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A mutation is a permanent change in the nucleotide sequence of a gene. Mutations may be either gross, so that large area of chromosome is changed, or may be subtle with a change in one or a few nucleotides.

Causes of Mutations

1) Spontaneous

Spontaneous mutations on the molecular level include:

  • Tautomerism – A base is changed by the repositioning of a hydrogen atom.
  • Depurination – Loss of a purine base (A or G).
  • Deamination – Changes a normal base to an atypical base; C  U, (which can be corrected by DNA repair mechanisms), or spontaneous deamination of 5-methycytosine (irreparable), or A  HX (hypoxanthine).
  • Transition – A purine changes to another purine, or a pyrimidine to a pyrimidine.
  • Transversion – A purine becomes a pyrimidine, or vice versa.

2) Induced by Mutagens

Induced mutations on the molecular level can be caused by:

  • Chemicals
    • Nitroso compounds
    • Hydroxylamine NH2OH
    • Base analogs
    • Simple chemicals (e.g. acids)
    • Alkylating agents (e.g. N-ethyl-N-nitrosourea (ENU)) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA when the analog is incorporated in replicating the DNA.
    • Methylating agents  
    • Polycyclic aromatic hydrocarbons e.g. benzopyrenes
    • DNA intercalating agents (e.g. ethidium bromide)
    • DNA cross linker (e.g. platinum)
    • Oxidative damage caused by oxygen(O)] radicals
  • Radiation
    • Ultraviolet radiation (nonionizing radiation) – excites electrons to a higher energy level. DNA absorbs ultraviolet light. Two nucleotide bases in DNA – cytosine and thymine-are most vulnerable to excitation that can change base-pairing properties. UV light can induce adjacent thymine bases in a DNA strand to pair with each other, as a bulky dimer.
    • Ionizing radiation
  •  Biological- Viruses

DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal mutation rate. A hotspot can be at an unusual base, e.g., 5-methylcytosine.

Classification of mutations-

Structurally, mutations can be classified as:

A) Point mutations, often caused by chemicals or malfunction of DNA replication, and include single nucleotide changes-

Ø     Substitution-exchange a single nucleotide for another. Most common is the transition that exchanges a purine for a purine (A  G) or a pyrimidine for a pyrimidine, (C  T). A transition can be caused by nitrous acid, base mis-pairing, or mutagenic base analogs. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T  A/G). An example of a transversion is adenine (A) being converted into a cytosine (C).

Ø   Insertions add one nucleotide into the DNA. They are usually caused by transposable elements or errors during replication of repeating elements (e.g. AT repeats). Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frame shift), both of which can significantly alter the gene product.

 Ø   Deletions remove one nucleotide from the DNA. Like insertions, these mutations can alter the reading frame of the gene.

B ) Large-scale mutations in chromosomal structure, including:

a)     Amplifications (or gene duplications) leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.

b)    Deletions of large chromosomal regions, leading to loss of the genes within those regions.

c)     Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g. bcr-abl). These include:

§  Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.

§  Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes.

§  Chromosomal inversions: reversing the orientation of a chromosomal segment.

Effects of mutations

Although the initial change may not occur in the template strand of the double-stranded DNA molecule for that gene, after replication, daughter DNA molecules with mutations in the template strand will segregate and appear in the population of organisms.

If the nucleotide sequence of the gene containing the mutation is transcribed into an RNA molecule, then the RNA molecule will possess a complementary base change at this corresponding locus.(See figure)

Single-base changes in the mRNA molecules may have one of several effects when translated into protein:

(1) There may be no detectable effect because of the degeneracy of the code; such mutations are often referred to as silent mutations. This would be more likely if the changed base in the mRNA molecule were to be at the third nucleotide of a codon. Because of wobble, the translation of a codon is least sensitive to a change at the third position. E.g. valine has 4 codons GUU, GUC, GUA, or GUG, the change in the third nucleotide will have the incorporation of same amino acid, thus there will not be any effect on the functional capacity of the protein.

(2) A missense effect will occur when a different amino acid is incorporated at the corresponding site in the protein molecule. This mistaken amino acid—or missense, depending upon its location in the specific protein—might be acceptable, partially acceptable, or unacceptable to the function of that protein molecule. From a careful examination of the genetic code, one can conclude that most single-base changes would result in the replacement of one amino acid by another with rather similar functional groups. This is an effective mechanism to avoid drastic change in the physical properties of a protein molecule. If an acceptable missense effect occurs, the resulting protein molecule may not be distinguishable from the normal one. A partially acceptable missense will result in a protein molecule with partial but abnormal function. If an unacceptable missense effect occurs, then the protein molecule will not be capable of functioning in its assigned role.

a) Acceptable Missense mutations- The sequencing of a large number of hemoglobin mRNAs and genes from many individuals has shown that the codon for valine at position 67 of the beta chain of hemoglobin is not identical in all persons who possess a normally functional bets chain of hemoglobin. The codon changes by point mutation from GUU (Of valine) to GAU of Aspartic acid in Hb Bristol. Similarly in Hb Sydney the codon changes from GUU to GCU for Alanine. Both Hb Bristol and Hb Sydney are normal Hb variants with normal oxygen carrying capacity. Thus these are acceptable mutations. Hemoglobin Hikari has been found in at least two families of Japanese people. This hemoglobin has asparagine substituted for lysine at the 61 position in the beta chain. The corresponding transversion might be either AAA or AAG changed to either AAU or AAC. The replacement of the specific lysine with asparagine apparently does not alter the normal function of the beta chain in these individuals.

b) Partially acceptable Missense mutations

A partially acceptable missense mutation is best exemplified by hemoglobin S, which is found in sickle cell anemia. Here glutamic acid, the normal amino acid in position 6 of the beta chain, has been replaced by valine. The corresponding single nucleotide change within the codon would be GAA or GAG of glutamic acid to GUA or GUG of valine. Clearly, this missense mutation hinders normal function and results in sickle cell anemia when the mutant gene is present in the homozygous state. The glutamate-to-valine change may be considered to be partially acceptable because hemoglobin S does bind and release oxygen, although abnormally.

c) Unacceptable Missense Mutations For example, the hemoglobin M mutations generate molecules that allow the Fe2+ of the heme moiety to be oxidized to Fe3+, producing met hemoglobin. Here the single nucleotide change alters the properties of a protein to such an extent that it becomes non functional. Hb M results from histidine to tyrosine substitution.

Distal Histidine of alpha chain of Globin is replaced by Tyrosine. The codon CAU is changed to UAU with the resultant incorporation of Tyrosine and formation of Met Hb. Met hemoglobin cannot transport oxygen.

(3) A nonsense codon may appear that would then result in the premature termination of a peptide chain and the production of only a fragment of the intended protein molecule. The probability is high that a prematurely terminated protein molecule or peptide fragment will not function in its assigned role.e.g. The codon UAC for Tyrosine may be mutated to UAA or UAG, both are stop codons. Beta Thalassemia is an example of non sense mutation.

In certain conditions as a result of mutational event the stop codon may be changed to normal codon (UAA to CAA) . This results in the elongation of protein to produce “Run on polypeptides”. The resultant protein is a functionally abnormal protein.

Frame shift Mutations

frame shift mutation is a mutation caused by inserts or deletes of a number of nucleotides from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is.

If three nucleotides or a multiple of three are deleted from a coding region, the corresponding mRNA when translated will provide a protein from which is missing the corresponding number of amino acids. Because the reading frame is a triplet, the reading phase will not be disturbed for those codons distal to the deletion.

Triplet deletion

A triplet deletion removes exactly one amino acid from the polypeptide ,the most common mutation in cystic fibrosis is Delta F508 (i.e. deletion of amino acid number 508 (a phenylalanine, F)).

Trinucleotide expansion

The commonest inherited cause of mental retardation is a syndrome originally known as Martin-Bell syndrome. Patients are most usually male, have a characteristic elongated face and numerous other abnormalities including greatly enlarged testes. In 1969 the name of the syndrome was changed to the fragile X syndrome. The mutation was tracked down to a trinucleotide expansion in the gene now named FMR1 (Fragile site with Mental Retardation).  A number of diseases have now been ascribed to trinucleotide expansions. These include Huntington’s disease and Myotonic dystrophy.

Gene deletions Alpha Thalassemia is an example of Gene deletion. The clinical manifestations are as per the number of genes deleted.

Consequences of Mutations

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. To function correctly, each cell depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. A condition caused by mutations in one or more genes is called a genetic disorder. However, only a small percentage of mutations cause genetic disorders; most have no impact on health. For example, some mutations alter a gene’s DNA base sequence but don’t change the function of the protein made by the gene.

If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. On the other hand, a mutation can occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant, and thus cause cancer.

Often, gene mutations that could cause a genetic disorder are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognise and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease.

Beneficial mutations

A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes. The CCR5 mutation is more common in those of European descent.

Summary of Mutations

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