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Mutation

Mutation. Mutation. Means change Definition: An event that gives rise to an alteration in the genotype It also can be the change itself Mutation does not mean “bad” Mutations are IMPORTANT for a variety of reasons. Mutation ‘Levels’. DNA Level Chromosomal Level Genome Level.

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Mutation

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  1. Mutation

  2. Mutation • Means change • Definition: An event that gives rise to an alteration in the genotype • It also can be the change itself • Mutation does not mean “bad” • Mutations are IMPORTANT for a variety of reasons

  3. Mutation ‘Levels’ • DNA Level • Chromosomal Level • Genome Level

  4. DNA Level • At or below the gene level • 1) Addition or Deletion of one or two nucleotides (+ and – frameshifts) • 2) Substitution of one nucleotide for another • 3) Inversion within a gene • 4) Crossingover within a gene • Equal • Unequal • 1 and 2 are often referred to as POINT MUTATIONS

  5. Chromosomal Level • 1) Duplications • 2) Deletions • 3) Translocations • Reciprocal • Non-reciprocal • 4) Inversions • ? ‘Standard’ crossing over ? • 3 and 4 may result in POSITION EFFECTS

  6. Genome Level • These result in ploidy changes • Aneuploidy • Plus or minus one or a few chromosomes • Euploidy (true polyploidy) • Involves whole SETS of chromosomes • Autopolyploidy • Allopolyploidy

  7. Additional Points • ALL genes can mutate • Observed levels are usually low • Some genes have very high rates of mutation (Mutable Genes) • Some genes seem to increase the rate of mutation in adjacent genes (Mutator Genes)

  8. What Causes Mutations ? • 1) Spontaneous (?????) • 2) Chemically induced • 3) Radiation induced • Most (if not all) really come down to a chemical level • No such thing as a “spontaneous” mutation • “Spontaneous” means…

  9. Chemicals • Many chemicals are mutagens; many others are promutagens • Chemicals (just like radiation) can cause point mutations. • Chemicals (just like radiation) can cause chromosome breakage (e.g. - LSD, Mercury, Caffeine --- at least in cell culture)

  10. DNA Level Mutations • + and – Frameshifts and their effects • + or – one nucleotide • + or – a whole codon • Multiple frameshifts • The effects depend on WHERE it occurs • The effects depend on what the change is • ?????? One change equals one change, or does it ??????

  11. DNA Level Mutations • Substitutions • Transitions (more common) • Purine (A, G) for a purine OR pyrimidine (T, C) for a pyrimidine • Transversions (less common) • Purine for a pyrimidine (or pyrimidine for a purine • GENERALLY have less chance of an effect than frameshifts. WHY?

  12. Other DNA Level Mutations • Inversions within a gene • Crossingover within a gene

  13. Substitution Mutations • Results from a temporary type of isomerization (tautomerization) during replication • Base enters a “rare” state (unstable) • Can be in a base already in the DNA strand • Can be in one of the incoming bases • We will look at both for a TRANSITION • Requires two divisions to get the “stable” mutation

  14. Substitution Mutations • One nucleotide is replaced by another • Transition --- insertion of a one purine base for the other or one pyrimidine base for the other (results in an “odd” purine-pyrimidine pair) • Transversion --- replacement of a purine base with a pyrimidine or vice versa (results in a temporary purine-purine pair or pyrimidine-pyrimidine pair)

  15. Substitution Mutations • Base analogs increase the rate of formation of substitution mutations • 5-bromouracil (5BU) • Use of 5-fluorouracil

  16. Radiation Induced Mutations • By non-ionizing radiation (UV) • Dimer formation (especially ThT dimers) • Light Repair System (enzyme breaks dimers)

  17. Radiation Induced Mutations • By non-ionizing radiation (UV) • Dimer formation (especially ThT dimers) • Dark Repair System (excision repair) • Endonuclease, exonuclease,DNA polymerase, ligase

  18. Radiation Induced Mutations • By ionizing radiation • Mechanisms- “Target Hypothesis”- “Physical-Chemical” Hypothesis • Temperature, hydration, and oxygen contentall have an effect

  19. Mechanism

  20. Mechanism

  21. Ionizing Radiation and Mutation • Late 1920s • Stadler – working on barley and corn • Muller – working on Drosophila • Muller later received a Nobel Prize (1948) • Why H. Muller and not Stadler?

  22. SOME GENERALIZATIONS FOR IONIZING RADIATION • Mutation frequency is DIRECTLY proportional to the dose • Doesn’t matter if given in one large dose or several small ones • No lower limit (no threshold) • Safe amount?????

  23. Additions and Deletions • Chemical basis • Caused by intercalation (insertion) of some nucleotide like chemical into the chain • Before replication --- increases length • Results in a Plus (+) frameshift mutation • During replication --- decreases length • Results in a Minus (-) frameshift mutation • Acridines are capable of doing this

  24. Additions and Deletions • Requires 2 divisions to get the “stable” mutation • Proflavin • Acridine Orange (very potent)

  25. Additions and Deletions

  26. - frameshift Intercalation of Proflavin DURING DNA replication

  27. + frameshift Intercalation of Proflavin PRIOR TO DNA replication

  28. Chemicals Besides Acridines • Too many to mention…but… • Mustard gas (adds a methyl group) • Formaldehyde • Phenol • Nitrous Oxide (replaces NH2 with O)

  29. Mutation Concluded • Temperature has an effect • Carcinogens and Mutagens • Somatic vs. germinal mutations • Somatic are “dead-end” in animals • In plants somatic can be “passed on” asexually by vegetative propagation(runners, bulbs, corms, cuttings, grafting) • In plants somatic mutations can get into the germ line!

  30. Testing for Mutagens & Promutagens • Ames test • Uses a histidine deficient (dependent) strain of Salmonella • Looks for reverse mutation to histidine independence above the background rate • For suspected promutagens: first treat substance with a liver (human or rat) extract and then do the test

  31. Teratogenesis • Teratogen – an agent that induces a non-inheritable defect during embryonic development (Proteratogen) • In humans --- about 4% of births • How do they work? • Interfere with mitosis or cell migration • Interfere with differentiation (disturb gene regulation, translation or activity of ultimate gene products)

  32. Teratogens • Radiation • Viruses (Rubella and pregnant women) • Thalidomide (really a proteratogen) • Diethylstilbestrol (DES) (taken by pregnant women - results in genital tract abnormalities in their children) • Dioxins (found as a contaminant in herbicides such as Agent Orange) • Hexachlorophene (a bacteriocide)

  33. Teratogens • Smoking (CO reduces O2 available to the fetal circulation; nicotine constricts blood vessels and reduces blood flow) • Progestin (artificial progesterone-like compound; causes masculinization of female fetuses) • Alcohol – microcephaly, low birth weight, some mental retardation) • Caffeine, Aspirin and numerous legal and not so legal drugs

  34. Some Other Birth Defects • Cleft lip and/or cleft palate • Spina bifida • Club foot • Heart disease and malformations • Cataracts • Deafness • Intestinal tract disorders • Low birth weight

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