"Molecular Evolution of the γ-Herpersvirinae" Questions

1. Why is the elevated mutation rate in herpes viruses a positive aspect for this phylogenetic study?

Mutation is a source of genetic variation and when it acts with selection it is a major force of evolution. The elevated mutation rate is important in this study because it allows them to follow the evolution of this virus and build a phylogenetic tree based on evolutionary relationships.

2. What do the eight core genes code for (page 422)? Why did this study choose to focus on these genes?

The eight core genes are 06, 07, 08, 09, 25, 29, 44, and 46.

06- encoding the major DNA binding protein

07- DNA packaging function

08- virion glycoprotein B

09- catalytic subunit of DNA polymerase

25- major capsid protein

29- DNA-packaging protein

44- DNA helicase

46- uracil-DNA glycosylase

They chose these genes to study because they are sufficiently well conserved over the whole family. This allowed adequate amino-acid sequence alignments when looking at phylogenic relationships.

3. Herpes viruses tend to “capture” genes from their host genomes and incorporate them into their own genomes. That said, explain the relationships you see in the phylogenies in Figure 4 on page 427.

The EBV, HPV, and HVS viruses incorporate the host genome into their own during the infection process. By capturing a healthy cell's machinery, the viruses can efficiently transcribe proteins necessary to the infection process and also become less prone to immune attack by incorporating non-foreign genes into their genome. The phylogenies in figure 4 compare IL-10 and DHFR genes in organismal cells and in viruses. IL-10 is a protein involved in cytokine synthesis and when expressed, can reduce inflammation and the immune response. This has obvious advantages in a virus. DHFR is a gene used in purine production and makes for efficient transcription and translation. If incorporated, the virus will more readily proliferate. With this knowledge, the two genes were examined in a variety of organisms, including humans, and comparing them to the viral genes. The phylogenies in figure 4 show a progression in genome complexity, with the virus first incorporating genes in more simple organisms and eventually moving to incorporation of the human genes. The viral IL-10 and DHFR are closely related to the human genes, showing the viruses success in infecting humans. It is rare for a virus to show such a similarity to human genes, but EBV, HPV, and HVS have evolved in such a way to be able to fend off the human immune system and pirate its genetic machinery for more efficient proliferation.

4. Part 5, beginning on page 431, discusses genetic characteristics of two Epstein-Barr viral strains. On page 432, the author explains that there are four genes involved but that only two combinations of their alleles (i.e. four haplotypes) predominate. What do we call this evolutionary phenomenon? Do these combinations have any evolutionary advantage?

This is an example of linkage disequilibrium. This is evidenced by the fact that there are only two combinations of alleles (or four haplotypes) because the genes are linked and only inherited together. This offers an evolutionary advantage because the combinations of genes that are most infective are selected for and are going towards fixation.

5. Why might it be important to study protein folding in these viruses?

The folding of a protein determines its shape. Its shape determines whether it can be catalyzed by an enzyme to participate in a reaction, or if the protein is an enzyme, whether it can catalyze a reaction. Proteins control all of the major functions in a cell or virus from replication of genetic material to the actual infection process. If a protein vital to Herpes virus’ function is isolated and its folding is determined, steps can be taken to inhibit its folding or catalysis and effectively stop the virus from proliferating.

6. The last paragraph of this paper states that EBV genes respond to allele frequencies of MHC genes in human populations. How would human MHC genes (and changes in their frequencies) act as a selection pressure on viral gene frequencies?

MHC genes express protein fragments on the cell walls of immune cells (natural killer and macrophages). These protein fragments are often processed proteins from a bacterium or virus that were recognized as foreign. The MHC fragments allow immune cells to recognize these foreign invaders if they happen to reappear in the body. After recognition they can attack and eradicate them.

The EBV virus frequency will gradually decrease as its proteins are recognized and expressed by MHC molecules. The immune system will become more efficient in attacking them as they become more common in the body. As a result, EBV must incorporate healthy cellular genes/proteins from the organism it is attacking to essentially hide from the immune system. If a virus incorporates non-foreign genes, the immune system will not recognize and attack it. This leaves two evolutionary options for EBV, either gradually decrease in frequency as the immune system becomes completely proficient in attacking it, or diverge by incorporating new genes and "hiding" from the immune system.