Permanent, heritable alterations in the base sequence of the DNA are referred to as a mutation. It arises due to spontaneous errors during DNA replication or due to the damaging of DNA by physical or chemical agents.
Causes of mutations
1. Error during DNA replication:
Spontaneous mutation occurs due to errors in the DNA replication process and evades the proofreading function of DNA polymerases.
These mutations are called mismatches (the inserted nucleotide in the daughter polynucleotide does not match the nucleotide at the corresponding position in the template DNA through base pairing).
Example: Spontaneous mutation rate in E. Coli is 1 in 1010 bases incorporated during replication.
2. External influences:
- Mutagen (the chemical or physical factor that causes genetic mutations) reacts with the parental DNA, creating a genetic mutation that affects the ability of the altered nucleotide pair.
- Usually, this change affects only one strand of the parental helix, so only one of the daughter molecules carries the mutation.
Types of mutations
1. Point mutation
- A point mutation is a change in one or a few nucleotides.
- It can either be a transition, purine, or pyrimidine replaced by the other or transversion, purine replaced by a pyrimidine, and vice versa.
- These are very minute changes when compared to large-scale mutations.
- Point mutations are further divided into two categories:
A. Base-pair substitutions
It is a replacement of one base pair with another.
- Silent mutation: a change in one base pair does not affect the protein produced by the gene. This is allowed due to the redundancy in the genetic code. Example: Both GGC and GGU code for the amino acid glycine. Thus, the mutation is “silent”.
- Missense mutation: A change in one base pair causes a single amino acid to be changed in the resulting protein. It is called “missense” since the code changes. Example: GGC when changed to AGC, results in different amino acids. The effect of a missense mutation on the protein is random. It could create a protein that improves reproductive success or survivability or it could create an anomalous protein, leading to diseased conditions ex. Sickle cell anemia.
- Nonsense mutation: A change in a single base pair creates a stop codon. A stop signal is created in the middle of a normal functional gene, resulting in a usually nonfunctional protein, hence “nonsense” mutation.
B. Base-pair insertions or deletions (frameshift mutations)
- Insertions and deletions are addition or losses of one or more nucleotides in a gene.
- These kinds of mutations have a disastrous effect on the resulting protein.
- Because the genetic code is read as a triplet, insertion or removal of several nucleotide bases that are not three-fold causes a shift in the reading frame. It is therefore called frameshift mutation.
- Translated protein in the C-terminal side of mutation is completely changed.
- These mutations can result in an entirely new set of amino acids (extensive missense) and probably also premature termination (nonsense).
2. Large-scale mutations
A. Gene duplication:
- An entire gene, or block of genes, is repeated on the chromosome.
- Gene duplications are often the outcome of unequal crossing over during meiosis.
- It causes the loss of genes from one chromosome and a gain on the other.
- Repetition of specific genes may produce certain phenotypic changes and act as mutations.
B. Gene deletion
- Loss of a gene or a block of genes.
- Unequal recombination during meiosis sometimes causes gene deletion.
- An effective mutagen for inducing chromosomal rearrangements is -ionizing radiation.
- How the chromosome breaks rejoin determines the kind of rearrangement produced.
C. Chromosomal translocation:
- The movement of genes from one chromosome to another non-homologous chromosome.
- Translocation that gives rise to an adaptive advantage is very rare and is often associated with negative consequences such as aneuploidy, infertility, or cancer.
- Depending on the chromosome breakpoints, a translocation can result in the disruption or misregulation of normal gene function. These molecular rearrangements, in many cases, are considered to be the primary cause of various cancers Ex: Burkitt’s lymphoma.
- Usually, all of the translocations observed in tumors are known to rise through somatic mutations, therefore are not inheritable.
D. Chromosomal inversion:
- A section of the gene is reversed on the chromosome.
- Happens when two breaks occur within a single chromosome and the region between the breaks rotates 180o before rejoining.
- Inversions do not change the overall amount of the genetic material, so inversions are generally viable and show no particular abnormalities at the phenotypic level but sometimes can lead to reproductive problems.
- And sometimes, if the break is within a gene of essential function, that breakpoint acts as a lethal gene mutation linked to the inversion.