MUTATIONS, MUTAGENESIS, AND CARCINOGENESIS
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1 MUTATIONS, MUTAGENESIS, AND CARCINOGENESIS
2 How do different alleles arise? ( allele : form of a gene; specific base sequence at a site on DNA) Mutations: heritable changes in genes Mutations occur in DNA But their effects involve proteins Point mutations Structural genes Silent Mis-sense Nonsense Frameshift Intron/exon boundaries (splicing) Control genes Promoter/enhancer sequences Transcription factors
3 Which would have the most severe effect on a gene product s (protein s) structure? (a) Changing a base in the gene, e.g. a C to a G. (b) Changing an AUG codon to a UAG. (c) Adding a base after the first codon of the gene. (d) Adding two bases after the first codon of the gene. (e) Adding three bases after the first codon of the gene.
4 A base change that leads to a new codon for the same amino acid is a silent mutation.
5 A base change that gives a codon for a different amino acid is a mis-sense mutation. Original sequence:
6 A base change that produces premature termination (from new UAA, UAG, or UGA codons) is a nonsense mutation. Original sequence:
7 The addition or deletion of a base (or 2 bases) produces a frame-shift mutation. Original sequence:
8 There are many ways to change a base Spontaneous base changes (tautomerization) Errors at replication Chemical reactions Reactive oxygen ( 1 O 2, O 3,. OH, HNO 2 ) Oxidation through radiation Bulky adducts (benz-pyrene) Photochemical reactions (T<>T dimers)
9 Oxidation of guanine is one of the most common mutations Oxo-G pairs with either C or A C G C G A o G o ROS DNA replication A T A G C G dg o TP DNA replication o DNA replication o DNA replication DNA replication A T C G
10 Repair processes limit mutations from mismatched bases
11 The UV radiation in sunlight is a potent mutagen most damage is removed and repaired, but some repair is inaccurate.
12 Chromosomal mutations are extensive changes in chromosome structure breakage rejoining deletion duplication and deletion inversion translocation
13 Transposons ( jumping genes ) can cause mutations by insertion Transposons and similar DNA insertion elements are useful tools for genetic engineering Transposons and viruses can also move genes from one species to another-- certain rotifers have genes from bacteria, fungi, and plants
14 Carcinogenesis: sunlight and cancer! Cancers associated with inactivation of genes! First evidence that DNA damage induces cancer came from study of UV radiation and skin cancer
15 Sunlight-induced cancer results from the inactivation of more than one gene other genes p53 gene other genes p53 gene TT other genes CC p53 gene UV TT C=C error in repair other genes p53 gene UV T=T TT TT TT UV other genes p53 gene T=T CC apoptosis p53 p53 cell division delay (allowing for repair) no apoptosis, no cell division delay, more mutagenesis rapid cell division, especially if adjacent cells die from sunburn
16 Research on DNA repair may illuminate important ways of controlling cancers See Science magazine, 11 September 2009, page 1319; online at
17 Is the genetic code random?! Crick: a frozen accident! Evidence: code is universal, no selective value
18 If you wanted to design a genetic code to minimize the effects of a mutation, what would you like to avoid? (a) Changing a + side chain to a - side chain (b) Changing a hydrophilic side chain to a hydrophobic side chain. (c) Changing a proline (bend) to a glycine (-H) (d) Changing a glycine (-H) to a proline (bend) (e) Changing a cysteine (-SH) to a glycine (-H).
19 Is the genetic code random?! Not frozen: some variation! The grouping of codes for hydrophobic and hydrophilic amino acids minimizes change Hydrophobic Hydrophilic
20 Summary! Mutations involve base changes and changes in the structure of chromosomes! Mutations occur spontaneously and through exposure to chemicals and radiation, including UV in sunlight! Some mutations are repaired; some mutant cells are removed; but! Mutations in germ cells and embryos can cause developmental defects; mutations in adult cells can cause cancer! The genetic code has apparently evolved to minimize the effects of mutation
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