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Gene Mutation Classification of Mutations Can Be Made at the: • • • • DNA level Protein level Cellular level Organismal level Mutation at the DNA Level Change from one allele to a different allele Forward mutation Wild type mutant Reverse mutation Mutant wild type Quantifying Mutation Mutation rate = number of mutations per unit time Mutation frequency = frequency of a specific mutation in a population of cells or individuals Both are low in value and vary by location. Mutation at the DNA Level • Spontaneous mutation Results from natural processes • Induced mutation Results from exposure to environmental chemicals or radiation Mutation at the Cellular Level • Somatic Mutation – arises in body cells that will not give rise to gametes (not passed to offspring) – can lead to mutant cell population – mutation of proto-oncogenes leads to cancer development • Germ-Line Mutation – arises in cells giving rise to gametes – can be passed on to offspring Germ-line mutation to X-linked recessive allele for hemophilia. Characteristics of Mutations at the DNA Level •Base substitutions: change of one nucleotide into another Type of Mutation Examples Transition ATGC TACG GCAT CGTA Purinepurine Pyrimidinepyrimidine Transversion Purinepyrimidine Pyrimidinepurine ATCG GCTA TAGC CGAT ATTA GCCG TAAT CGGC Mutations at the DNA Level Lead to Changes in Protein Composition Transition -A-A-G-T-T-C- -A-G-G-T-C-C- lysine arginine Transversion -A-A-G-T-T-C- -A-C-G-T-G-C- lysine threonine Characteristics of Mutations at the DNA Level • Insertions and Deletions – addition or removal of one or more nucleotide pairs – cause frameshift mutations – changes in multiples of three cause in-frame deletions or insertions Characteristics of Mutations at the DNA Level • Expanding Trinucleotide Repeats – may arise as a result of formation of hairpin structures during DNA replication – could also be due to unequal crossing over when repeated regions do not align properly Effects of Mutations at the Protein Level Silent Substitution of a Nucleotide Synonymous (Neutral) Missense Nonsense Deletion or Insertion of Nucleotide(s) Frameshift AGG CGG Arg Arg AAA AGA Lys Arg AAA GAA Lys Glu CAG UAG Gln Stop AA(A)GACUUACCAA Lys-asp-leu-pro Lys-thr-tyr-gln Classification of Mutations Based on Protein Function • Recessive mutations – Loss of function • Example: Mutant Tumor Suppressor Genes • Dominant mutations – Gain of function • Example: Oncogenes Applying Your Knowledge 1. 2. 3. 4. 5. Transversion Germ-line mutation Recessive mutation Transition Somatic mutation Which type of mutation A. can be passed on to offspring? B. represents a loss of protein function? C. involves a pyrimidine being substituted for a purine? Spontaneous Mechanisms of Mutation: Replication Errors • Nonstandard base pairings due to flexibility in DNA structure substitutions Spontaneous Mechanisms of Mutation: Replication Errors • Strand slippage due to looping of one nucleotide strand during replicationinsertions or deletions Spontaneous Mechanisms of Mutation: Replication Errors • Unequal crossing overinsertions or deletions Spontaneous Mechanisms of Mutation: Spontaneous Chemical Changes • Depurination – Hydrolysis of purine base from the sugar-phosphate backbone Spontaneous Mechanisms of Mutation: Spontaneous Chemical Changes • Depurination – Random base inserted opposite the apurinic site during replication can lead to mutation -G-G-C-C-C-G- -G- -C-C-C-G- -G- -C-C-A-G- -G-T-C-C-A-G- Mutant codes for valine -G-G-C-C-C-G- Wild type codes for glycine Spontaneous Mechanisms of Mutation: Spontaneous Chemical Changes • Deamination of cytosine – Converts cytosine to uracil Spontaneous Mechanisms of Mutation: Spontaneous Chemical Changes • Deamination of cytosine – DNA replication causes G-C A-T change -C-G-C-G-C-G- -C-G-C-G-U-G- Is this a 1. transition or 2. transversion? -C-G-C-G-C-G- -C-A-C-G-U-G- Wild type codes for arginine -C-A-C-G-T-G-C-A-C-G-U-G- Mutant codes for histidine Inducing Mutations Mutagens are environmental agents that increase the rate of mutation. •Chemicals •Radiation Mechanisms of Mutation Due to Chemicals Causing Type of Mutagen Example Change Substitutions Base analogs 5-bromouracil (analog of T) T:AC:G (incorporated into DNA due to structural similarities) Mechanisms of Mutation Due to Chemicals Causing Type of Mutagen Example Change Substitutions Alkylating agents EMS (ethylmethylsulfonate) C:GT:A (cause mispairing through chemical modification of bases) Mechanisms of Mutation Due to Chemicals Causing Type of Mutagen Example Change Substitutions Deaminating agents Nitrous Acid C:GT:A A:TG:C (chemicals that convert cytosine to uracil) Mechanisms of Mutation Due to Chemicals Causing Type of Mutagen Substitutions Hydroxylating agents Hydroxylamine C:GT:A (adds a hydroxyl group to cytosine, causing C to A pairing) Example Change Mechanisms of Mutation Due to Chemicals Causing Type of Reaction Substitutions Oxidative reaction Hydrogen (oxidative changes to peroxide or bases that cause Oxygen radicals mispairing) Example Change G:CT:A Mechanisms of Mutation Due to Chemicals Causing Type of Mutagen Deletions or Insertions Intercalating agents Examples Acridine Orange (insert between adjacent Ethidium Bromide DNA bases) Mechanisms of Mutation Due to Radiation • Formation of Pyrimidine dimers – Ultraviolet radiation produces dimers from adjacent thymines (thymine-thymine dimers) – Dimers interfere with DNA function Applying Your Knowledge 1. Substitution 2. Deletion or Insertion 3. Pyrimidine Dimer Formation Which type of mutation is caused by A. intercalating agents like acridine orange? B. ultraviolet light? C. alkylating agents like EMS? Repair Mechanisms Type of Repair Directed at Mismatch Repair (methyl-directed in bacteria) Mispaired bases Portion of new DNA strand with mismatch is removed Mismatch is recognized along with nearby methyl-A DNA polymerase restores missing nucleotides Repair Mechanisms Type of Repair Directed at Photoreactivation Thymine-Thymine Dimers (Type of direct repair) In Bacterial Cells Repair Mechanisms Type of Repair Directed at Direct Repair: restores original structure O6-Methylguanine which pairs with adenine Repair Mechanisms Type of Repair Base-Excision Repair: Base removed then entire nucleotide replaced Directed at Modified bases such as uracil product of cytosine deamination Adds new nucleotide to exposed 3’-OH group Removes damaged base Seals gap in backbone Cleaves backbone removes sugar Repair Mechanisms Type of Repair Directed at Nucleotide Excision Thymine-Thymine Dimers (eukaryotes) Repair Other large distortions in helix Uses of Mutants • Genetic dissection: understanding how normal biological processes work Antennapedia Bithorax Fruit Fly mutants used to study developmental processes Uses of Mutants • Mutation breeding: selection of traits induced by a mutagen Applying Your Knowledge 1. Mismatch Repair 2. Photoreactivation 3. Direct Repair 4. Base Excision Repair 5. Nucleotide Excision Repair Which mechanism A. is used to reverse Thymine-Thymine dimers in bacteria? B. identifies an old DNA strand based on methylation of bases? C. is used to remove chemically modified bases?