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Instability: Mutation and DNA repair

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  1. Instability: Mutation and DNA repair • Mutations • DNA repair

  2. Instability: Mutation and DNA repair • Substitution rates vary throughout the genome.

  3. 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)

  4. Instability: Mutation and DNA repair • Higher mutation rates in males • Greater number of cell divisions

  5. 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

  6. Instability: Mutation and DNA repair • Mechanism of mutation • Simple sequence repeats and strand slippage

  7. Instability: Mutation and DNA repair • Mechanism of mutation • Homologous equal crossover yields fusion genes.

  8. Instability: Mutation and DNA repair • Mechanism of mutation • Unequal crossover causes insertions and deletions.

  9. Instability: Mutation and DNA repair • Mechanism of mutation • Unequal crossover in a tandem repeat array can result in sequence homogenization.

  10. Instability: Mutation and DNA repair • Mechanism of mutation • Tandem gene duplication by unequal crossover or sister chromatid exchange facilitated by short interspersed elements.

  11. Instability: Mutation and DNA repair • Mechanism of mutation • Gene conversion Non reciprocal sequence exchange between allelic or nonallelic genes.

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  13. Instability: Mutation and DNA repair • Mechanism of mutation • Splicing mutations • Intron retention • Exon skipping • Activation of cryptic splice sites

  14. Instability: Mutation and DNA repair • Mechanism of mutation • Short tandem repeats are deletion insertion hotspots.

  15. Instability: Mutation and DNA repair • Mechanism of mutation • Spinocerebellar ataxia (SCA1) triplet repeat expansion.

  16. Instability: Mutation and DNA repair • Mobile elements and mutations • Alu element • Insertion events • Recombination events

  17. Pol III transcription 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

  18. 1. Interspersed Elements • 2. 70 - 300 Bases in Length • 3. Very High Copy Numbers • (>100,000 Copies/Genome) What are SINEs?

  19. Instability: Mutation and DNA repair • DNA repair • Photodimer • DNA glycosylase /AP endonucleases • E-coli mismatch repair • Human mismatch repair

  20. Instability: Mutation and DNA repair • DNA repair • Photodimer

  21. Instability: Mutation and DNA repair • DNA repair • DNA glycosylase /AP endonucleases

  22. Instability: Mutation and DNA repair • DNA repair • E-coli mismatch repair • Human mismatch repair

  23. Instability: Mutation and DNA repair • DNA repair • Human mismatch repair