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Following the spectacular advances in molecular gentics that emerged from the study of bacterial viruses, and later, tumorigenic viruses, efforts have been made to understand the gentic properties and processes of other animal viruses. This work has involved the selection of apprapriate mutants, the construction of genetic maps by recombination and complementation test, and study of functions of the products of the genes in wheih mutations occur.
The most important and universal changes in the nucleic acid sequences of viral genomes are due to mutations. In viral infection of an animal or cell culture, one or a small number of virus particles replicate to produce millions of progeny. In such large populations, errors in copying the nucleic acid (i.e. mutations) inevitably occur. Many such mutations are lethal.
Rates of mutation involving base substitutions (point mutations) are probably the same in DNA viruses as they are in DNAs of prokaryotic and eukaryotic cells, since replication usually occurs in the nuclei of such cells and is subject to the same "proofreading" exonuclease error correction as operates in cells, such errors are estimated to occur at a rate of 10-8 or 10-11 per incorporated nucleoticle (ie. per base pair replication).
RNA is not the repository for genetic information in eukaryotic cells so it is assume that there is no "proofreading" mechanism for it, hence, the error rate in the replication of viral RNA is much higher than that of DNA. For example, the base substitution rate per incorporated nucleotide in the 11-kl genome or vesicular stomatitis virus is 10-3 - 10-4, so that nearly every progeny genome will be different from its parent and sisters in at least one base.
The terms "strain, type, variant and mutant" have been used to designate a virus that differs in some heritable way from a parental or "wild-type" virus.
5.1.2.1Classification of Mutations
- 1. Mutations can be classified according to the kind of Mutations can be classified according to the kind of change in the nucleic acid; the most common are nucleotide substitution (point mutations), small deletions or large deletions. The physio- logical effects of mutations depend not only on the kind and location of the mutation but also on the activity of other genes. The phenotypic expression of a mutation in one gene may be reversed not only by a backmutation in the substituted nucleotide but, alternatively, by a suppressor mutation occuring elsewhere in the same, or even in a different gene.
5.1.2.2 Conditional lethal mutants.
- Produced by mutation that so affects a virus that it cannot grow under certain conditions but can replicate under certain specific or permissive conditions.
Temperature-sensitive mutations:
Temperature- sensitive mutants are produced by missense mutations that alter the nucleotide sequence of a gene so that the resulting protein product is unable to assume or maintain its functional configuration at the non- permissive (high) temperature. The protein is how- ever, able to assume a functional configuration at permissive (low) temperature, a property that allow the mutant to be propargated. Generally its mutants produce full-size proteins that usually have the same immunologic specificity as the wild type protein. Wild-type animal viruses can generally multiply over a temperature range that extends from a lower limit of about 20o - 24oC to an upper limit of about 39.5oC formammalian viruses and 40o - 41oC for avian ones. Hot mutants. Some mutants can grow at temperature higher than needed by wild type virus. e.g. the upper limit of temperature growth range for polio-virus is 41o, utant strain exist that grow as well at 41oC as at 37oC, or even better. Such strain are very virulent, since they can multiply rapidly in patient with higher fever, when the multiplication of wild type virus is at least partially inhibited.
Cold-sensitive (CS) mutants.
Any viral genome lacking adequate function in one or more of the essential genes required for autonomous viral replication is defective. Defective viruses require helper activity from another virus genome or virus genes for replication and/or maturation.
5.1.2.3.1 The defective interfering (DI) viruses
The defective interfering (DI viruses, also referred
to as defective interfering (DI) particles. DI particle are subgenomic deletion mutants which have lost essential segments of the genome or parental virus that generate them. The percentage of the parental virus genome deleted may vary from a small amount to 90% of the genome. The DI particles thus become "helper-dependent", requiring simutaneous infection of host cells by a related helper virus to restore the deleted genetic function necessary for replication. Furthermore, DI particles inhibit the replication of infectious helper virus by diverting virus-supplied gene products toward DI particle replication and away from virus repli- cation.
Most DI particles interfere markedly with helper virus, but helper-dependent defective genomes exist which cause very little interference with helper virus. Also, certain DI particles may be strongly interfering in some cell types but only weakly interfering in other cell types. In most cases, the yield of defective genome is achieved at the expense of at least slightly reduced yields of infectious helper virus.
When viruses are passaged repeatedly at high multi- plicity, the progeny frequently includes, in addi- re virus particles, defective virus particles that are capable of interfering with the multiplication of homologous virus. These virus have the following properties:
