MUTATIONS, MUTAGENESIS, AND CARCINOGENESIS. (Start your clickers)

Transcription

1 MUTATIONS, MUTAGENESIS, AND CARCINOGENESIS (Start your clickers)

2 How do mutations arise? And how do they affect a cell and its organism? Mutations: heritable changes in genes Mutations occur in DNA But their effects generally involve proteins (structure, activity, amount)

3 An example of a mutation--sickle cell anemia-- the DNA change and its phenotype Gene for Hb A: (atg) gtg cat ctg act cct gag gag Gene for Hb S: (atg) gtg cac ctg act cct gtg gag Hb A a.a. sequence: val-his-leu-thr-pro-glu-glu--- Hb S a.a. sequence: val-his-leu-thr-pro-val-glu--- Hb A quaternary structure: individual tetramers Hb S quaternary structure: fibers (under low O 2 )

4 Potential results of base-change mutations on gene products (proteins) Silent Mis-sense Nonsense Frameshift

5 A base change that leads to a new codon for the same amino acid is a silent mutation.

6 A base change that gives a codon for a different amino acid is a mis-sense mutation. Original sequence:

7 A base change that produces premature termination (from new UAA, UAG, or UGA codons) is a nonsense mutation. Original sequence:

8 The addition or deletion of a base (or 2 bases) produces a frame-shift mutation. Original sequence:

9 Does a silent mutation have any effect? CCU pro first mutation silent CCA pro CAU his CAA gln second mutation maybe not

10 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 (UV, T<>T dimers) (binds to G at DNA synthesis) (binds to A at DNA synthesis) (binds to G at DNA synthesis) (binds to A at DNA synthesis)

11 Oxidation of guanine is one of the most common mutations Oxo-G pairs with either C or A C G C G o ROS DNA replication A T A G dg o TP DNA replication o DNA replication A G o DNA replication A T C G o DNA replication C G Notice that a mutation is fixed only after replication

12 Repair processes correct mutations from mismatched bases

13 The UV radiation in sunlight is a potent mutagen most damage is removed and repaired, but some repair is inaccurate.

14 DNA breaks can be repaired--dna can be rejoined--but errors can change the amount and pattern of gene expression Many genetic diseases are caused by extensive changes in chromosome structure (chromosomal mutations )

15 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

16 Carcinogenesis: sunlight and cancer! Cancers are associated with inactivation (or activation) of genes! First evidence that DNA damage induces cancer came from study of UV radiation and skin cancer

17 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

18 Research on DNA repair may illuminate important ways of controlling cancers See Science magazine, 11 September 2009, page 1319; online at

19 Questions regarding changes in DNA sequence Somatic vs. germline mutations Is a mutation inherited? Loss of function vs. gain of function Is a new allele dominant/recessive/co-dominant? How do new mutations spread (or decline) in a population? ---selection positive--lack of pigment in northern Europeans negative--xeroderma pigmentosum (loss of DNA repair) balanced--sickle-cell anemia HbS Malaria

20 Is the genetic code random?! Crick: a frozen accident! Evidence: code is universal, no selective value

21 Is the genetic code random?! Not frozen: some variation! The grouping of codes for hydrophobic and hydrophilic amino acids minimizes change Hydrophobic Hydrophilic

22 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