MUTATIONS

TYPES OF GENE MUTATIONS

[CLASSIFICATION]

• A heritable genetic change in the genetic material of an organism that gives rise to alternate forms of any gene is called mutation.

• The process by which mutations is produced is called mutagenesis.

• This may occur spontaneously or be induced by mutagens.

• An organism exhibiting a novel phenotype as a result of the presence of a mutation is referred to as a mutant.

General characteristics of mutation

• Mutations are generally recessive, but dominant mutations also occur.

• Mutations are generally harmful to the organisms.

• Mutations are random, occur at any time and in any cell of an organism.

• Mutations are recurrent i.e., the same mutation may occur again and again

Types Of Mutations

Somatic Versus Germinal Mutations

• In multicellular organisms, genes can mutate in either somatic or germinal tissue, and the changes are called somatic mutations and germinal mutations, respectively.

• A germinal mutation arises in the germ line, a special tissue that is set aside during development to form gametes. If a mutant gamete participates in fertilization, then the mutation will be passed on to the next generation.

Hereditary Versus Acquired Mutations

• Gene mutations occur in two different ways: they can be inherited from a parent or acquired during a person's lifetime. Mutations that are passed from parent to offspring are called hereditary mutations. This type of mutation is present throughout a person's life in virtually every cell in the body.

• Mutations that occur in the DNA of a cell at some time during a person's life are termed acquired mutations. These changes can be caused by environmental factors such as ultraviolet radiation or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.

Forward Versus Back Mutation

• A mutation that changes the phenotype from wild-type to a mutant phenotype is said to be a forward mutation, whereas a mutation that causes a change of the phenotype from mutant to wild-type is said to be a back mutation (or reverse mutation). A back mutation occurs at the same site in the gene as the original mutation, restoring the wild-type nucleotide sequence.

• A second mutational event that changes the phenotype to its original state is referred to as a reversion mutation, and the wild type produced in this way is called a revertant. A reversion may result from a true back mutation, an exact reversal of the alteration in the base sequence that occurred in the original forward mutation, restoring the wild-type DNA sequence. A reversion may also result from the occurrence of a second mutation at some other site in the genome that compensates for the effect of the original mutation (termed suppressor mutation).

Suppressor Mutations

A suppressor mutation is a second mutation that restores a function lost by the first mutation. Mutations of this kind are called suppressor mutations because they suppress the effects of the first mutation. True back mutation restores the original wild-type nucleotide sequence of the gene, whereas a suppressor mutation does not. Suppressor mutations may occur at distinct sites in the same gene as the first mutation or in different genes, even on different chromosomes. So, a suppressor mutation can be intragenic (if a mutation occurs at distinct sites within the same gene) or intergenic (if a mutation occurs in a different gene).

1. Intragenic suppressor mutations can restore the activity of a mutant protein by many means. The intragenic suppressor may change a nucleotide in the same codon altered by the first mutation, producing a codon that specifies the same amino acid as that specified by the original, unmutated codon. The suppression of one frameshift mutation by another frameshift mutation in the same gene is another example of intragenic suppression. If the original frameshift resulted from the removal of a base pair, the addition of another base pair close by can restore the correct reading frame. A third way in which an intragenic suppressor may work is by making compensatory changes in the protein. A first missense mutation may alter the folding of a polypeptide chain by changing the way in which amino acids in the protein interact with one another. A second missense mutation at a different site (the suppressor) may recreate the original folding pattern by restoring interactions between the amino acids.

2. Intergenic (or extragenic) suppressors do not occur in the same gene as the original mutation. There are many ways in which intergenic suppression can occur. The suppressing mutation may restore the activity of the mutated gene product or provide another gene product to take its place. One of the best known examples of intergenic suppressor mutation is a mutant tRNA gene that suppresses the effects of a nonsense mutation in a protein-coding gene (nonsense suppression). Let us take one wild-type gene 'A', encoding a tRNA that recognizes a 5' UAC 3' codon in the mRNA and inserts tyrosine into the growing polypeptide chain. A mutation in the gene changes the anticodon so that it recognizes the stop codon 5' UAG 3' in the mRNA and, instead of terminating, inserts a tyrosine at that position in the polypeptide chain.

Missense and Nonsense Mutation

A mutation that alters the codon so that it specifies a different amino acid is known as a missense (non-synonymous) mutation. One common example of a missense mutation is sickle cell hemoglobin. Hemoglobin (Hb) is the oxygen-transporting macromolecule present in the RBCs of chordate animals. HbA (adult hemoglobin) contains two identical α-chains and two identical β-chains. Each α-chain consists of a specific sequence of 141 amino acids. The β-chain in sickle cell hemoglobin (HbS) undergoes a substitution of valine at amino acid position 6, resulting in the mutation giving rise to the HbS gene. This substitution is caused by the replacement of adenine for thymine in the transcribed strand of DNA.

Sickle Cell Hemoglobin

In sickle cell hemoglobin (HbS), the sixth amino acid, glutamate (a negatively charged amino acid), from the amino terminal end of the β-chain is replaced by valine (no charge). This change alters the shape of hemoglobin. A mutation that changes a codon in a gene to one of the three termination codons (UAA, UGA, or UAG) is described as a nonsense mutation. Nonsense mutations result in a shortened protein because the translation of the mRNA stops at this new termination codon.

Conditional Mutations

Not all mutations reliably produce a mutant phenotype, regardless of environmental conditions. A conditional mutant allele expresses a mutant phenotype only in a certain environmental condition, called the restrictive condition, but produces a wild-type phenotype in some different environmental condition, called the permissive condition. For example, some conditional mutants are called temperature-sensitive mutants, which give a wild-type phenotype at low temperatures (the permissive temperature) but exhibit a mutant phenotype at high temperatures (the restrictive temperature).

Silent and Neutral Mutation

Not all mutations in DNA lead to a detectable change in the phenotype. Mutations without apparent effects are called silent mutations. If a mutation results in a new codon specifying the same amino acid as the unmutated codon, it is a case of a silent or synonymous mutation. Because it has no effect on the coding function of the genome, the mutated gene codes for exactly the same protein as the unmutated gene. For example, the change of ACG into CGG both codes for arginine.

A codon that specifies a different but functionally equivalent amino acid and does not alter protein function is called a neutral mutation (for example, AAA to AGA: changing basic lysine to basic arginine).

Loss- and Gain-of-Function Mutations

Wild-Type Phenotype

In principle, the mutation of a gene might cause a phenotypic change in either of two ways:

1. Loss of Function (Null) Mutation: The product may have reduced or no function.

2. Gain of Function Mutation: The product may have increased or new function.

Because mutation events introduce random genetic changes, most of the time, they result in a loss of function. Generally, loss of function mutations are found to be recessive. In a wild-type diploid cell, there are two wild-type alleles of a gene, both making normal gene products. In heterozygotes, the single wild-type allele may be able to provide enough normal gene product to produce a wild-type phenotype. In such cases, loss of function mutations are recessive. However, some loss of function mutations are dominant. In such cases, the single wild-type allele in the heterozygote cannot provide the necessary amount of gene product needed for the cells to be wild-type. Gain of function mutations usually cause dominant phenotypes because the presence of a normal allele does not prevent the mutant allele from behaving abnormally.

Spontaneous Mutations

These occur naturally without the influence of external factors. They are the result of internal processes within the cell and are responsible for the natural genetic variation observed in populations. Spontaneous mutations can occur because of:

- Replication Error: Mistakes during DNA replication can lead to mutations such as base substitution mutations or frameshift mutations.

- Spontaneous Lesions: These include chemical changes in DNA such as deamination, depurination/de-pyrimidination, and oxidative damage.

- Transposition: Movement of transposable elements during the normal growth of the cell can cause mutations.

Spontaneous Mutation Due to Replication Error:

- Errors during DNA replication may result in base substitution mutations (also known as point mutations or single site mutations) or frameshift mutations.

Base Substitution Mutation:

- A mutation where one base pair is substituted for another or one base for another in the case of single-stranded DNA genomes.

- Base substitution mutations can be classified as either:

- Transition Mutation: The most common type, where a purine (A or G) is replaced by another purine, or a pyrimidine (C or T) is replaced by another pyrimidine.

- Transversion Mutation: Less common, where a purine is replaced by a pyrimidine or vice versa.

Examples:

- Transition: G↔A; A↔G; C↔T; T↔C

- Transversion: A↔C; G↔T; A↔T; G↔C; C↔A; T↔G; C↔G; T↔A

Note: Most mispairing mutations are transitions. This is because A-C or G-T mispairs do not distort the DNA double helix as much as A-G or C-T base pairs.

How Base Substitution Mutations Occur:

- Tautomeric Shifts: Each of the common bases in DNA can undergo a transient tautomeric shift, changing from their more stable forms (keto, amino) to less stable forms (enol, imino). Though rare, these shifts can lead to base-pairing errors during DNA replication.

Details:

- Stable Form: Amino form for adenine and cytosine, keto form for thymine and guanine.

- Rare Form: Imino form for adenine and cytosine, enol form for thymine and guanine.

- These rare forms can pair with the wrong base during DNA replication, leading to transitions between different base pairs (e.g., AT→GC or GC→AT).

Frameshift Mutation:

• Aberrant replication can also result in the insertion or deletion of extra nucleotides within the polynucleotide being synthesized, leading to frameshift mutations.

• These mutations can disrupt the entire reading frame of the gene, leading to the production of non-functional proteins.

Spontaneous Lesions

Spontaneous lesions refer to naturally occurring chemical changes in DNA that can result in mutations. These lesions are caused by the inherent instability of the DNA molecule and the chemical environment within the cell. Spontaneous lesions are a significant source of genetic variation and can lead to various types of mutations if not properly repaired.

There are three main types of spontaneous lesions:

Deamination:

- Deamination is the removal of an amino group from a nucleotide base. This chemical reaction can alter the base-pairing properties of the affected nucleotide, leading to mutations during DNA replication.

Common Example:

- Cytosine to Uracil:

Deamination of cytosine results in the formation of uracil. Normally, cytosine pairs with guanine, but uracil pairs with adenine. If this lesion is not repaired before replication, the original GC base pair can be replaced by an AT base pair, leading to a transition mutation.

- Adenine to Hypoxanthine:

Deamination of adenine produces hypoxanthine, which can pair with cytosine instead of thymine, leading to a transition mutation.

Depurination and Depyrimidination:

- Depurination:

Refers to the loss of a purine base (adenine or guanine) from the DNA. This occurs when the bond between the purine base and the sugar-phosphate backbone is hydrolyzed, leaving an apurinic site (AP site).

- Depyrimidination:

Refers to the loss of a pyrimidine base (cytosine or thymine) in a similar manner, leaving an apyrimidinic site.

- Consequences:

If not repaired, these sites can lead to mutations during replication. DNA polymerase may insert an incorrect base opposite the AP site, or it may skip the site entirely, causing a deletion.

Oxidative Damage:

- Oxidative damage to DNA is caused by reactive oxygen species (ROS), which are byproducts of normal cellular metabolism. These reactive molecules can cause various chemical modifications to DNA bases.

- Example:

- 8-oxoG Formation: One of the most common oxidative lesions is the formation of 8-oxo-7,8-dihydroguanine (8-oxoG) from guanine. 8-oxoG can mis-pair with adenine instead of cytosine during replication, leading to a GC to TA transversion mutation.

Transposition:

Transposition refers to the movement of specific DNA sequences, known as transposable elements or "jumping genes," within the genome. This process can cause mutations by disrupting genes or regulatory regions when the transposable element inserts into a new location. Transposition is a natural mechanism that contributes to genetic diversity and evolution.

1. Types of Transposable Elements:

- Class I: Retrotransposons:

- Retrotransposons move within the genome by a "copy-and-paste" mechanism. They are first transcribed into RNA, which is then reverse-transcribed into DNA before being inserted into a new genomic location.

- Example: Long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs).

- Class II: DNA Transposons:

- DNA transposons move by a "cut-and-paste" mechanism. They excise themselves from their original location and integrate into a new site within the genome.

- Example: Insertion sequences (IS elements) in bacteria.

2. Mechanism of Transposition:

Retrotransposons:

1. Transcription: The retrotransposon is transcribed from DNA into RNA.

2. Reverse Transcription: The RNA is reverse-transcribed into complementary DNA (cDNA) by reverse transcriptase.

3. Integration: The cDNA is then integrated into a new location in the genome by the enzyme integrase.

- DNA Transposons:

Excision: The transposon is cut out of its original location by transposase, an enzyme encoded by the transposon itself.

Integration: The excised transposon is inserted into a new genomic location, potentially disrupting a gene or regulatory sequence.

3. Effects of Transposition:

- Gene Disruption: If a transposable element inserts into a coding region or regulatory sequence of a gene, it can disrupt gene function, leading to a loss of function mutation.

- Gene Duplication: Transposition can lead to gene duplication if the transposable element carries adjacent gene sequences with it to a new location. This can result in the evolution of new gene functions.

- Regulatory Changes: Transposable elements can carry regulatory elements such as promoters or enhancers, which can alter the expression of nearby genes when they insert into a new location.

4. Regulation of Transposition:

- Transposition is tightly regulated in cells to prevent excessive genome instability.

Mechanisms include:

- Methylation: DNA methylation can prevent transposable elements from being transcribed, reducing their activity.

- RNA Interference (RNAi): Small RNA molecules can target and degrade transposon-derived RNAs, preventing their transposition.

- Repressor Proteins: Some cells produce repressor proteins that bind to transposable elements and inhibit their activity.

Induced Mutations

These are caused by external agents called mutagens, which can be physical or chemical. Mutagens increase the frequency of mutations beyond the natural background level.

Mutagen {Simple_Understanding}

A physical or chemical agent that causes genetic changes by increasing the frequency of mutations above the natural background level of an organisms.

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