mutations, mutagenesis, and c a r c in o g e n e s is · silent •mis-sense •nonsense...
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MUTATIONS, MUTAGENESIS, AND
CARCINOGENESIS
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How do different alleles arise? (“allele”: form of agene; specific base sequence at a site on DNA)
Mutations: heritable changes in genes
•Mutations occur in DNA•But their effects involve proteins
Structural genes
•Silent •Mis-sense •Nonsense •Frameshift •Intron/exon boundaries(splicing)
Control genes
•Promoter/enhancer sequences•Transcription factors
Point mutations
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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.
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A base change that leads to a new codon for the same aminoacid is a silent mutation.
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A base change that gives a codon for a different aminoacid is a mis-sense mutation.
Original sequence:
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A base change that produces premature termination (fromnew UAA, UAG, or UGA codons) is a nonsense mutation.
Original sequence:
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The addition or deletion of a base (or 2 bases) produces a frame-shift mutation.
Original sequence:
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There are many ways to change a base
Spontaneous base changes (tautomerization)Errors at replicationChemical reactions
Reactive oxygen (1O2, O3, .OH, HNO2)
Oxidation through radiationBulky adducts (benz-pyrene)Photochemical reactions (T<>T dimers)
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Oxidation of guanine is one of the most common mutations
C
G
C
G
C
G
C
G G
Go
A
o
A
T
o
A
T
A
G
C
dGoTPROS
o
Oxo-G pairswith either C or A
DNA replication
DNA replication
DNA replication
DNA replication
DNA replication
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Repair processeslimit mutations from mismatchedbases
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The UV radiation in sunlight is a potent mutagen
most damage is removed and repaired,but some repair is inaccurate.
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deletion
duplication and deletion
inversion
translocation
Chromosomal mutations are extensive changes in chromosome structure
•breakage•rejoining
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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
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Carcinogenesis: sunlight and cancer
! Cancers associated with inactivation of genes! First evidence that DNA damage induces cancer
came from study of UV radiation and skincancer
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p53 gene
other genes TT
CC
CC
T=T
p53 gene
other genes
p53 gene
other genesTT
TT
p53 gene
other genesTT
T=T
p53 gene
other genesC=C
TT
Sunlight-induced cancer results from theinactivation of more than one gene
UV
UV
error in repair
UV
apoptosis
cell division delay(allowing for repair)
no apoptosis, nocell division delay, more mutagenesis
rapid cell division,especially if adjacentcells die from sunburn
p53
p53
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Research on DNA repair may illuminate important ways of controlling cancers See Science magazine, 11 September 2009, page 1319; online at http://www.sciencemag.org/cgi/reprint/325/5946/1319.pdf
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Is the genetic code random? ! Crick: a “frozen accident”
! Evidence: code is universal, no selective value
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If you wanted to design a genetic code to minimize the effects of amutation, 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).
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Is the genetic code random? ! Not frozen: some variation ! The grouping of codes for hydrophobic and
hydrophilic amino acids minimizes change
Hydrophobic Hydrophilic
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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