MUTATIONS, MUTAGENESIS, AND

CARCINOGENESIS

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

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.

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

A base change that gives a codon for a different aminoacid is a mis-sense mutation.

Original sequence:

A base change that produces premature termination (fromnew UAA, UAG, or UGA codons) is a nonsense mutation.

Original sequence:

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

Original sequence:

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)

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

Repair processeslimit mutations from mismatchedbases

The UV radiation in sunlight is a potent mutagen

most damage is removed and repaired,but some repair is inaccurate.

deletion

duplication and deletion

inversion

translocation

Chromosomal mutations are extensive changes in chromosome structure

•breakage•rejoining

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

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

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

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

Is the genetic code random? ! Crick: a “frozen accident”

! Evidence: code is universal, no selective value

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).

Is the genetic code random? ! Not frozen: some variation ! The grouping of codes for hydrophobic and

hydrophilic amino acids minimizes change

Hydrophobic Hydrophilic

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