Mutations - PDF

Mutations DR: Samer Ahmed Mutation is the change of base sequence of nucleotides in the genetic code due to replacement(substitution), deletion (removal) or insertion (addition) of one or more bases resulting in altered gene product or a structural or numerical abnormality in chromosomes. Causes of...

Mutations DR: Samer Ahmed Mutation is the change of base sequence of nucleotides in the genetic code due to replacement(substitution), deletion (removal) or insertion (addition) of one or more bases resulting in altered gene product or a structural or numerical abnormality in chromosomes. Causes of mutations: a) Physical (most common) such as: UV, X and  radiations. b) Chemical carcinogens : Nitrate & nitrite preservatives. c) Environmental pollutants-derived oxidative free radical such as nitrous acid, smoking ,…. d) Genomic instability, errors of DNA replication and defective repair. Any agent which will increase DNA damage or cell proliferation can cause increased rate of mutations also. Such substances are called mutagens. Types of mutations: 2 types: 1-Gene mutation: 2-Choromosome mutation: 1-Gene mutations:(Small-scale mutations): affect a gene & include: a) Point mutation b) Deletions or Insertions Point mutations(substitution): Definition and types: - It is a single base change that can be: 1- Transition mutation(Most common) : a purine base is changed to another purine base, e.g., adenine into guanine or a pyrimidine base to another pyrimidine base, e.g., thymine into cytosine. 2-Or, Transversion mutation(Less common): a purine base is changed into a pyrimidine base and vice versa. Transition mutation & Transversion mutation Fate (or effect) of point mutation: 1-Silent mutation: the changed base leads to a codon, which produces the same amino acid. In this case, the change lies in the third base of the codon, which has several alternative names for same amino acid. Then the mutation is silent and has no effect on the phenotype. For example, CUA is mutated to CUC; both code for leucine, so this mutation has no effect. Also called Synonymous mutations Silent mutation : 2-Missense mutation: The change occurred either in first or second base of the codon producing a different amino acid. The effect of missense mutation on the protein produced is dependent on the position and nature of the replacement amino acid. This protein could be partially functioning or non-functioning. Also called Non-Synonymous mutations. Example is Sickle cell anemia or hemoglobin S In these cases a functional protein is produced. The function may be altered or deficient. Clinical manifestations also are present, but compatible with life. Produced by a mutation of the beta chain in which the 6th position is changed to valine, instead of the normal glutamate. Here, the normal codon GAG is changed to GUG. HbS has abnormal electrophoretic mobility and subnormal function, leading to sickle-cell anemia. Sickle cell anemia or hemoglobin S Sickle cell anemia: Unacceptable mutation: Single amino acid substitution alters the properties of the protein to such an extent that it becomes nonfunctional and the condition is incompatible with normal life. For example, HbM results from histidine to tyrosine substitution (CAU to UAU) of the distal histidine residue of alpha chain. There is methemoglobinemia which considerably decreases the oxygen carrying capacity of hemoglobin. 3- Non-sense mutation: The altered base results in a non-sense termination codon. This leads to pre-mature stopping of protein synthesis leading to truncated protein e.g., c-erbB2 oncogene or no protein is produced at all. Deletion or Insertion: Deletions: Deletions may be subclassified into: 1- Large gene deletions: e.g. alpha thalassemia (entire gene) or hemophilia (partial). 2- Deletion of a codon: e.g. cystic fibrosis (one amino acid, 508th phenyl alanine is missing in the CFTR protein. 3- Deletion of a single base: which will give rise to frameshift effect. Insertion Insertions or additions or expansions are subclassified into: 1- Single base additions: leading to frameshift effect. 2-Trinucleotide expansions: In Huntington's chorea, CAG trinucleotides are repeated 30 to 300 times. This leads to a polyglutamine repeat in the protein. The severity of the disease is increased as the number of repeats are more. Frameshift: Frameshift mutation: This is due to addition or deletion of base. The reading frame shifts. A "garbled" protein, with altered amino acid sequence is produced. An example is given below: Frameshift mutation: