Mutation Part II PDF

 The Molecular Basis of Mutation Mutations alter the nucleotide sequences of genes in several ways, for example the substitution of one base pair for another or the deletion or addition or one or a few base pairs.  Base Substitutions A transition replaces a pyr...

 The Molecular Basis of Mutation Mutations alter the nucleotide sequences of genes in several ways, for example the substitution of one base pair for another or the deletion or addition or one or a few base pairs.  Base Substitutions A transition replaces a pyrimidine with another pyrimidine or a purine for another purine. A transversion replaces a pyrimidine with a purine or a purine with a pyrimidine.  Tautomeric Shifts Movement of H atom H atom can move from one position in a purine or pyrimidine to another position The movement of H atom will cause change in base form Pyrimidines  Tautomeric Shifts H atom can move from one position in a purine or pyrimidine to another position Purines Tautomeric Shifts Affect Base-Pairing Mutation Caused by Tautomeric Shifts  Simple Tandem Repeats Simple tandem repeats are repeated sequence of one to six nucleotide pairs. (Eg: CCG, GAGCCG Trinucleotide repeats can increase in copy number and cause inherited diseases. Examples: CCG repeats at the X-chromosome about 6 to 50 copies. Fragile X Syndrome- mental retardation  Simple Tandem Repeats CAG and CTG repeats cause Huntington disease and spinocerebellar ataxia – Inherited Neurological disease the increased severity of disease happen when the trinucleotide copy number increases. Mutations by Transposons  Factors Influencing the Rate of Spontaneous Mutations Accuracy of the DNA replication machinery Efficiency of the DNA repair mechanisms for the damaged DNA Degree of exposure to mutagenic agents in the environment  Induced Mutations Induced mutations occur upon exposure to physical or chemical mutagens.  Physical mutagen Hermann J. Muller and Edgar Alternburg measured the frequency of X-linked recessive lethal mutations in Drosophila. Muller demonstrated that exposing Drosophila sperm to X-rays increased the mutation frequency. Irradiation Dosage and Mutation Frequency The Electromagnetic Spectrum Mutagenesis by Ultraviolet Irradiation Hydrolysis of cytosine to a hydrate may cause mispairing during replication Cross-linking of adjacent thymine forms thymidine dimers, which block DNA replication  Ionizing Radiation Causes Changes in Chromosome Structure Ionizing radiation breaks chromosomes and can cause deletions, duplications, inversions, and translocations.  Types of Chemical Mutagens Chemicals that are mutagenic to both replicating and nonreplicating DNA (e.g., alkylating agents and nitrous acid) Chemicals that are mutagenic only to replicating DNA (e.g., base analogs and acridine dyes)  Alkylating Agents Alkylating agents are chemicals that donate alkyl groups to DNA molecules. Induce transitions, transversions, frameshifts, and chromosome aberrations. Can change base-pairing properties in replicating and nonreplicating Alkylating agents can also activate DNA repair mechanism Alkylating agent Chemical Mutagens – Alkylating agents  Ethyl methane sulfonate Add ethyl group at 7 position of Guanine base to become 7-ethylguanine 7-ethylguanine base pair with thymine Cause transition G:C ➔A:T  Ethyl methane sulfonate When the DNA replicate, GC pairing will turn to AT pairing Chemical Mutagens- Deamination agent Nitrous acid (NHO2) acts on either replicating and non- replicating DNA; converts the amino groups to keto groups  Nitrous acid convert adenine to hypoxanthine cause AT to GC transition Nitrous acid convert cytosine to uracil cause GC to AT transition Nitrous Acid Causes Oxidative Deamination of Bases  Base analogs structures similar to normal bases & incorporated into DNA during replication; A Base Analog: 5-Bromouracil Mutagenic Effects of 5-Bromouracil (5- BU) Enol form Keto form 5-BU can mimic T or C Chemical Mutagens- Acridines dyes -Induce frameshift mutation -Mechanism – intercalate (positively charged) between staked base pairs Intercalation of an Acridine Dye Causes Frameshift Mutations