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Hemant
- 1. Seminar OnSeminar On MutagensMutagens andand Their ActionsTheir Actions
- 2. Mutation Heritable changes in DNA or gene Mutagen Chemical Mutagens Radiation Biological Mutagens Conclusion Introduction
- 3. The process that produces an inheritable alteration in DNA Structure Chromosome Structure There are two types of mutations Spontaneous Mutation Induced Mutation
- 4. A.Spontaneous Mutation Natural error during DNA replication or recombination. Caused by background radiation. Arise randomly as a result in cells. NO ARTIFICIAL TREATMENT Spontaneous Mutation vs. Induced Mutation
- 5. Induced Mutation Caused by exposure to known mutagenic agents Mutagens A natural or human-made agent which can alter the structure or sequence of genetic material and induce
- 6. There are three main types of mutagens classifying by their sources: Chemical Mutagens Radiation Biological Mutagens
- 7. Chemical Mutagens: Base analogs Chemical modification agents Intercalating agents Radiation: Ionizing Radiation UV Radiation Biological Mutagens: Transposable element
- 8. Chemical Mutagens: First discovery of a chemical mutagen was made by Charlotte Auerbach Base Analogs: Chemicals with structures similar to that of any of the four standard bases of DNA DNA polymerases cannot distinguish these analogs They may be incorporated into newly synthesized DNA molecules
- 10. 5-bromouracil an analog of thymine N N 1 2 3 6 5 4 O O 5BU Br N N 1 2 3 6 5 4 CH₃ T O O
- 11. 5-Bromouracil: analog of a pyrimidine Resembles Thymine(T) . has Br atom at C-5 instead of methyl group as in T. can incorporate into DNA and pair with either A or G due to tautomerization.
- 12. 5-Bromouracil: analog of a pyrimidine TAUTOMERIZATION –spontaneous structural alternations between 2 forms, ketoform and enolform
- 15. GAC CTG Strand seperation 3’ 5’ 3’ 5’ GAC 3’ 5’ CTG 5’ 3’ GAC 3’ 5’ CBG 5’ 3’ CTG 5’ 3’ GAC 3’ 5’ GAC 3’ 5’ CBG 5’ 3’ GAC 3’ 5’ CTG 5’ 3’ CBG 5’ 3’ GGC 3’ 5’ CBG 5’ 3’ GGC 3’ 5’ CBG 5’ 3’ GAC 3’ 5’ GGC 3’ 5’ CCG 5’ 3’replication Incorporated error
- 17. 2-amino purine (P) Base analog of adenine Normally pairs with thymine May mispair with cytosine Causes a transition mutation
- 18. GTC CAG Strand separation 3’ 5’ 3’ 5’ GTC 3’ 5’ CAG 5’ 3’ GTC 3’ 5’ CPG 5’ 3’ CAG 5’ 3’ GTC 3’ 5’ GTC 3’ 5’ CPG 5’ 3’ GTC 3’ 5’ CAG 5’ 3’ CPG 5’ 3’ GCC 3’ 5’ CPG 5’ 3’ GCC 3’ 5’ CAG 5’ 3’ GTC 3’ 5’ GCC 3’ 5’ CGG 5’ 3’ replication Incorporated error T.A C.G
- 21. Both base analogs produce transition mutations Mutations by base analogs can be reversed by treatment with the same analog or different analog
- 22. Alkylating agents: Chemicals that donate alkyl groups e.g. ehylmethanesulfonate(EMS) It adds an ethyl group to guanine and produces 6- ethylguanine, which pairs with thymine and leads to CG:TA transitions Also adds an ethyl group to thymine to produce 4- ethylthymine, which then pairs with guanine, leading to a TA:CG transition Mutations produced by EMS can be reversed by additional treatment with EMS. Mustard gas is another alkylating agent.
- 23. Modify the normal bases by adding alkyl groups. Common alkylatingagents Ethylmethanesulfonate(EMS) Nitrosoguanidine(NG) Di-(2-chloroethyl) sulfide (Sulfur mustard) Di-(2-chloroethyl) methylamine (Nitrogen mustard) Alkylating agents
- 24. Ethylmethanesulfonate(EMS) Mechanism of Ethylmethanesulfonate(EMS) Ethylatebase’s 7-N & 6-O positions
- 25. Mechanism of Ethylmethanesulfonate(EMS) Ethylatebase’s 7-N & 6-O positions
- 27. Deaminating agents Nitrous acid (HNO2) is one of common deaminatingagents Convert the amino group (-NH2) into ketogroup (=O). Change H-bonding potential of the modified bases.
- 28. Nitrous acid: causes deamination Cytosine Uracil N N CYTOSINE 1 2 3 6 5 4 NH2 O H N N 1 2 3 6 5 4 O o HNo2 URACIL H
- 29. U G U G U A GC U A U A AT C.G TA C G HNO2 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 3’ 5’ 5’ 3’ 5’ 5’ 3’ 3’3’ 5’ 5’ 3’ 3’ 3’5’ 5’
- 30. H T H T H C A T H C H C G C A.T G.C A T HNO2 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 3’ 5’ 5’ 3’ 5’ 5’ 3’ 3’3’ 5’ 5’ 3’ 3’ 3’5’ 5’ Adenine changes into Hypoxanthin which then pairs with Cytosine
- 31. Guanine (G) →Xanthine Mechanism of Nitrous acid
- 32. X C X C X T C G X T X T A T A.TG.C G C HNO2 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 3’ 5’ 5’ 3’ 5’ 5’ 3’ 3’3’ 5’ 5’ 3’ 3’ 3’5’ 5’ Guanine changes into Xanthin which pairs with Cytosine. Xanthin can also pair with Thymine
- 33. Nitrous acid produces exclusively transition mutations Both C.G T.A & T.A C.G transitions are produced Thus mutations can be reversed with the nitrous acid
- 34. Hydroxl amine Specific base modifying mutagen which adds a hydroxyl group to cytosine producing hydroxlamine cytosine which pairs with adenine instead of guanine This Leads to C.G T.A tranisitions Acts only on cytosine thus can not revert the mutation produced
- 35. hC G hC G hC A G C hC A hC A T A T.AC.G C G 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 3’ 5’ 5’ 3’ 5’ 5’ 3’ 3’3’ 5’ 5’ 3’ 3’ 3’5’ 5’ Cytosine changes into hydroxlamine Cytosine which pairs with Adenine instead of Guanine NH₂OH
- 36. Oxidative reactions: Reactive forms of oxygen like superoxide radicals, hydrogen peroxide and hdroxyl radicals produced in the course of normal aerobic metabolism or by radiation, ozone, peroxides, and certain drugs Cause damage to DNA & induce mutations by chemical changes Oxidation converts guanine into 8-oxy-7,8- dihydrodeoxyguanine which mispairs with adenine leading to G.C T.A transversion
- 37. Intercalating agents Proflavin, acridine orange, ethidium bromide, and dioxin They are about the same size as a nucleotide They produce mutations by sandwiching themselves (intercalating) between adjacent bases in DNA They distort the three-dimensional structure of the helix and cause single-nucleotide insertions and deletions in replication These insertions and deletions frequently produce frameshift mutations
- 39. Physical Mutagens Ionising radiation e.g. x rays, γrays, cosmic rays Non-ionising radiation e.g. UV radiation
- 40. Ionizing Radiation (high energy and penetrating) Effects Organelle failure Cell division blockage Cell death Interaction with DNA Breaks in one or both strands (can lead to rearrangements, deletions, chromosome loss death if unrepaired) Damage to/loss of bases (mutation) Crosslinkingof DNA to itself or proteins
- 41. Non-Ionizing Radiation (Less energy, Non-penetrating) Take UV radiationas an example Its wavelengths are preferentially absorbed by bases of DNA and by aromatic amino acids of proteins. Normally classified in terms of its wavelengths: UV-A, UV-B, UV-C (in decreasing order of wavelengths)
- 43. UV Radiation, Pyrimidine dimers 5’--CCGAATTCAG--3’ 3’--GGCTTAAGTC--5’ ©2001 Lee Bardwell tt Thymine Dimer T T
- 46. Mutation rates The frequency with which a gene changes from the wild type to a mutant is reffered to as the mutation rate. Expressed as the number of mutations per biological unit i.e. mutations per cell division, per gamete per round of replication e.g. mutation rate for achondroplasia (hereditary dwarfism) is about 4 mutations per 100,000 gametes
- 47. Mutation frequency: Incidence of a specific type of mutation with in a group of individual organism e.g. for achondroplasia, the mutation frequency in united states is about 2x10⁻⁴
- 48. Principles of Genetics An Introduction of Genetic Analysis DNA replication http://pharmacology.unmc.edu/cancer/a ntibio.htm References