Genes and Heredity

Mutations

Mutations cause changes in the genome that can impact the phenotype in a positive, negative, or neutral way. They can occur as point mutations or frameshift mutations and can be randomly introduced (spontaneous) or induced by exposure to a mutagen.

A mutation is a change in DNA sequence. A spontaneous mutation is a change in the genetic sequence that occurs randomly and without external influence. Spontaneous mutations are the driving force behind evolution and natural selection. About every 10,000 base pairs, DNA polymerase makes a mistake. E. coli's genome is over 4.5 million base pairs long. That's a chance of 450 spontaneous mutations every time the genome is replicated. Mutations can also occur as a result of exposure to environmental factors such as chemicals, radiation, or viruses. A mutagen is any agent that produces mutations above baseline. Mutations can be harmful, beneficial, or silent.

There are two main types of mutation: frameshift mutation and point mutation. A frameshift mutation is an insertion or deletion of a number of nucleotides that is not divisible by three, resulting in the ribosome reading a "shifted" codon code. When this occurs early in the DNA sequence, the end protein produced is highly altered from the original. A point mutation is a replacement of one nucleotide, resulting in a change to one codon. This codon change will result in a different amino acid being incorporated during translation. When a point mutation results in the production of a start or stop codon, it is called a nonsense mutation. If a different amino acid is produced as a result of the point mutation, this is called a missense mutation. Nonsense mutations always result in nonfunctional or misfunctional protein production, while proteins produced with missense mutations may still function. Should the point mutation result in the production of the same amino acid, this is called a silent mutation. A silent mutation is one that results in no change to the phenotype.

Types of Mutations

Mutations that cause a change in even a single nucleotide base can result in incorrect or incomplete protein production.
Lethal mutations are those that affect vital functions within the bacterial cell, thereby rendering it nonviable. Conditional lethal mutations are those that may affect the organism in such a way that it can only survive under certain environmental conditions.

However, not all mutation results in negative consequences for microbes. Occasionally, a mutation results in a phenotype that significantly improves survival. As time goes on, this genetic trait is selected for, driving evolution of the species. Mutation has allowed various strains of viruses and bacteria to become resistant to antiviral and antibacterial medications, respectively. Many antibiotics function by inactivating a protein essential to bacterial function. A mutation that alters the protein can prevent antibiotics from binding and having their intended effect.

One specific example of mutation-induced resistance is in the bacteria Mycobacterium tuberculosis. Resistance has been documented in M. tuberculosis to two key drugs in its treatment: isoniazid and rifampicin. A mutation in the promoter region results in decreased affinity, or binding ability, for isoniazid. In order for rifampicin to exert its antibacterial effects, it must bind the beta-subunit of M. tuberculosis's RNA polymerase. However, mutations in the gene that code for the beta-subunit of RNA polymerase have resulted in a decreased affinity of the drug. M. tuberculosis organisms with these mutations survive when exposed to these drugs. They, in turn, reproduce to create further generations of drug-resistant organisms.

Bacterial Drug Resistance

When bacteria replicate, some mutations that occur may be beneficial to the survival of the organism. This includes resistance to certain drugs. The bacteria with the mutation survive and continue to replicate.
Methicillin-resistant Staphylococcus aureus (MRSA) is an example of a bacterium that, through mutation and natural selection, was able to survive in the presence of penicillin-based antibiotics. Mutations in genome replication of S. aureus resulted in the mecA gene. This gene prevents beta-lactam antibiotics such as methicillin or nafcillin from inactivating the enzymes needed for cell wall synthesis. Those S. aureus bacteria with this mutation survived and thrived in the presence of beta-lactam penicillins. They continued to reproduce, while the S. aureus bacteria without the mutation died off. Through horizontal gene transfer, MRSA continued to spread this genetic material to other Staphylococcus bacteria. This has resulted in massive resistance of S. aureus to beta-lactam antibiotic therapy.

Viruses have a higher mutation rate than other organisms because of their high replication rate. Viral genetic mutation can occur via antigenic drift and antigenic shift. Antigenic drift involves the mutation of individual bases of viral DNA and RNA. Antigenic shift describes a major change in the viral genome, and both recombination and reassortment are examples. Recombination involves the exchange of genetic material between viruses and occurs when two different viruses co-infect a host cell. Viral reassortment involves chromosomal crossover of genetic material between two viruses infecting the same host cell.