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Molecular Mechanism of Mutation

Molecular Mechanism of Mutation. Shikha Yashveer 1 , Jayanti Tokas 2, Shalini Jain 3 and Hariom Yadav 4 1 Department of Molecular Biology and Biotechnology, 2 Department of Biochemistry, CCS HAU, Hisar, Haryana, India 3 Department of Biochemistry, PGIMER, Chandigarh, India

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Molecular Mechanism of Mutation

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  1. Molecular Mechanism of Mutation Shikha Yashveer1, Jayanti Tokas2, Shalini Jain3 and Hariom Yadav4 1Department of Molecular Biology and Biotechnology, 2Department of Biochemistry, CCS HAU, Hisar, Haryana, India 3Department of Biochemistry, PGIMER, Chandigarh, India 4National Agri-Food Biotechnology, Mohali, Punjab, India Email: yadavhariom@gmail.com

  2. Any sudden change occurring in hereditary material is called as mutation • They may be harmful, beneficial or neutral

  3. In multicellular organism, two broad categories of mutations: Somatic mutations & germ line mutations

  4. Somatic mutations • Arise in the somatic cells • Passed on to other cells through the process of mitosis • Effect of these mutations depends on the type of the cell in which they occur & the developmental stage of the organism • If occurs early in development, larger the clone of the mutated cells

  5. Germ line mutations • They occur in the cells that produce gametes • Passed on to future generations • In multicellular organisms, the term mutation is generally used for germ line mutations

  6. Some Facts • Term mutation was given by Devries in 1901 while studying evening • primerose Oenothera lamarckiana • Most of these were chromosomal variations • Some were point variations • Originally the term mutation was given to both chromosomal as well as point mutations

  7. Cont. • Recently chromosomal mutations are studied separately • The term mutation is now given only to point mutations

  8. Definition • DNA is a highly stable molecule that replicates with amazing accuracy • Some errors of replication do occur • A mutation is defined as an inherited change in genetic information

  9. Types of gene mutation • Number of ways to classify gene mutations: • On the basis of the molecular nature of the defect • On the nature of the phenotypic effect-- amino acid sequence of the protein is altered or not • On the basis of the causative agent of the mutation

  10. Mutations on the basis of the molecular nature of the defect: • Base substitution • Insertions & deletions

  11. Base substitution: • Simplest type of gene mutation • Involves the alteration of a single • nucleotide in the DNA

  12. A base substitution usually leads to base pair substitution GGG AGT GTA GAT CGT CCC TCA CAT CTA GCA GGG AGT GCA GAT CGT A base substitution CCC TCA CAT CTA GCA First cycle of DNA replication GGG AGT GCA GAT CGT CCC TCA CAT CTA GCA CCC TCA CGT CTA GCA GGG AGT GTA GAT CGT

  13. Base substitution is of two types: Transition: Purine is replaced with a purine Pyrimidine is replaced with a pyrimidine A G G A C T T C

  14. Transversions: A purine is replaced by a pyrimidine A C A T G C G T or a pyrimidine is replaced by a purine C G C A T G T A

  15. The number of possible transversions is twice the number of possible transitions But Transitions are usually more frequent in vivo

  16. Insertions & deletions: • 2nd major class of gene mutation • Addition or the removal, respectively, of one or more nucleotide pair • Usually changes the reading frame, altering all amino acids encoded by codons following the mutation • Also called as frame shift mutations

  17. cont. • Additions or deletions in the multiples of three nucleotides will lead to addition or deletion of one or more amino acids • These mutations are called in-frame insertions and deletions, respectively.

  18. Mutations on the basis of the Phenotypic effects of mutations: • Most common phenotype in natural populations of the organism is called as wild type phenotype • The effect of mutation is considered with reference to wild type phenotype

  19. Forward mutation: • a mutation that alters the wild type phenotype • Reverse mutation (reversion): • a mutation that changes a mutant phenotype back in to the wild type

  20. Missense mutation: a base is substituted that alters a codon in the mRNA resulting in a different amino acid in the protein product TCA TTA AGT AAT UCA UUA Ser Leu

  21. Nonsense mutation: changes a sense codon into a nonsense codon. Nonsense mutation early in the mRNA sequence produces a greatly shortened & usually nonfunctional protein TCA TGA AGT ACT UCA UGA Stop codon Ser

  22. Silent mutation: alters a codon but due to degeneracy of the codon, same amino acid is specified TCA TCG AGT AGC UCA UCG Ser Ser

  23. Neutral mutation: mutation that alters the amino acid sequence of the protein but does not change its function as replaced amino acid is chemically similar or the affected aa has little influence on protein function. CTT ATT GAA TAA CUU AUU Leu Ile

  24. Loss of function mutations: • Complete or partial loss of the normal function • Structure of protein is so altered that it no longer works correctly • Mutation can occur in regulatory region that affects transcription , translation or spilicing of the protein • Frequently recessive

  25. Gain of function mutations: • Produces an entirely new trait • Causes a trait to appear in inappropriate tissues or at inappropriate times in development • Frequently dominant

  26. Conditional mutations: • Expressed only under certain conditions • Lethal mutations: • Cause the death of the organism

  27. Suppressor mutation: • Suppresses the effect of other mutation • Occurs at a site different from the site of original mutation • Organism with a suppressor mutation is a double mutant but exhibits the phenotype of un mutated wild type • Different from reverse mutation in which mutated site is reverted back into the wild type sequence

  28. On the basis of Causative agent of mutation: • Spontaneous: • Mutations that result from natural changes in DNA • Induced: • Results from changes caused By • environmental chemicals & radiations • Any environmental agent that increases the rate of mutation above the spontaneous is called a mutagen such as chemicals & radiations

  29. 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

  30. 5-bromouracil an analog of thymine O O 4 4 N Br CH₃ N 3 5 3 5 5BU T 2 2 6 6 O O 1 1 N N

  31. OH O 4 4 N Br 3 5 Br N 3 5 5BU 5BU 2 2 6 6 O O 1 1 N N Keto pairs with A Enol mispair with G

  32. TRANISITION T C A G T A 5dBU 5dBU A 5dBU G C G

  33. 3’ 5’ 3’ 5’ GAC GAC 3’ 5’ CTG 5’ 3’ GAC 3’ 5’ CBG 5’ 3’ GAC 5’ 3’ CBG CBG 5’ 3’ 3’ 5’ Incorporated error GGC 3’ 5’ GAC Strand seperation CTG 3’ 5’ 5’ 3’ 5’ 3’ CBG GGC 3’ 5’ 3’ 5’ 3’ 5’ GAC CTG GAC GGC CTG 5’ 3’ 5’ 3’ CBG CCG replication 5’ 3’ 5’ 3’

  34. G TRANISITION G A C T C 5dBU G 5dBU 5dBU A A T

  35. 2-amino purine (P) • Base analog of adenine • Normally pairs with thymine • May mispair with cytosine • Causes a transition mutation

  36. T.A C.G Incorporated error 3’ 5’ 3’ 5’ 3’ 5’ 3’ 5’ GTC GTC GTC GTC 3’ 5’ CAG 5’ 3’ CPG GTC Strand separation 5’ 3’ 5’ 3’ CPG CAG 3’ 5’ CPG 5’ 3’ 5’ 3’ GTC GCC CAG 3’ 5’ 5’ 3’ CAG 5’ 3’ 5’ 3’ 3’ 5’ CPG GCC replication 3’ 5’ 3’ 5’ GTC GCC CAG CGG 5’ 3’ 5’ 3’

  37. T TRANISITION T C A G A 2AP T 2AP C 2AP C G

  38. C TRANISITION C T G A G 2AP C 2AP T 2AP T A

  39. Both base analogs produce transition mutations • Mutations by base analogs can be reversed by treatment with the same analog or different analog

  40. 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.

  41. C T G A EMS EMS T 4ET 6EG G C T G A

  42. Nitrous acid: causes deamination Cytosine Uracil NH2 o 4 4 N N 3 5 3 5 HNo2 2 2 6 6 O 1 1 O N N H H CYTOSINE URACIL

  43. 5’ 3’ C HNO2 5’ 3’ 3’ G 5’ 5’ 3’ U 5’ 3’ U A U 3’ 5’ G 5’ 3’ 3’ 5’ 3’ 5’ G U A 3’ 5’ 5’ 3’ 5’ 3’ 3’ 5’ C U T G A A 3’ 5’ 3’ 5’ 5’ 3’ C.G TA

  44. Adenine changes into Hypoxanthin which then pairs with Cytosine 5’ 3’ A HNO2 5’ 3’ 3’ T 5’ 5’ 3’ H 5’ 3’ H C H 3’ 5’ T 5’ 3’ 3’ 5’ 3’ 5’ T H C 3’ 5’ 5’ 3’ 5’ 3’ 3’ 5’ T H C A C G 3’ 5’ 3’ 5’ 5’ 3’ A.T G.C

  45. Guanine changes into Xanthin which pairs with Cytosine. Xanthin can also pair with Thymine 5’ 3’ G HNO2 5’ 3’ 3’ C 5’ 5’ 3’ X 5’ 3’ X T X 3’ 5’ C 5’ 3’ 3’ 5’ 3’ 5’ C X T 3’ 5’ 5’ 3’ 5’ 3’ 3’ 5’ G X T C T A 3’ 5’ 3’ 5’ 5’ 3’ G.C A.T

  46. 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

  47. 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

  48. Cytosine changes into hydroxlamine Cytosine which pairs with Adenine instead of Guanine 5’ 3’ C NH₂OH 5’ 3’ 3’ G 5’ 5’ 3’ hC 5’ 3’ hC A hC 3’ 5’ G 5’ 3’ 3’ 5’ 3’ 5’ G hC A 3’ 5’ 5’ 3’ 5’ 3’ 3’ 5’ C hC A G A T 3’ 5’ 3’ 5’ 5’ 3’ C.G T.A

  49. 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

  50. 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

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