1. Instability: Mutation and DNA repair Mutations DNA repair

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

4. Instability: Mutation and DNA repair Different mutation rates in primates and rodents Species PairSitesPercent Divergence Substitution rate (x 10 9 ) Human/Chimp9211.91.3 (7 myr) Human/Old world monkey99811.02.2 (25 myr) Mouse/rat388623.77.9 (15 myr)

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

7. Instability: Mutation and DNA repair Sex-specific differences in mutation rates Gene Mutation Ratio of male/female mutations NF1Point4.5 VHLPoint1.3 RBPoint8.5 ZFX/ZFYMutations in last intron6

8. Instability: Mutation and DNA repair Mechanism of mutation –Simple sequence repeats and strand slippage

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

14. Instability: Mutation and DNA repair Mechanism of mutation –Unequal crossover causes insertions and deletions.

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

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

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

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

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

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

31. Instability: Mutation and DNA repair Mobile elements and mutations –Alu element –Insertion events –Recombination events

32. 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

34. What are SINEs? 1.Interspersed Elements 2.70 - 300 Bases in Length 3.Very High Copy Numbers (>100,000 Copies/Genome)

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

43. Instability: Mutation and DNA repair DNA repair –Photodimer

45. Instability: Mutation and DNA repair DNA repair –DNA glycosylase /AP endonucleases

47. Instability: Mutation and DNA repair DNA repair –E-coli mismatch repair –Human mismatch repair

50. Instability: Mutation and DNA repair DNA repair –Human mismatch repair