Chapter 18 - DNA Mutation and Repair

VIrginia Tech BIOL 2004 Genetics Kamran

What is a mutation?

heritable change in DNA sequence

What is the source of genetic variation (needed for evolution)?

mutations

In which cells can mutations occur?

• somatic cells

• germ line cells (gametes)

Are mutations in somatic cells passed down to offspring?

NO

Are mutations in gametes passed down to offspring?

YES

4 ways in which mutations can be classified:

• how they originate

• where they occur

• how the DNA is changed

• phenotypic effect

2 ways that mutations originate:

• spontaneous

• induced

spontaneous mutation

• naturally made

• caused by replication errors or chemical changes

induced mutation

• artificially made

• caused by mutagens (chemicals or radiation)

2 types of cells where mutations occur:

• somatic cells

• germ line cells (gametes)

3 ways in which DNA is changed:

• base substitutions

• insertion/deletions

• expanding nucleotide repeats

base substitution mutation

• one nucleotide is replaced

• transition

• transversion

base substitution mutation: transition

purine —> purine, pyrimidine —> pyrimidine

base substitution mutation: transversion

purine —> pyrimidine, pyrimidine —> purine

insertion/deletion mutation

• nucleotides added/removed

• can cause:

  • frameshift mutation

  • in frame mutation

insertion/deletion mutation: frameshift mutation

• addition/removal of nucleotides changes the reading frame

• affects production of amino acids

insertion/deletion mutation: in frame mutation

• adds/removes multiples of 3 nucleotides (codons)

expanding nucleotide repeats mutation

• repeats like CAG, CGG increase in number

• cause diseases: Huntington’s disease, Fragile X syndrome

5 phenotypic effects of mutations

• missense mutations

• nonsense mutations

• silent mutations

• neutral mutations

• functional effects of mutations

missense mutations

produce a different amino acid

nonsense mutations

produce a stop codon (shortens the protein)

silent mutations

mutation exists, no amino acid change

neutral mutations

mutation exists, amino acid changes, but there’s no functional effect

functional effects of mutations

• loss of function (proteins don’t work)

• gain of function (new/overactive function)

• lethal mutation (organism dies)

• conditional mutation (only expressed under certain conditions)

forward mutation

wild type becomes a mutant

reverse mutations

mutants turn back to wild type

suppressor mutation

a second mutation fixes the effects of the original mutation

suppressor mutation: intragenic

mutation on the same gene

suppressor mutation: intergenic

mutation on a different gene

What do mutation rates depend on?

• how often DNA changes occur

• how well DNA repair works

• whether a mutation is detected

What are the 3 causes of mutations (mutagenesis)?

• spontaneous mutations

• chemically-induced mutations

• radiation induced mutations

spontaneous mutations

• replication errors

• tautomer shifts

• wobble pairing

• strand slippage

• unequal crossing over

• chemical changes

spontaneous mutations: replication errors

DNA polymerase makes mistakes

spontaneous mutations: tautomer shifts

nonstandard base pairing AC GT

spontaneous mutations: wobble pairing

incorrect base pairing during replication

spontaneous mutations: strand slippage

DNA loop forms, causing insertions/deletions

spontaneous mutations: unequal crossing over

misaligned chromosomes causes one chromosome to gain DNA and

spontaneous mutations: chemical changes

• depurination (loss of purine bases = wrong base is inserted)

• deamination (cytosine replaced with uracil = base substitution)

chemically induced mutations

• base analogs

• alkylating agents

• intercalating agents

chemically induced mutations: base analogs

compounds that mimic normal bases —> leads to mispairing

chemically induced mutations: alkylating agents

modify bases —> incorrect pairing

chemically induced mutations: intercalating agents

molecules insert between bases —> frameshift mutations

radiation induced mutations

• UV radiation —> forms pyrimidine dimers and blocks DNA replication

• ionizing radiation —> causes DNA breaks

What is the Ames test?

a test to see if a chemical is a mutagen

What are transposable elements?

DNA sequences that move within the genome

Who discovered transposable elements?

McClinktock

How do transposable elements cause mutations?

they insert into genes and cause rearrangements

2 types of transposable elements

• DNA transposons

• Retrotransposons (RNA intermediate)

What are 2 key features of transposable elements?

• terminal inverted repeats

• flanking direct repeats

What are the 4 mechanisms for DNA repair?

• mismatch repair

• direct repair

• base excision repair

• nucleotide excision repair

DNA repair: mismatch repair

• fixes replication errors

• removes incorrect section of new strand

DNA repair: direct repair

• fixes damage directly

• e.g. removing a methyl group

DNA repair: base excision repair

• removes single damaged base

• replaces with correct base

DNA repair: nucleotide excision repair

removes large damaged region, replaces with correct one

What’s an example of failed DNA repair?

Xeroderma Pigmentosum

What is Xeroderma Pigmentosum?

• defect in nucleotide excision repair

• extreme UV sensitivity and high skin cancer risk