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![Page 1: 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”](https://reader031.fdocuments.net/reader031/viewer/2022032721/56649cd65503460f9499ddf3/html5/thumbnails/1.jpg)
Mutation
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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
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Mutation ‘Levels’
• DNA Level
• Chromosomal Level
• Genome Level
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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
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Chromosomal Level• 1) Duplications• 2) Deletions• 3) Translocations
–Reciprocal–Non-reciprocal
• 4) Inversions• ? ‘Standard’ crossing over ?• 3 and 4 may result in POSITION EFFECTS
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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
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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)
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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…
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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)
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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 ??????
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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?
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Other DNA Level Mutations
• Inversions within a gene• Crossingover within a gene
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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
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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)
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Substitution Mutations
• Base analogs increase the rate of formation of substitution mutations
• 5-bromouracil (5BU)• Use of 5-fluorouracil
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Radiation Induced Mutations• By non-ionizing radiation (UV)• Dimer formation (especially TT dimers)• Light Repair System (enzyme breaks dimers)
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Radiation Induced Mutations• By non-ionizing radiation (UV)• Dimer formation (especially TT dimers)• Dark Repair System (excision repair)– Endonuclease, exonuclease,
DNA polymerase, ligase
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Radiation Induced Mutations• By ionizing radiation• Mechanisms
- “Target Hypothesis”- “Physical-Chemical” Hypothesis
• Temperature, hydration, and oxygen contentall have an effect
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Mechanism
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Mechanism
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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?
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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?????
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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
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Additions and Deletions• Requires 2 divisions to get the “stable” mutation• Proflavin
• Acridine Orange (very potent)
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Additions and Deletions
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- frameshift
Intercalation of Proflavin
DURING DNA
replication
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+ frameshift
Intercalation of Proflavin PRIOR TO
DNA replication
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Chemicals Besides Acridines
• Too many to mention…but…• Mustard gas (adds a methyl group)• Formaldehyde• Phenol• Nitrous Oxide (replaces NH2 with O)
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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!
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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
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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)
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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)
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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
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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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