chapter 18 – gene mutations and dna repair. mutation inheritable change in genetic material...
TRANSCRIPT
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
• 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
• 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; single-strand binding proteins stabilize
• Large section is removed
• DNA polymerase fills in; DNA ligase seals nicks