Download MUTATIONS, MUTAGENESIS, AND CARCINOGENESIS

MUTATIONS, MUTAGENESIS, AND
CARCINOGENESIS
(Start your clickers)
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 involve proteins
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 O2)
A base change that leads to a new codon for the same amino
acid is a silent mutation.
A base change that gives a codon for a different amino
acid is a mis-sense mutation.
Original sequence:
A base change that produces premature termination (from
new 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:
Does a “silent” mutation have any effect?
CCU
pro
CAU
his
first mutation silent
CCA
pro
CAA
gln
second mutation maybe not
There are many ways to change a base
Spontaneous base changes (tautomerization)
Errors at replication
Chemical reactions
Reactive oxygen (1O2, O3, .OH, HNO2)
Oxidation through radiation
Bulky adducts (benz-pyrene)
Photochemical reactions (UV, T<>T dimers)
Oxidation of guanine is one of the most common mutations
C
A
G
T
dGoTP
ROS
DNA replication
Oxo-G pairs
with either
C or A
C
A
Go
Go
DNA replication
DNA replication
A
C
Go
Go
DNA replication
DNA replication
A
C
T
G
Notice that a
mutation is
“fixed”
only after
replication
Repair processes
correct mutations
from mismatched
bases
The UV radiation in sunlight is a potent mutagen
most damage is removed and repaired,
but some repair is inaccurate.
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”)
deletion
duplication and deletion
inversion
translocation
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 (or
activation) of genes
! First evidence that DNA damage induces cancer
came from study of UV radiation and skin
cancer
Sunlight-induced cancer results from the
inactivation of more than one gene
TT
other genes
apoptosis
UV
CC
p53 gene
other genes
UV
other genes
p53 gene
p53 gene
TT
C=C
error in repair
p53 gene
other genes
p53 gene
TT
p53
CC
p53
other genes
T=T
T=T
UV
TT
TT
cell division delay
(allowing for repair)
no apoptosis, no
cell division delay,
more mutagenesis
rapid cell division,
especially if adjacent
cells die from sunburn
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
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
Is the genetic code random?
! Crick: a “frozen accident”
! Evidence: code is universal, no selective value
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