Instability Mutation and DNA repair Mutations DNA repair
Instability: Mutation and DNA repair • Mutations • DNA repair
Instability: Mutation and DNA repair • Substitution rates vary throughout the genome.
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)
Instability: Mutation and DNA repair • Higher mutation rates in males – Greater number of cell divisions
Instability: Mutation and DNA repair • Sex-specific differences in mutation rates Gene Mutation Ratio of male/female mutations NF 1 VHL RB ZFX/ZFY Point Mutations in last intron 4. 5 1. 3 8. 5 6
Instability: Mutation and DNA repair • Mechanism of mutation – Simple sequence repeats and strand slippage
Instability: Mutation and DNA repair • Mechanism of mutation – Homologous equal crossover yields fusion genes.
Instability: Mutation and DNA repair • Mechanism of mutation – Unequal crossover causes insertions and deletions.
Instability: Mutation and DNA repair • Mechanism of mutation – Unequal crossover in a tandem repeat array can result in sequence homogenization.
Instability: Mutation and DNA repair • Mechanism of mutation – Tandem gene duplication by unequal crossover or sister chromatid exchange facilitated by short interspersed elements.
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
Instability: Mutation and DNA repair • Mechanism of mutation – Short tandem repeats are deletion insertion hotspots.
Instability: Mutation and DNA repair • Mechanism of mutation – Spinocerebellar ataxia (SCA 1) triplet repeat expansion.
Instability: Mutation and DNA repair • Mobile elements and mutations – Alu element – Insertion events – Recombination events
Reverse transcription and insertion Pol III transcription 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
What are SINEs? 1. Interspersed Elements 2. 70 - 300 Bases in Length 3. Very High Copy Numbers (>100, 000 Copies/Genome)
Instability: Mutation and DNA repair • DNA repair – Photodimer – DNA glycosylase /AP endonucleases – E-coli mismatch repair – Human mismatch repair
Instability: Mutation and DNA repair • DNA repair – Photodimer
Instability: Mutation and DNA repair • DNA repair – DNA glycosylase /AP endonucleases
Instability: Mutation and DNA repair • DNA repair – E-coli mismatch repair – Human mismatch repair
Instability: Mutation and DNA repair • DNA repair – Human mismatch repair
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