Insertional Mutagenesis - Virus Insertional Mutagenesis

Virus Insertional Mutagenesis

As mentioned in the introduction, insertional mutagenesis refers to mutation of an organism caused by the insertion of additional DNA bases into the organism's preexisting DNA. Because many viruses (not all of them) integrate their own genome into the genome of their host cells in order to replicate, mutagenesis caused by viral infections is a fairly common occurrence. Not all integrating viruses cause insertional mutagenesis, however.

It is important to note that not all DNA insertions will lead to a noticeable mutation. In fact, most will not. However, it is a common enough occurrence in viral DNA insertions that biologists researching gene therapy will avoid using viruses that integrate their DNA in the host genome when it is not necessary to do so, opting instead for viruses that transiently express their DNA (leave their DNA free-floating within the cell, rather than integrate it into the genome of the host). For those viruses that do integrate their DNA into that of the host, the severity of any ensuing mutation depends entirely on the location within the host's genome wherein the viral DNA is inserted. If the DNA is inserted into the middle of an essential gene the effects on the cell will be drastic. Additionally, insertion into the promoter region of a gene can cause equally drastic effects. For instance, if the viral DNA is inserted into a repressor, the gene corresponding to that promoter may be over expressed - leading to an overabundance of its product and altered cellular activity. If the DNA is inserted into an enhancer region, the gene may be under-expressed - leading to relative absence of its product, which can significantly interrupt the activity of the cell.

Alteration of different genes will have varying effects on the cell. Not all mutations will significantly affect the proliferation of the cell. However, if the insertion occurs in an essential gene or a gene that is involved in cellular replication or programmed cell death, the insertion may compromise the viability of the cell or even cause the cell to replicate interminably - leading to the formation of a tumor, which may become cancerous.

Below is an example of a significant change in cell activity due to insertion of a viral gene into a portion of the hosts genome that controls replication.

Virus insertional mutagenesis is only possible with a replication competent virus. The virus inserts a gene (known as a viral onocogene) normally near the cellular myc (c-myc)gene. The c-myc gene is normally turned off in the cell, however when it is turned on it is able to push the cell into the G1 phase of the cell cycle and cause the cell to begin replication which allows the viral gene to be replicated. After many replications where the viral gene stays latent tumours begin to grow. These tumours are normally derived from one mutated/ transformed cell (clonal in origin). Avian leukosis virus is an example of a virus that causes a disease by insertional mutagenesis. Newly hatched chicks infected with Avian leukosis virus will begin to form tumours begin to appear in their bursa of fabricus (like the human thymus). This viral gene insertion is also known as a promoter insertion as it drives the expression of the c-myc gene. There is an example of an insertional mutagenesis event caused by a retrotransposon in the human genome where it causes Fukuyama-type muscular dystrophy .