Presented by guest lecturer Saul Silverstein, Ph.D.
Visit the virology W3310 home page for a complete list of course resources.
Vincent, Alan, and Matt discuss a project to study the RNA virome of Northeastern American bats, failure to detect XMRV in UK chronic fatigue syndrome patients, and DNA of bornavirus, an RNA virus, in mammalian genomes.
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Links for this episode:
Weekly Science Picks
Matt 100 Incredible lectures from the world’s top scientists
Alan The Amateur Scientist CD
Vincent The Immortal Life of Henrietta Lacks by Rebecca Skloot
Send your virology questions and comments (email or mp3 file) to firstname.lastname@example.org or leave voicemail at Skype: twivpodcast. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.
On episode 49 of the podcast ‘This Week in Virology”, Vincent and Dick continue Virology 101 with a discussion of the seven different types of viral genomes, and how to use the pathway to mRNA to understand viral replication.
Click the arrow above to play, or right-click to download TWiV #49 (45 MB .mp3, 62 minutes)
Links for this episode:
Dick talks about hookworm on Radio Lab
Dick’s video page at BigThink
The seven types of viral genome
Animation of HIV replication (thanks axiomatically atypical!)
Changes in transcript abundance relating to colony collapse disorder in honey bee (thanks Judi!)
Send your virology questions and comments (email or mp3 file) to email@example.com or leave voicemail at Skype: twivpodcast. You can also send articles that you would like us to discuss to delicious and tagging them with to:twivpodcast.
The recent series of posts on polymerase error rates and viral evolution has elicited many excellent and thought provoking comments from readers of virology blog. Here is one that I had not thought of before, and which I’ll use on an exam in my virology course:
Here’s a tough question. In the follow up blog to this, you say that the high mutation rates of RNA viruses is beneficial to survival in a complex environment. If this is true, why don’t DNA viruses evolve high mutation rates also? It would be simple for them to delete their proofreading domain.
There is no answer to this question, so I’ll speculate. I believe that DNA viruses have error correction mechanisms so that they can have very long genomes. RNA viral genomes are no longer than 27-31 kb. This limit is probably imposed by their high error rate: if RNA genomes were longer, they would likely sustain too many lethal mutations to survive. Error correction mechanisms allow for DNA viral genomes up to 1.2 million bases in length. Smaller DNA viruses don’t have their own DNA polymerases – they use those of the cell. Cellular DNA polymerases have error repair to avoid mutations that lead to diseases such as cancer. Both forms of reproduction are evolutionarily sustainable: shorter RNAs with lots of errors; longer DNAs with fewer errors.
The reader who posed the original question then came back with this retort:
If reduced fidelity is beneficial to RNA viruses, because of the complex environment they are in, why don’t DNA viruses do the same thing?
I think the same endpoint, in terms of surviving in complex environments, is achieved by both strategies. RNA viruses have high diversity; DNA genomes have many more gene products which allow them to survive in diverse situations. Both strategies appear to be evolutionarily sustainable.
It’s important to keep in mind that the goal of viral evolution is survival. Evolution does not move a viral genome from “simple” to “complex”, or along a trajectory aimed at “perfection”. Change is effected by elimination of the ill adapted of the moment, not on the prospect of building something better for the future.
While researching this subject I came across a series of papers on DNA synthesis by African swine fever virus, a virus with a DNA genome of 168-189 kb. The viral genome encodes a complete DNA replication apparatus, including DNA polymerase and DNA repair enzymes. Incredibly, the DNA repair pathway itself is error-prone, which is believed to contribute to the genetic variability of the virus. There is some controversy concerning the error rate for this virus, so we don’t know the consequence of this observation for fidelity of DNA replication. Nevertheless, these observations suggest that evolution has seen fit to tinker with, and perhaps increase, the error rates of certain DNA based organisms.
Lamarche, B., Kumar, S., & Tsai, M. (2006). ASFV DNA Polymerase X Is Extremely Error-Prone under Diverse Assay Conditions and within Multiple DNA Sequence Contexts. Biochemistry, 45 (49), 14826-14833 DOI: 10.1021/bi0613325
None of the four human polymaviruses that were known in early 2008 – JC, BK, KI and WU – had been shown to cause cancer. The subsequent identification of a new polyomavirus associated with Merkel cell carcinoma demonstrates the type of evidence that is required to prove that a virus is oncogenic in humans.
Merkel cell carcinoma (MCC) is a relatively rare human skin cancer, although its incidence has increased in the past twenty years from 500 to 1500 cases per year. This cancer occurs more frequently than expected in individuals who are immunosuppressed, such as those who have received organ transplants or who have AIDS. A similar pattern of susceptibility is also observed for Kaposi’s sarcoma, a tumor that is caused by the herpesvirus HHV-8. Therefore it was suggested that MCC might also be caused by an infectious agent.
To identify the etiologic agent of MCC, the nucleotide sequence of total mRNA from several MCC tumors was determined and compared with the sequence of mRNA from a normal human cell. This analysis revealed that the MCC tumors contained a previously unknown polyomavirus which the authors named Merkel cell polyomavirus (MCV or MCPyV). The viral genome was found to be integrated at different sites in human chromosomal DNA from MCC tumors.
If MCV infection causes MCC, then the viral genome should be present in tumors but not in normal tissues. MCC DNA was found in eight of ten MCC tumors, each obtained from a different patient. The viral genome was not detected in various tissues samples from 59 patients without MCC. Furthermore, the viral genome had integrated into one site in the chromosome of one tumor and a metastasis dervied from it. This observation indicates that integration of the viral genome occurs first, before division of the tumor cells.
In subsequent studies MCV DNA has been detected in 40-85% of the MCC tumors examined. The viral DNA is not found in small cell lung carcinoma, which, like MCC, is also a neuroendocrine carcinoma. MCV particles have also been detected by electron microscopy in the cytoplasm and nucleus of tumor cells from one patient, suggesting ongoing viral replication.
How might MCV cause Merkel cell carcinoma? Expression of the viral protein known as T antigen might be sufficient to transform cells. Alternatively, integration of the viral DNA into human DNA could lead to unregulated synthesis of a protein that transforms cells. To prove that MCV causes Merkel cell carcinoma, it will be necessary to demonstrate that infection with the virus, or transfection with viral DNA, transforms and immortalizes cells in culture.
Feng, H., Shuda, M., Chang, Y., & Moore, P. (2008). Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma Science, 319 (5866), 1096-1100 DOI: 10.1126/science.1152586
Wetzels, C., Hoefnagel, J., Bakkers, J., Dijkman, H., Blokx, W., & Melchers, W. (2009). Ultrastructural Proof of Polyomavirus in Merkel Cell Carcinoma Tumour Cells and Its Absence in Small Cell Carcinoma of the Lung PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004958