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 NF1 Point 4.5 VHL Point 1.3 RB Point 8.5 ZFX/ZFY Mutations in last intron 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 (SCA1) 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 Photodimer DNA glycosylase /AP endonucleases E-coli mismatch repair Human mismatch repair

Instability: Mutation and DNA repair Photodimer

Instability: Mutation and DNA repair DNA glycosylase /AP endonucleases

Instability: Mutation and DNA repair E-coli mismatch repair Human mismatch repair

Instability: Mutation and DNA repair Human mismatch repair