Mutations ariane

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Mutation, Types of Mutations, Mutagens and Transposons

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Mutations ariane

  1. 1. WHAT IS MUTATION?
  2. 2. Which picture do you think is a case of Mutation?
  3. 3. EXAMPLES OF HUMAN MUTATION
  4. 4. Key Idea: Mutation: • Changes in DNA that affect genetic information
  5. 5. Objectives: • Determine the different types of Mutations and how it affects the gene expression of an organism. • Determine the different mutagens and how it affects the proteins during translation phase. • Explain the concept and mechanisms of transposons as a one of the factors of Mutation
  6. 6. Protein Synthesis and Mutation • • Gene Regulation in Prokaryotes Mutation(Permanent, heritable DNA changes) – Point mutation (base substitutions) • Missense mutation • Nonsense mutation (premature stop) • Silent mutation – Insertions/deletions • Frameshift mutation – Dramatic change in amino acids – Run-ons, premature stops (nonsense mut.) • The Creation of Mutation (mutagenesis) – Spontaneous mutation • Occurs in DNA replication (1 in 109 bp) – Chemical mutagens • Base pair changers (nitrous acid) • Base analogues (e.g.. 5 bromouracil) • Frameshift mutagens (aflatoxin, benzpyrene) – Radiation • X rays, gamma rays break DNA, bases • UV light causes knots in DNA strand Proteins are made by translation of genetic instructions by a ribosome. Mutations in the genetic instructions usually changes the resultant protein with deleterious effects.
  7. 7. Mutation: Some Definitions • • • • A heritable change in the genetic material Mutations may be neutral, beneficial, or harmful Mutagen: Agent that causes mutations Spontaneous mutations: Occur in the absence of a mutagen
  8. 8. Mutation: Base Substitution (Point Mutations) G G C C Glu (a) Silent mutation (d) Run-on mutation
  9. 9. Regulation of Bacterial Gene Expression • Steps in Translation of mRNA – Initiation, Elongation, Termination • Mutation(Permanent, heritable DNA changes) – Point mutation (base substitutions) • Missense mutation • Nonsense mutation (premature stop) • Silent mutation – Insertions/deletions • Frameshift mutation – Dramatic change in amino acids – Run-ons, premature stops (nonsense mut.) • The Creation of Mutation (mutagenesis) – Spontaneous mutation • Occurs in DNA replication (1 in 109 bp) – Chemical mutagens • Base pair changers (nitrous acid) • Base analogues (e.g.. 5 bromouracil) • Frameshift mutagens (aflatoxin, benzpyrene) – Radiation • X rays, gamma rays break DNA, bases • UV light causes knots in DNA strand Proteins are made by translation of genetic instructions by a ribosome. Mutations in the genetic instructions usually changes the resultant protein with deleterious effects.
  10. 10. Mutation: Insertions and Deletions THEBIGCATATETHERAT THEBIGCBATATETHERAT Figure 8.17a, d
  11. 11. Summary of Mutation Types Run-on mutation Stop codon lost so protein is extra long (can also produce nonsense and run-ons)
  12. 12. Protein Synthesis and Mutation • Steps in Translation of mRNA – Initiation, Elongation, Termination • Mutation(Permanent, heritable DNA changes) – Point mutation (base substitutions) • Missense mutation • Nonsense mutation (premature stop) • Silent mutation – Insertions/deletions • Frameshift mutation – Dramatic change in amino acids – Run-ons, premature stops (nonsense mut.) • The Creation of Mutation (mutagenesis) – Spontaneous mutation • Occurs in DNA replication (1 in 109 bp) – Chemical mutagens • Base pair changers (nitrous acid) • Base analogues (e.g.. 5 bromouracil) • Frameshift mutagens (aflatoxin, benzpyrene) – Radiation • X rays, gamma rays break DNA, bases • UV light causes knots in DNA strand Proteins are made by translation of genetic instructions by a ribosome. Mutations in the genetic instructions usually changes the resultant protein with deleterious effects.
  13. 13. What causes MUTATION? • Reasons 1. Spontaneous errors in DNA replication or meiotic recombination 2. A consequence of the damaging effects of physical or chemical mutagens on DNA
  14. 14. Errors in Meiosis (Dr.RS) • Errors during DNA Replication – Errors during meiosis introduce variation in the DNA sequence. The effect of this variation depends on a number of factors: • The size of the variant. It may be as small as a change to a single base or as large as the rearrangement of whole chromosomes. • The pathogenicity of the variant. It may have no effect on gene function or may severely disrupt the function of the gene. – Some variants, such as single nucleotide polymorphisms (SNPs) are relatively common in the population. In other cases,mutations responsible for rare genetic conditions may be specific to an individual family.
  15. 15. Errors in Meiosis (Dr.RS) • Errors during Recombination – Recombination involves the 'swapping' of genetic material between both chromosomes of the same pair (homologous chromosomes). They align sideby-side and pair exactly, break, swap lengths of DNA and rejoin. – If chromosomes of the same pair misalign, the exchange of material may result in duplications (extra genetic material) or deletions (missing genetic material). – If a chromosome mispairs with a chromosome from a different pair (nonhomologous chromosomes) the exchange of material will lead to a chromosome translocation. This may involve the swapping of material (a reciprocal translocation) or result in chromosomes becoming stuck together end-to-end (a Robertsonian translocation). – Translocations may lead to gene dosage problems. Extra copies of genes can cause disease through overexpression, resulting in disrupted cell function. Loss of genetic material may lead to the cell missing copies of genes essential to its activity.
  16. 16. Errors in Meiosis (Dr.RS) Errors during segregation • Errors can occur when the chromosomes segregate into the gametes during meiosis resulting in egg or sperm with too many or too few chromosomes. • As a result, fertilised eggs and the ensuing embryos may have trisomy (an extra chromosome of a particular pair) in each cell or monosomy (one chromosome fewer in each cell). • For example in trisomy 21 Down syndrome, cells have an extra copy of chromosome 21 (trisomy 21). In Turner syndome cells have only one X chromosome (monosomy X) and no Y chromosome as shown in the following karyotype.
  17. 17. Spontaneous and Induced Mutation • Spontaneous mutation rate = 1 in 109 (a billion) replicated base pairs or 1 in 106 ( a million) replicated genes. Mistakes occur during DNA Replication just before cell division. This is natural error rate of DNA polymerase. • Mutagens increase mistakes to to 10–5 (100 thousand) or 10–3 ( a thousand) per replicated gene
  18. 18. Effects of Spontaneous Mutation • Congenital Heart Disease • Mental Retardation
  19. 19. Mutagen • Mutation relevant • Cause DNA damage that can be converted to mutations.
  20. 20. 1 Mutaagenesis Physical mutagens High-energy ionizing radiation: X-rays and g-rays strand breaks and base/sugar destruction Nonionizing radiation : UV light pyrimidine dimers Chemical mutagens Base analogs: direct mutagenesis Nitrous acid: deaminates C to produce U Alkylating agents Intercalating agents Lesions-indirect mutagenesis
  21. 21. Chemical Mutagens Base pair altering chemicals (base modifiers) deaminators like nitrous acid, nitrosoguanidine, or alkylating agents like cytoxan cytoxan Nitrous acid Base analogues “mimic” certain bases but pair with others - E.g. 5fluorouracil, cytarabine Acts like a “C” cytarabine
  22. 22. BASE PAIR ALTERING CHEMICALS
  23. 23. Deaminating Agent • *Deaminating agent - Nitrous acid - removes the anime group from Adenine and Cytosine • Nitrous acid is a deaminating agent that converts cytosine to uracil, adenine to hypoxanthine, and guanine to xanthine. The hydrogen-bonding potential of the modified base is altered, resulting in mispairing.
  24. 24. BASE ANALOGS
  25. 25. Alkylating agents • Alkylating agents like EMS/MMS(ethyl/methly methyl sulphonate) add methyl groups to Guanosine . Bulky attachment to the side groups or bases.
  26. 26. Hydroxilating Agents • Addition of OH (Hydroxyl Group) hydroxylamine (HA)
  27. 27. Intercalating Agents • Intercalation agents are compounds that can slide between the nitrogenous bases in a DNA molecule. • This tends to cause a greater likelihood for slippage during replication, resulting in an increase in frameshift mutations. • Example (Sodium Azide)
  28. 28. Chemical Frameshift Mutagens Intercalate into DNA Carboplatin (anti-cancer drug) Benzpyrene in cigarette smoke Aflatoxin from Aspergillus fungus growing on corn AT GC TA GC CG AT GC TA GC CG AT GC CG TA GC CG Daunarubicin (anti-cancer drug) Bleomycin (anti-cancer drug produced by Streptomyces)
  29. 29. Protein Synthesis and Mutation • Steps in Translation of mRNA – Initiation, Elongation, Termination • Mutation(Permanent, heritable DNA changes) – Point mutation (base substitutions) • Missense mutation • Nonsense mutation (premature stop) • Silent mutation – Insertions/deletions • Frameshift mutation – Dramatic change in amino acids – Run-ons, premature stops (nonsense mut.) • The Creation of Mutation (mutagenesis) – Spontaneous mutation • Occurs in DNA replication (1 in 109 bp) – Chemical mutagens • Base pair changers (nitrous acid) • Base analogues (e.g.. 5 bromouracil) • Frameshift mutagens (aflatoxin, benzpyrene) – Radiation • X rays, gamma rays break DNA, bases • UV light causes knots in DNA strand Proteins are made by translation of genetic instructions by a ribosome. Mutations in the genetic instructions usually changes the resultant protein with deleterious effects.
  30. 30. Mutation: Ionizing Radiation • Ionizing radiation (X rays, gamma rays, UV light) causes the formation of ions that can react with nucleotides and the deoxyribose-phosphate backbone. • Nucleotide excision repairs mutations
  31. 31. X-rays and Gamma Rays Cause Breaks in DNA
  32. 32. Ionizing Radiation: UV • UV radiation causes thymine dimers, which block replication. • Light-repair separates thymine dimers • Sometimes the “repair job” introduces the wrong nucleotide, leading to a point mutation. Figure 8.20
  33. 33. Protein Synthesis and Mutation • Steps in Translation of mRNA – Initiation, Elongation, Termination • Mutation(Permanent, heritable DNA changes) – Point mutation (base substitutions) • Missense mutation • Nonsense mutation (premature stop) • Silent mutation – Insertions/deletions • Frameshift mutation – Dramatic change in amino acids – Run-ons, premature stops (nonsense mut.) • The Creation of Mutation (mutagenesis) – Spontaneous mutation • Occurs in DNA replication (1 in 109 bp) – Chemical mutagens • Base pair changers (nitrous acid) • Base analogues (e.g.. 5 bromouracil) • Frameshift mutagens (aflatoxin, benzpyrene) – Radiation • X rays, gamma rays break DNA, bases • UV light causes knots in DNA strand Proteins are made by translation of genetic instructions by a ribosome. Mutations in the genetic instructions usually changes the resultant protein with deleterious effects.
  34. 34. TRANSPOSONS
  35. 35. Transposable elements in eukaryotes: Barbara McClintock (1902-1992) Cold Spring Harbor Laboratory, NY Nobel Prize in Physiology and Medicine 1983 “for her discovery of mobil genetic elements” • Studied transposable elements in corn (Zea mays) 1940s-1950s (formerly identified as mutator genes by Marcus Rhoades 1930s) • Also known for work demonstrating crossing over as part of the chromosomal basis of inheritance.
  36. 36. McClintock’s discovery of transposons in corn: • c/c = white kernels and C/- = purple kernels • Kernal color alleles/traits are “unstable”. • If reversion of c to C occurs in a cell, cell will produce purple pigment and a spot. • Earlier in development reversion occurs, the larger the spot. • McClintock concluded “c” allele results from a non-autonomous transposon called “Ds” inserted into the “C” gene (Ds = dissassociation). • Autonomous transposon “Ac” controls “Ds” transposon (Ac = activator).
  37. 37. 21.1 Introduction  transposon (transposable element) : a DNA sequence able to insert itself at a new location in the genome, without having any sequence relationship with the target locus.  Transposons fall into two general classes: transposons and retrotransposons.  Transposons that mobilize via DNA are found in both prokaryotes and eukaryotes. A genome may contain both functional and nonfunctional (defective) elements. Often the majority of elements in a eukaryotic genome are defective. A eukaryotic genome contains a large number and variety of transposons. The fly genome has >50 types of transposon, with a total of several hundred individual elements.  Transposable elements confer neither advantage nor disadvantage on the phenotype, but could constitute “selfish DNA,” concerned only with their own propagation.
  38. 38. Figure 21.1 A major cause of sequence change within a genome is the movement of a transposon to a new site. This may have direct consequences on gene expression. Unequal crossing-over between related sequences causes rearrangements. Copies of transposons can provide targets for such events.
  39. 39.  insertion sequences (IS) : the simplest small bacterial transposon, each of which codes only for the proteins needed to sponsor its own transposition.  inverted terminal repeats : the short related or identical sequences present in reverse orientation at the ends of some transposons.  direct repeats : identical (or closely related) sequences present in two or more copies in the same orientation; they are not necessarily adjacent.  transposase : the enzyme involved in insertion of transposon at a new site.
  40. 40. Figure 21.2 Transposons have inverted terminal repeats and generate direct repeats of flanking DNA at the target site. In this example, the target is a 5 bp sequence. The ends of the transposon consist of inverted repeats of 9 bp, where the numbers 1 through 9 indicate a sequence of base pairs. the most common length is 9 bp
  41. 41.  replicative transposition : the element is duplicated during the reaction, so that the transposing entity is a copy of the original element (Figure 21. 6).  resolvase : the enzyme involved in site-specific recombination between two transposons present as direct repeats in a cointegrate structure.  nonreplicative transposition : the transposing element moves as a physical entity directly from one site to another and is conserved (Figure 21. 7).  conservative transposition : another sort of nonreplicative event, in which the element is excised from the donor site and inserted into a target site by a series of events in which every nucleotide bond is conserved (Figure 21. 8).
  42. 42. Figure 21.5 The direct repeats of target DNA flanking a transposon are generated by the introduction of staggered cuts whose protruding ends are linked to the transposon.
  43. 43. Figure 21.6 Replicative transposition creates a copy of the transposon, which inserts at a recipient site. The donor site remains unchanged, so both donor and recipient have a copy of the transposon. Requires resolvase as well as transposase
  44. 44. Fig. 7.20, Integration of IS element in chromosomal DNA.
  45. 45. Host repair system required Figure 21.7 Nonreplicative transposition allows a transposon to move as a physical entity from a donor to a recipient site. This leaves a break at the donor site, which is lethal unless it can be repaired. Requires only a transposase
  46. 46. Figure 21.8 Conservative transposition involves direct movement with no loss of nucleotide bonds; compare with lambda integration and excision. Resembles the mechanism of lambda integration
  47. 47. Models of transposition: • Similar to that of IS elements; duplication at target sites occurs. • Cointegration = movement of a transposon from one genome (e.g., plasmid) to another (e.g., chromosome) integrates transposon to both genomes (duplication). • Transposition may be replicative (duplication) or non-replicative (transposon lost from original site). • Result in same types of mutations as IS elements: insertions, deletions, changes in gene expression, or duplication. • Crossing-over occurs when donor DNA with transposable element fuses with recipient DNA.
  48. 48. Control of Transposons • Autoregulation: Some transposases are transcriptional repressors of their own promoter(s) • e.g., TpnA of the Spm element • Transcriptional silencing: mechanism not well understood but correlates with methylation of the promoter (also methylation of the IRs)
  49. 49. Biological Significance of Transposons • They provide a means for genomic change and variation, particularly in response to stress (McClintock’s "stress" hypothesis) (1983 Nobel lecture, Science 226:792) • or just "selfish DNA"? • No known examples of an element playing a normal role in development.
  50. 50. • Transposable elements cause genetics changes and make important contributions to the evolution of genomes: • Insert into genes. • Insert into regulatory sequences; modify gene expression. • Produce chromosomal mutations.
  51. 51. THE END

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