Lecture 9 Mutation

LECTURE 9 MUTATION Introduction • Mutation is a change in genetic material (amount, arrangement or structure of the DNA) of an organism. • Mutations range from a change in a single nucleotide pair up to a change in vast regions of a chromosome. • There are broadly two types of mutation; i) Gene mutation and ii) Chromosomal mutation. • Gene mutation is a change in the sequence of bases in the DNA. • Chromosomal mutation is a result of change in the number or structure of chromosomes. • A mutation may result in the change in the appearance of a characteristic in a population (phenotype) especially if they are passed on to the next generation. • Germ-line mutations are those that occur in the sex cells (gametes) and are passed on to subsequent generation. • Somatic mutations are those that occur in body cells and are not passed on to the next generation. • Somatic mutation can be lethal as they can sometimes lead to development of cancer. Causes of Mutation • Some mutation are spontaneous, they happen for no apparent reason while others are induced by environmental influences. 1. Spontaneous Mutations; • Due to error in normal biological processes ( i.e mitosis and meiosis). • Specifically due to errors during DNA replication processes such as miss pairing of base, gene deletion, translocation of chromosome portion, etc. • Some errors are corrected through proofreading by DNA polymerase but some are not. 2. Induced Mutation; • Induced mutations are caused by mutagens. • A mutagen is any factor of a physical or chemical nature that causes mutation. • These mutagens can be chemicals or radiations that alter the base composition or structure of the DNA. • Chemical mutagens are present in some of the food and many industrial chemicals. • All chemical carcinogens can cause mutations: industrial compounds e.g benzene, formaldehyde, heavy metals, dyes, tobacco, asbestos, pesticides. • Ultra-violet (UV) radiation has short wavelength and high energy to damage biological molecules like DNA. • Ionizing radiation, such as x-rays, gamma rays, and other radioactive substances can also be quite damaging due to their shorter wavelengths and high energies. GENE MUTATION • Mutation resulting from change in nucleotide sequence. • It can change the amino acid sequences due to a change in a codon. • A mutant gene is a section of DNA (gene) whose base sequence/pair has been altered. • Mutations can alter the structure and function of protein that DNA codes for. • For example, in a gene for haemoglobin, mutation can result in soluble glutamic acid being replaced by a less soluble amino acid valine (sickle cell disease) Figure 1: Gene mutation (haemoglobin) leading to sickle cell when adenine (A) is replaced by thymine (T) Types of Gene (Point) Mutation • Gene mutation is also called Point mutation because it applies to a specific gene locus. • Point mutations usually involve a change in just a single nucleotide. • There are three types of point mutations and these are substitution, deletion and insertion. • Substitution is when a nucleotide base is replaced by different one. • Insertion involves the addition of one or more nucleotide bases to the DNA nucleotide sequence. • Deletion involves the removal of one or more nucleotide bases from the DNA nucleotide sequence. Figure 2: Types of gene (point) Substitution Mutation • For example, a substitution mutation replaces the nucleotide base cytosine (C) with thymine (T) base. • This sequence of bases transcribes into CAU on the mRNA that codes for histidine instead of arginine (CGU) that Figure 3: Substitution mutation was in this position before. • The subsequent codon on the mRNA remain as • Substitution may or may not affect the amino acid sequence and hence has the least effect because it only affects one codon of the mRNA. • Insertion and Deletion mutations have the greatest effect because they affect many amino acids and consequently the whole protein. • Note that point mutation may involve a change of one or more than one nucleotide bases. Insertion mutation • An example of an insertion mutation is when a nucleotide base adenine (A) is inserted between cytosine and guanine. • The reading frame on the DNA strand shifts and becomes AGC instead of GCA. • This sequence of bases on DNA gives the codon UCG Figure 4: Insertion mutation on the mRNA that codes for serine instead of arginine that was in this position before. Deletion Mutation • An example of a deletion mutation occurs when guanine (G) nucleotide base is removed from the DNA sequence. • The reading frame on the DNA strand shifts and becomes CAT instead of GCA. • This sequence of bases (CAT), gives a codon GUA on the mRNA that codes Figure 5: Deletion mutation for valine instead of arginine that was in this position before. Frameshift mutation • Point mutations can bring about frameshift mutation. • A frameshift mutation is a genetic mutation caused by the addition or removal of one or more nucleotides in a DNA nucleotide sequence that is not a multiple of three. • Since bases are read in triplet of nucleotide sequences, the frameshift mutation takes effect if the number of nucleotides being added or removed is not a multiple of three. • This is because every codon after the point of insertion or deletion is altered causing a shift in the reading frame. • For example: THE-CAT-ATE-THE-RAT; Removing or adding a letter results in the distortion of the whole message. • These alterations on the base sequence results in a shift in the reading of the triplet code. • The new nucleotide sequence may code for entirely different amino acids or may result in a premature termination of a protein. • If a mutation affects one of the stop codons UAA, UGA or UAG, the resulting message on the mRNA would no longer carry the ‘stop’ message. • Therefore, a protein being manufactured could be much longer than usual. • The resulting protein would not be functional because it consist of abnormal sequence of amino acids. • Point mutation may be called nonsense, missense or silent mutation depending on the effect of the mutation. Nonsense and Missense mutation • Nonsense mutation is a point mutation that results in a premature stop codon. • They are called “nonsense” because all the codons following the stop codon are never translated, they are nonsense. • Missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. • This mutation does not cause a premature stop, it only results in a change in amino acid sequence. Silent Mutation • This is a mutation where a change in the DNA sequence occurs but does not change the protein that is to be produced. • For example, the amino acid arginine is coded for by several DNA triplet bases including GCA, GCG, GCT, and GCC: • If the DNA sequence GCA is changed to GCG through substitution mutation, the amino acid arginine will still be produced. • Note that the last base A of the codon is substituted for G. Figure 8: Types of point mutations Thymine dimer • This is another type of mutation often caused by UV radiation or chemical mutagenic agents. • This mutation result from greater tendency for attraction between neighbouring thymine bases in the DNA. • During DNA replication, two adjacent thymine bases will covalently bond and produce a thymine dimer. Figure 9: Formation of thymine dimer • Thymine dimers can be repaired either by photo-reactivation or excision. • In photoreactivation repair, a photolyase (DNA repair enzyme) binds to the dimer. • In the presence of visible light, the enzyme helps to break the chemical bonds in the dimer, allowing each thymine to form a normal base pair • In excision repair, a distortion in the double helix triggers activity by an endonuclease. • This enzyme cuts (excises) the nucleic acid from inside and removes the dimer. • When UV causes adjoining thymine bases to bond together making a lump in the strand. • Endonucleases recognize the error, remove the dimer, and replaces it with correct DNA nucleotide. • Xeroderma pigmentosum (XP) is a genetic disorder in which a person is born without the exonuclease enzyme that repairs thymine-thymine dimers. • The affected are highly susceptible to skin cancers if they are exposed to UV light. • During the day they must remain indoors at all times and can only go outside at night Figure 10: Xeroderma pigmentosum (XP). A rare genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. END OF LECTURE! THANK YOU.