Mutations

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  • Non-function proteins – misfolding, active site can’t bind b/c of a.a. change
  • Mutations

    1. 1. MutationsGenetic Code Chapter 17: page 306-309Mutations Chapter 17: page 322-325Transposons Chapter 19: page 360-361
    2. 2. The Genetic Code is Universal All living things use the same 4 bases All living things use the same code: codons code for the same amino acid no matter what the organism
    3. 3. The Genetic Code is Redundant 64 different codons on mRNA But only 20 different amino acids Conclusion?More than one codoncan code for thesame amino acid.
    4. 4. The Genetic Code is Redundant 64 different codons on mRNA But only 45 different tRNA molecules Conclusion?Some tRNAs recognizemore than one codon. Fig. 17.4
    5. 5. Wobble Hypothesis Base pairing rules are flexible in the wobble position Wobble position: third base of the mRNA codon and its corresponding tRNA anticodon Fig. 17.4
    6. 6. Inosine in the wobble position Inosine:  a modified form of adenine that is found in tRNA (anticodon)  can form H bonds with U, C, or A on the mRNA Inosine Adenosine From http://bio.winona.msus.edu/berg/ChemStructures/Inos-ade.gif
    7. 7. Inosine in the wobble positionExample: tRNA anticodon CGI Can bind to codons GCU, GCC and GCA All result in the addition of the amino acid alanine Fig. 17.4
    8. 8. Reading the Genetic Code
    9. 9. Characteristics of the Code Degenerate / Redundant  There are 64 codons, but only 20 amino acids  The same amino acid may be coded by more than one codon  E.g. GCU and GCC both specify alanine No ambiguity  Each codon only specifies one amino acid
    10. 10. Marshall Nirenberg (1961)  Deciphered first codon  Awarded Nobel Prize in 1968 for the interpretation of the genetic code  Discovery Channel 100 Greatest Discoveries – History of Genetics (Nirenberg @ 25:25-28:49) http://www.youtube.com/w atch?v=0qgMd0obEkchttp://upload.wikimedia.org/wikipedia/commons/thumb/1/10/Marshall_Nirenberg_performing_experiment.jpg/481px-Marshall_Nirenberg_performing_experiment.jpg http://profiles.nlm.nih.gov/ps/access/JJBBWR.jpg
    11. 11. Nirenberg’s Experiment Synthesized artificial mRNA with identical RNA nucleotides  E.g. UUUUUUUUUUUUUUU  Thus only 1 type of codon (e.g. UUU)  Resulted only in one type of amino acid in the polypeptide (e.g. phenylalanine) Repeated with other nucleotides Other techniques used to decode mixed triplets
    12. 12. Tutorial: Reading the GeneticCode http://learn.genetics.utah.edu/units/basics/transcribe/
    13. 13. Mutation a change in the genetic material of an organism genetic disorder or hereditary disease: harmful mutations in gametes that are passed onto the next generation
    14. 14. Origin/Cause of Mutation Spontaneous:  errors in the genetic machinery during DNA replication  due to enzymes Induced: arising from exposure to mutagenic agents Transposable elements:  errors during recombination (crossing over)  transposons
    15. 15. Mutagen a substance that can cause mutations Physical mutagen  Radiation, UV light, x-rays Chemical mutagen  Base analogues:  chemical similar to normal DNA bases but pair incorrectly during DNA replication  e.g. used in a drug for treating HIV  Distort DNA helix interfering with replication  e.g. ethidium bromide, used in gel electrophoresis for visualizing DNA  Changing pairing properties in bases
    16. 16. Effect of MutationsAffects 3 levels: RNA codons:  Point mutation  Frameshift mutation Amino acid sequence on polypeptide:  Missense  Nonsense  Silent Protein function  Negative  Positive  Neutral
    17. 17. Types of Mutations Point mutations Frameshift mutations Chromosomal mutations
    18. 18. Point Mutations: Substitution a small change in a DNA basepair where one nucleotide is replaced with another
    19. 19. Frameshift Mutation:Insertion & Deletion Reading frame: triplet grouping (codons) of a genetic message Frameshift mutation: number of nucleotides added/lost is not a multiple of 3 thus altering the reading frame  Insertion: addition of one or more nucleotide pairs in a gene  Deletion: loss of one of more nucleotide pairs in a gene No frameshift: number of nucleotides added/lost is a multiple of 3  Leads to extra or missing amino acid
    20. 20. FrameshiftMutations Frameshift deletion Frameshift insertion No frameshift Fig. 17.24
    21. 21. Effects of mutations on polypeptide Missense mutation:  altered codon codes for a different amino acid  May or may not have an effect on protein function Nonsense mutation:  changes an amino acid codon into a stop codon  Results in truncated protein. Most are digested by the cell.  often lethal at the embryonic stage Silent mutation:  altered codon codes for same amino acid  No effect on protein function
    22. 22. Missense MutationFig. 17.4 Fig. 17.24
    23. 23. Example: Sickle Cell Anemia Substitution missense: A  T changes amino acid glutamine to valine
    24. 24. Nonsense MutationFig. 17.4 Fig. 17.24
    25. 25. Silent MutationFig. 17.4 Fig. 17.24
    26. 26. Wild Type:Two men sat and had hot teaMutations Two men Sat and had hot tea Two men sat and had hot sea Two me. Two men sat and had hot tte a Two mes ata ndh adh ott ea Missense Frameshift Insertion Silent Nonsense Frameshift Deletion
    27. 27. Point/Frameshift MutationSummary Types Missense effect Nonsense effect SilentPoint Mutation Substitution Frameshift Insertion or DeletionNo Frameshift Insertion or Deletion
    28. 28. Point/Frameshift MutationSummary Types Missense effect Nonsense effect SilentPoint Mutation    Substitution Frameshift  Insertion or   Deletion extensiveNo Frameshift  Insertion or (extra or missing   Deletion amino acid)
    29. 29. Effect of mutation on proteinfunction / organism Negative mutations  Changes protein function to make it detrimental to the organism  From missense or nonsense mutations  Example: most molecular biological research is related to this idea Positive mutations  Changes protein function to benefit the organism  From missense mutations  Example: back mutations / reversions that restore original sequence  Example: antibiotic resistance Neutral mutations  Silent mutations: no change in amino acid  Sometimes missense: change in amino acid without changing protein function  Example: mutations in introns doesn’t affect expressed protein
    30. 30. HW Question The genetic code is redundant but not ambiguous. Explain what that means.
    31. 31. MaCS Enrichment The topic of transposons is for MaCS enrichment only
    32. 32. Transposons DNA segments that naturally move around the genome  Transposable elements  Mobile genetic elements
    33. 33. Transposons Barbara McClintock was awarded the Nobel Prize in 1983 for her discovery of transposons in maize (corn) Discovery Channel 100 Greatest Discoveries – History of Genetics (McClintock @ 11:18-16:10) http://www.youtube.com/watch? v=0qgMd0obEkc http://profiles.nlm.nih.gov/ps/access/LLBBQQ.jpg
    34. 34. Transposon in humans Almost half the human genome consists of transposons:  Retrotransposons accounting 42%  DNA transposons (most if not all are inactive) accounting for 2-3%  Reference: http://www.nature.com/nature/journal/v409/n6822/full/409860a0.html No known function. Junk DNA.
    35. 35. Types of Bacterial Transposons Insertion sequence Composite transposon
    36. 36. Insertion Sequence Simplest type of bacterial transposon Consists only of DNA needed for the act of transposition Transposon contains:  gene for transposase  Transposase: enzyme that catalyzes movement of transposon  Inverted repeats  at ends of transposons  where transposase binds Fig 18.16
    37. 37. Insertion Sequence Effect Can cause mutations when they land in DNA region that regulates gene expression or the coding region of a gene Mutation due to insertion sequence is rare (1 in 10 million generations) No known benefit
    38. 38. Composite Transposon Longer transposon and more complex Contain genes other than transposase Beneficial in bacterial reproduction  confer antibiotic resistance Fig 18.18
    39. 39. Mechanism of Transposition DNA transposon  Transposition by cut-and-paste mechanism  Transposition by replicative mechanism Retrotransposon  Transposition by an RNA intermediate  Uses reverse transcriptase
    40. 40. AnimationTransposons “Shifting Segments of the Genome” http://highered.mcgraw- hill.com/sites/dl/free/0072556781/192785/anim0039.swfSimple Transposition (cut-and-paste) http://highered.mcgraw- hill.com/sites/0072995246/student_view0/chapter23/simple_transposition.ht mlMechanism of Transposition: Replicative http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi? it=swf::535::535::/sites/dl/free/0072437316/120082/bio36.swf::Mechanism %20of%20Transposition
    41. 41. Mechanism of Cut-and-Paste Transposition Transposase bind to both inverted repeats and target site Cut out transposon Cut open the target site Join transposon to target site Reseal DNA http://www.chrisdellavedova.com/wp-content/uploads/2008/01/transposons1.jpg
    42. 42. Mechanism of ReplicativeTransposition  transposon replicated at original site  copy inserts into new site  original transposon still at original site
    43. 43. Retrotransposon Transposons that transpose through an RNA intermediate Abundant in plants (e.g. maize = corn)
    44. 44. Mechanism of RetrotransposonMovement http://www.bio.miami.edu/~cmallery/150/gene/c7.19.16b.transposon.jpg
    45. 45. Mechanism of RetrotransposonMovement1. Retrotransposon RNA produced during transcription2. Translation of RNA makes:  Reverse transcriptase: enzyme that converts RNA  DNA  Enzymes that catalyze insertion of retrotransposon into target site3. Retrotransposon DNA synthesized by reverse transcriptase action on RNA4. DNA inserted into target site

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