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Chapter 13 Mutation, DNA Repair,…

Chapter 13 Mutation, DNA Repair,…

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Chapter 13 Mutation, DNA Repair,…

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  1. Chapter 13Mutation, DNA Repair,… © John Wiley & Sons, Inc.

  2. Amino acids in polypeptides are joined by what type of bond? a) Hydrogen b) no-Peptide c) Covalent d) Ionic e) Weak Which of the following is not a true statement about ribosomes? a) They are structured into large and small subunits b) They are comprised of RNA and protein c) The ribosomes in prokaryotes are typically larger than those found in eukaryotes d) The ribosome subunits associate during the initiation of translation e) All of these are false statements Which of the following is a secondary structure often observed in proteins? a) α helix b) β sheet c) σ subunit d) α helix and β sheet e) All of these

  3. Chapter Outline • Mutation: Source of the Genetic Variability Required for Evolution • The Molecular Basis of Mutation • Mutation: Basic Features of the Process • Mutation: Phenotypic Effects • Assigning Mutations to Genes by the Complementation Test • Screening Chemicals for Mutagenicity: The Ames Test • DNA Repair Mechanisms • Inherited Human Diseases with Defects in DNA Repair • DNA Recombination Mechanisms © John Wiley & Sons, Inc.

  4. Mutation: Source of the Genetic Variability Required for Evolution • Mutation --A change in the genetic material (molecular level) • Mutant • --an organism that exhibits a novel phenotype © John Wiley & Sons, Inc.

  5. Types of Mutations • Changes in chromosome number and structure • Point mutation--changes at specific nucleotide in a gene (A,T,C,G) • Insertion mutations--insert fragment of DNA • Deletion mutations--delete fragment of DNA © John Wiley & Sons, Inc.

  6. “Virus”

  7. Disruption of FGF -Receptor Function

  8. Fibroblast Growth Factor Signaling is Essential for Mesoderm Production in Frog Embryos

  9. Dominant mutations in human FGFR-3 (TM domain) Achondroplasia

  10. Mutation and Evolution • Mutation is the source of all genetic variation (e.g.,chromatin remodeling). • Natural selection preserves the combinations best adapted (or NOT) to the existing environment. © John Wiley & Sons, Inc.

  11. The Molecular Basis of Mutation Mutations alter the nucleotide sequences of genes in several ways, --the substitution of one base pair for another. (A for T) --the deletion (or addition) of one or a few base pairs. ( AT…….GC)

  12. A:T C:G . Tautomeric Shifts:--chemical fluctuations, --conformation states (stable==========unstable) Py Pu © John Wiley & Sons, Inc.

  13. Tautomeric Shifts Affect Base-Pairing C:T T:G . © John Wiley & Sons, Inc.

  14. Mutation Caused by Tautomeric Shifts © John Wiley & Sons, Inc.

  15. Base Substitutions • A transition replaces a pyrimidine with another pyrimidine or a purine for another purine. • A transversionreplaces a pyrimidine with a purine or a purine with a pyrimidine. © John Wiley & Sons, Inc.

  16. Frameshift Mutations: alteration of the open reading frame (ORF) © John Wiley & Sons, Inc.

  17. Mutation Frequency • Frameshift, transition, transversion mutations are infrequent • Bacteria and phage: 10–8 to 10–10 per nucleotide pair per generation • Eukaryotes: 10–7 to 10–9 per nucleotide pair per generation 1/107 to 1/109 Silent mutation:UCU=Ser; UCA, UCC, UCG = Ser © John Wiley & Sons, Inc.

  18. Induced Mutations • Induced mutations occur upon exposure to physical (energy)or chemical (reaction) mutagens. • Muller demonstrated that exposing Drosophila sperm to X-rays increased the mutation frequency. • Hermann J. Muller and Edgar Alternburg measured the frequency (>150 fold increase) of X-linked recessive lethal mutations in Drosophila. © John Wiley & Sons, Inc.

  19. C: crossover suppressor l: recessive lethal mutation B: bar-eye mutation © John Wiley & Sons, Inc.

  20. The Electromagnetic Spectrum • X-rays induce mutations through ionization.(DNA ionization--radical anions and cations-- G.+) • Ultraviolet light induces mutations through excitation. © John Wiley & Sons, Inc.

  21. Ionizing Radiation Causes Changes in Chromosome Structure • Ionizing radiation breaks chromosomes and can cause deletions, duplications, inversions, and translocations © John Wiley & Sons, Inc.

  22. Stability of carbon-containing molecules

  23. Mutagenesis by Ultraviolet Irradiation • Hydrolysis of cytosine to a hydrate may cause mis-pairing during replication • Cross-linking of adjacent thymine forms thymidine dimers, which block DNA replication and activate DNA repair mechanisms. © John Wiley & Sons, Inc.

  24. UV-A 320 to 400 nm UV-B/C <300 nm

  25. Types of Chemical Mutagens • Chemicals that are mutagenic to both replicating and non-replicating DNA (e.g., alkylating agents and nitrous acid) • Chemicals that are mutagenic only to replicating DNA (e.g., base analogs and acridine dyes) © John Wiley & Sons, Inc.

  26. Chemical Mutagens © John Wiley & Sons, Inc.

  27. Alkylating Agents • chemicals that donate alkyl groups to other molecules. • induce transitions, transversions, frameshifts, and chromosome aberrations (anomaly). • Alkylating agents of bases can change base-pairing properties. (GC to AT) • can also activate errors during repair processes. © John Wiley & Sons, Inc.

  28. A Base Analog: 5-Bromouracil --similar structures --incorporated into DNA --increase frequency of mis-pairing © John Wiley & Sons, Inc.

  29. Mutagenic Effects of 5-Bromouracil © John Wiley & Sons, Inc.

  30. Nitrous Acid Causes Oxidative Deamination of Bases © John Wiley & Sons, Inc.

  31. Intercalation of an Acridine Dye Causes Frameshift Mutations --(+) charges molecules --Incorporated into DNA --DNA is more rigid --Change conformation (non-bending) © John Wiley & Sons, Inc.

  32. Hydroxylamine(NH2OH) • Hydroxylamine is a hydroxylating (OH) agent. • Hydroxylamine hydroxylates the amino group of cytosine and leads to G:C A:T transitions. . © John Wiley & Sons, Inc.

  33. Mutations Induced by Transposons(Repeats) Fragmets/segments of DNA that are capable to shift / translocate/move from one location to another © John Wiley & Sons, Inc.

  34. Expansion of Trinucleotide Repeats • Simple tandem repeats are repeated sequence of one to six nucleotide pairs (CGG, CAG and CTG). • Trinucleotide repeats can increase in copy number and cause inherited diseases (Fragile X Syndrome, Huntington disease, Spinocerebellar ataxia) © John Wiley & Sons, Inc.

  35. Mutations are induced by • chemicals, • ionizing irradiation, • ultraviolet light, and • endo(exo)genous transposable genetic elements. • Point mutations are of three types: • Transitions—purine for purine and pyrimidine for pyrimidine substitutions, • Transversions—purine for pyrimidine and pyrimidine for purine substitutions, and • Frameshift mutations—additions or deletions of one or two nucleotide pairs, which alter the reading frame of the gene distal to the site of the mutation. Chromatin remodeling==Epigenetics © John Wiley & Sons, Inc.

  36. Mutation: Basic Features of the Process Mutations occur in all organisms from viruses to humans. They can occur spontaneously or be induced by mutagenic agents. Mutation is usually a random, non-adaptive process. © John Wiley & Sons, Inc.

  37. Mutation: Somatic or Germinal • Germinal mutationsoccur in germ-line cells and will be transmitted through the gametes to the progeny. • Somatic mutationsoccur in somatic cells; the mutant phenotype will occur only in the descendants of that cell and will not be transmitted to the progeny. puberty (10-14 years) © John Wiley & Sons, Inc.

  38. Mutation: Spontaneous or Induced • Spontaneous mutationsoccur without a known cause due to unknown agents in the environment. • Induced mutationsresult from exposure or organisms to mutagens, physical and chemical agents that cause changes in DNA, such as ionizing irradiation, ultraviolet light, or certain chemicals. © John Wiley & Sons, Inc.

  39. Factors Influencing the Rate of Spontaneous Mutations • Accuracy of the DNA replication machinery • Efficiency of the mechanisms for the repair of damaged DNA • Degree of exposure to mutagenic agents in the environment © John Wiley & Sons, Inc.

  40. Mutation: Usually a Random, Non-adaptive Process • Is mutation random (intrinsic) or directed by the environment? • Replica plating was used to identify the presence of antibiotic (chemical) resistant bacteria prior to treatment with an antibiotic (chemicals). • Environmental stress does not cause mutations but selects for mutants that are best adapted to the environmental stress. © John Wiley & Sons, Inc.

  41. © John Wiley & Sons, Inc.

  42. Mutation: A Reversible Process • Forward mutation—mutation of a wild-type allele to a mutant allele. • Reverse mutation (reversion)—a second mutation that restores the original phenotype. • Back mutation—a second mutation at the same site. • Suppressor mutation—a second mutation at a different location in the genome. © John Wiley & Sons, Inc.

  43. Phenotype is restored Phenotype is not suppressed © John Wiley & Sons, Inc.

  44. Mutation: Phenotypic Effects The effects of mutations on phenotype range from no observable change to lethality. DNA/RNA/ polypeptide © John Wiley & Sons, Inc.

  45. Types of Mutations • Isoalleleshave no effect on phenotype or small effects that can be recognized only by special techniques. • Null allelesresult in no gene product or totally non-functional gene products. • Recessive (Dominant) lethal mutationsaffect genes required for growth of the organisms and are lethal in the homozygous state. © John Wiley & Sons, Inc.

  46. X-linked Recessive Lethal Mutations Alter the Sex Ratio Monoploid: (Recessive or Dominant) positive mutational effect (phenotype) Diploid: (Recessive)--positive mutational effect (phenotype)--homozygous X-linked .....hemizygous © John Wiley & Sons, Inc.

  47. Recessive Mutations Often Block Metabolic Pathways (Recessive) lethal mutations Neutral mutations ( no effect on phenotype)

  48. Expression of Wild-type and Mutant Alleles © John Wiley & Sons, Inc.

  49. Mutations in Human Globin Genes • Adult hemoglobin (Hemoglobin A) contains two  chains and two  chains. • Hemoglobin in patients with sickle-cell anemia (Hemoglobin S) differs from Hemoglobin A at only one position. • The sixth amino acid in the  chain is glutamic acid in Hemoglobin A (HBBA) and is valinein Hemoglobin S (HBBS). This substitution is caused by mutation of a single base pair (T:A substitution). © John Wiley & Sons, Inc.

  50. Tay-Sachs Disease • Tay-Sachs disease is an autosomal recessive disease. • The mutation causing Tay-Sachs disease is in the gene encoding hexosaminidase A. not linked to sex chromosome © John Wiley & Sons, Inc.