Transcript Chapter 18 – Gene Mutations and DNA Repair

Chapter 18 – Gene Mutations
and DNA Repair
Mutation
• Inheritable change in genetic material
– Cells from cell division; offspring from reproduction
• Somatic mutations
– Mitosis yields genetically identical cells
• can lead to mosaicism
– Tumor – uncontrolled growth
• Germ-line mutations
– Arise in cells destined to become gametes
– Passed to offspring; present in every cell of organism
• Gene mutations
– Affect a single gene
• Chromosomal mutations
– Large-scale changes
– May be observable with a microscope
Types of mutations
• Base substitution/point mutation
– One base is replaced by another
– Transition
• One purine replaced by another purine; one
pyrimidine replace by another pyrimidine
– Transversion
• Purine replaced by a pyrimidine, or vice versa
Types of mutation
• Insertion or deletion
– One or more nucleotides
– Frameshift mutation
• In mRNA genes, affect all amino acids downstream, unless in
groups of three in normal codon place
• Expanding trinucleotide repeats
– Certain genes contain tandem repeats
– Number of repeats can increase in offspring due to
strand slippage or uneven crossing over
Phenotypic effects
• Missense mutation
– Causes incorrect amino acid to be placed in
polypeptide
– Neutral mutation – protein function is not affected due
to amino acids having similar properties
• Nonsense mutation
– Introduces a premature STOP codon
– Results in a truncated polypeptide
• Silent mutation
– Due to codon redundancy, mutation still codes for the
same amino acid
Phenotypic effects cont
• Loss of function
– Functional polypeptide is not made
– Recessive
• Normal gene still makes correct polypeptide
• Gain of function
– Abnormal polypeptide is produced
– dominant
Causes of mutations
• Spontaneous
– Natural changes/errors
– Replication errors or chemical changes
• Induced
– Caused by environmental agents
• Chemical, radiation
Spontaneous replication errors
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Tautomers
Wobble
Strand slippage
Unequal crossing over
Tautomers
• Various forms of
nitrogenous bases
– Position change of a proton
(hydrogen ion)
• Can exhibit
unconventional base
pairing
– Rare form of C can bond
with A; rare form of G can
bond with T
• Originally thought to be
major source of mutation –
no supporting evidence
Wobble
• Flexibility in DNA
helix
• Incorporated
error
– TA base pair
becomes CA
• One new
molecule will
have correct TA,
other will have
CG
– Since all bases
are correctly
paired, no repair
mechanism can
fix
Strand slippage
• Causes small
insertions or
deletions
• One nucleotide
loops out
– On new strand –
results in an
insertion
– On old strand –
results in a deletion
Strand slippage in trinucleotide
repeats
• Slippage of new
strand can result in
expanded number of
repeats in offspring
cells
• Cause of anticipation
Unequal crossing over
• Incorrect alignment of
homologous
chromosomes
• Crossing over results
in an insertion in one
molecule and a
deletion in the other
molecule
• Can also cause
expanded
trinucleotide repeats
Spontaneous chemical changes
• Depurination
– Nucleotide loses its purine base; apurinic
– Can’t act as a template
– A is usually the base placed in the new strand
Deamination
• Removal of an amino
group
• Deaminated cytosine
becomes uracil
– Since U is not present in
DNA, usually correctly by
repair mechanisms
• Deaminated
methylcytosine becomes
thymine
– Causes CG to AT – not
detected by repair
mechanisms
Chemically Induced Mutagens
• Mutagen – environmental agent with ability
to alter DNA sequence
• Base analogs
• Alkylating agents
• Deamination
• Oxidative reactions
• Intercalating agents
Chemically induced mutagens
• Base analogs
– Have structure similar
to normal nucleotides
– When ionized, exhibit
unconventional base
pairing
– Transition or
transversion mutation
shown?
Chemically induced mutations
• Alkylating agents
– Donates alkyl groups to bases
– Incorrectly base pair
• Deamination
– Can occur spontaneously or be induced
– Adenine becomes hypoxanthine (pairs with C)
– Guanine becomes xanthine (pairs with T)
Chemically induced mutagens
• Oxidative reactions
– Reactive forms of oxygen
– Causes transversions
• G pairs with A
• Intercalating agents
– Insert themselves into DNA
– distorts molecule
– Often causes frameshift
mutations
Radiation
• Ionizing radiation
– High energy breaks
phosphodiester bonds
– Results in double-stranded
breaks
• UV light
– Pyrimidine dimers – usually
thymine dimers
– Causes TpT to covalently
bond
• Replication of DNA is
blocked and cell dies, or
transcription is blocked
DNA repair
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Mismatch repair
Direct repair
Base excision repair
Nucleotide excision repair
Mismatch repair
• Corrects replication
errors/improper base
pairing not fixed by
DNA polymerase III
• Recognizes structural
distortions
• New strand section is
cut out and replaced
– Old strand is
methylated – strand
distinction
Direct Repair
• Converts altered nucleotide
back to original form
• Methylguanine binds with A
– Enzymes remove methyl
group to return to normal
guanine
• Photolyase
– Found in E. coli and some
eukaryotes (not humans)
– Break covalent bonds of
dimers
Base Excision Repair
• Repairs abnormal/ modified
bases
• Nitrogenous base is first
removed
– Apurinic or apyrimidic site
• Followed by removal of rest
of nucleotide
• DNA polymerase replaces
nucleotide; DNA ligase seals
nick by forming
phosphodiester bond
Nucleotide excision repair (NER)
• Removes lesions that distort DNA
helix
• Several enzymes/ genes involved
– Recognize distortion
• DNA strand is separated; singlestrand binding proteins stabilize
• Large section is removed
• DNA polymerase fills in; DNA ligase
seals nicks