humans:
* Grow, et al. Nature 2015. The premise of this paper was simple: do HERV-K, which still retain the capacity to make retroviral proteins, become reactivated in development, or are they viral “fossils” that exist in our genomes but are largely inert? In this paper we showed that HERV-K, which is re-expressed during preimplantation development, can trigger an innate immune response in a cellular system and that this can confer partial resistance to infection of exogenous viruses. Although most of these experiments involved boosting ERV expression levels (as LOF is tricky to do for dispersed/polymorphic ERV loci), we think that ERV re-expression and turning on innate immunity in early embryogenesis might serve as a protective mechanism before adaptive immunity appears later in development. Maybe that’s why ERVs sequences are retained in our genomes and re-expressed during critical times in development, in essence using fire to fight fire?
* Choung, et al. Science 2016, which was covered in TWiV 382: “Everyone’s a little bit viral”. Ed-C initially observed that many ERV sequences were strong DNA binding sites for transcription factors (TFs) in ChIP-seq datasets—especially binding sites for TFs involved in the interferon transcriptional response. The next question was: are these binding sites functional or not? This was one of the first examples of editing HERV sequences to perform loss-of-function analyses. ERV DNA sequences can be interferon-responsive and can serve as potent regulatory elements for protein-coding genes. In this paper, Ed-C showed that Aim2 is not as interferon-responsive if you delete it’s ERV regulatory region. Apart from this molecular defect, the cells with the ERV deletion at Aim2 (or the ancestral form with no IFN-inducible ERV insertion regulating its expression) would be predicted to be more susceptible to viral infections.
* Durruthy-Durruthy, et al. Nature Genetics 2016. An older ERV called HERV-H primarily can’t make proteins but encodes highly-expressed lincRNAs in human embryos and human embryonic stem cells. Although there were some nice experiments testing its function in cell lines (which you covered in Twiv 279, and subsequently reported by an independent group in Wang, et al. Nature 2015), it was unclear if these RNAs impacted human embryo development. This is one of the only examples in which true Loss-of-function studies were performed for HERVs in vivo (which addresses Pete’s original question). We started with a simple question: If HERV-H derived lincRNAs are essential for pluripotency in human embryonic stem cells, or contribute to reprogramming of fibroblasts to pluripotency in iPSC, do these HERV-H also affect pluripotency of cells in vivo in the embryo? After months of hemming and hawing, we convinced an amazing embryologist Mark Wossidlo to inject siRNAs targeting ERVs into human embryos. The cells with depleted ERV lincRNAs didn’t contribute to the inner-cell mass, the population of cells that will grow into the embryo, but instead contributed to the trophectoderm, which will form the placental tissues. These data indicate that ERVs can profoundly influence the developmental potential of early embryonic cells, and in some cases we have initial clues as to the mechanism through which they act.
* To recap, these three papers show that different ERV-derivatives (protein/viral RNA from ERVs, DNA from ERV LTRs, or lincRNAs derived from decayed ERVs—see #1-3 respectively) can provide beneficial functions for humans or human cells. So don’t be so sure that ERV sequences are non-functional—but many ERVists would reluctantly concede that the majority of ERVs are deleterious or neutral. Although evolutionary conservation analyses can help us triage which ERVs are maintained or subject to selection—the true test is loss-of-function studies, which can now (thanks to Crispr/Cas9) be performed in cell lines, organoids, or even in vivo in some cases.
Vincent and the gang, it appears that you might need to do a Virology 101 for ERVs, and since two of the best ERVists Steve Goff and Paul Bieniasz are both in NYC I bet you could make a damn good episode!
Automatic jargon identifier for scientists engaging with the public and science communication educators
This made me laugh, honestly it’s probably a good thing.
Hello TWiX team,
The AAAS gives an “Award for Public Engagement with Science”, and I think that the team should nominate Vincent. (Nominations are due by August 15th). The award is granted to scientists or engineers who get the general public interested in science, and to people who do that through basically any medium, including broadcasting. On the application page linked to above, the AAAS states that it’s especially interested in people who reach out to more distant audiences, and communicators who bring a relevant or complex message. I think the many TWiV episodes on emerging viruses or on outbreaks (like the Ebola epidemic in West Africa and the recent spread of Zika virus) count as both relevant and difficult – those episodes addressed events that concerned a lot of people and went into way more detail than the news ever could.
Hope you apply, and if you do, good luck!
Hello, Drs. TWiV!
First, thank you for your informative and engaging podcast. I’ve been listening for several years now and your podcasts never fail to liven up a run around campus or to make a long road trip feel shorter.
I’m writing to thank you for discussing the importance of organ donation and for encouraging organ donation on TWiV 455. I’m a student at UW-Madison, where I’ve been fortunate to get to see the hospital’s transplant program up close. It’s hard to describe the joy and gratefulness of a critically ill patient and their family who has just learned that a suitable donor has, finally, been found. So please continue encouraging your listeners to register as donors! One final plug in favor of donation: no matter how badly you may mess up during your life, I can state with anecdotal evidence that if you sign up as an organ donor your mother will still cry for how wonderful you are when you die.
This brings up a related topic I hope to at least get the word out about. Some organ transplant programs are considering making use of imminent death donation: a process whereby a terminally ill patient can choose to donate before she becomes so ill that her organs are no longer useful for transplant. This topic is of course fraught with ethical issues, which would require much more time than I would reasonably want to take up with an email, so I would suggest directing interested listeners to this article: https://www.theatlantic.com/magazine/archive/2015/04/as-they-lay-dying/386273/ Imminent death donation is of importance because it has potential to greatly reduce the number of people on the long waiting list for a transplant. This topic is also of personal importance to me since my family has a strong history of ALS, so there is a high likelihood I or a family member will at some point face a diagnosis portending death in an average of three years over which our bodies will become increasing useless and debilitated. The idea of being able to make my own untimely death into someone else’s miracle or second shot at life gives me at least a glimmer of hope. Anyway, thanks always for the fantastic work that you do, and keep fighting the good fight for science!
Ada (not my real name, but I’d rather my name not be used since my family’s ALS history is not commonly known among friends and colleagues)
In Beyond Freedom and Dignity Skinner notes that current students of Philosophy are directed to read the works of the ancient Greeks. No teacher of Physics today ever suggests that beginner study Aristotle. Skinner’s analysis is that the first questions asked about Science were good ones and so the field was able to progress. He goes on to say that the first questions asked about Philosophy were the wrong questions and so the field never gained traction.
I remember asking my 8th grade Science teacher if viruses were the original form of life. His answer was “Maybe.” I then asked what was simpler. He replied that that was not the only thing to look at. Viruses might have originally been something complicated that went on to specialize as parasites.
It’s interesting that almost fifty years later — a time when the progress of Biology could be compared to that of Physics in the first half of the 20th Century — ideas on the origin of viruses continue to travel in the same circle. Perhaps the questions being asked about the origin of viruses are the wrong questions?
On a separate note, during the opening discussion of TWiV 456, Dr. Condit says that — having left Florida — he thought that he was done with hurricanes. I might guess that you never thought that there’d be a Sandy in New York and New Jersey. We live in interesting times.