Instability: Mutation and DNA repair

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Instability Mutation and DNA repair

• Mutations
• DNA repair

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Instability Mutation and DNA repair

• Substitution rates vary throughout the genome.

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Instability Mutation and DNA repair

• Different mutation rates in primates and rodents
• Species Pair Sites Percent Divergence
  Substitution rate (x 109)
• Human/Chimp 921 1.9 1.3 (7 myr)
• Human/Old world monkey 998 11.0 2.2 (25 myr)
• Mouse/rat 3886 23.7 7.9 (15 myr)

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Instability Mutation and DNA repair

• Higher mutation rates in males
• Greater number of cell divisions

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Instability Mutation and DNA repair

• Sex-specific differences in mutation rates
• Gene Mutation Ratio of male/female mutations
• NF1 Point 4.5
• VHL Point 1.3
• RB Point 8.5
• ZFX/ZFY Mutations in last intron 6

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Instability Mutation and DNA repair

• Mechanism of mutation
• Simple sequence repeats and strand slippage

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Instability Mutation and DNA repair

• Mechanism of mutation
• Homologous equal crossover yields fusion genes.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Unequal crossover causes insertions and
  deletions.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Unequal crossover in a tandem repeat array can
  result in sequence homogenization.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Tandem gene duplication by unequal crossover or
  sister chromatid exchange facilitated by short
  interspersed elements.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Gene conversion
• Non reciprocal sequence exchange between allelic
  or nonallelic genes.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Splicing mutations
• Intron retention
• Exon skipping
• Activation of cryptic splice sites

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Instability Mutation and DNA repair

• Mechanism of mutation
• Short tandem repeats are deletion insertion
  hotspots.

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Instability Mutation and DNA repair

• Mechanism of mutation
• Spinocerebellar ataxia (SCA1) triplet repeat
  expansion.

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Instability Mutation and DNA repair

• Mobile elements and mutations
• Alu element
• Insertion events
• Recombination events

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Reverse transcription and insertion
1. Usually a single master copy 2. Pol III
transcription to an RNA intermediate 3. Target
primed reverse transcription (TPRT) enzymatic
machinery provided by LINEs
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What are SINEs?
1. Interspersed Elements 2. 70 - 300 Bases in
Length 3. Very High Copy Numbers (gt100,000
Copies/Genome)
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Instability Mutation and DNA repair

• DNA repair
• Photodimer
• DNA glycosylase /AP endonucleases
• E-coli mismatch repair
• Human mismatch repair

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Instability Mutation and DNA repair

• DNA repair
• Photodimer

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Instability Mutation and DNA repair

• DNA repair
• DNA glycosylase /AP endonucleases

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Instability Mutation and DNA repair

• DNA repair
• E-coli mismatch repair
• Human mismatch repair

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Instability Mutation and DNA repair

• DNA repair
• Human mismatch repair

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