Models for Microsatellite Mutation Tristan L. Stark University of - PowerPoint PPT Presentation

Models for Microsatellite Mutation Tristan L. Stark University of Tasmania tlstark@utas.edu.au November 7, 2013 Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 1 / 13

Microsatellites Repeats of a short motif, e.g. AT repeated 6 times: A T A T A T A T A T A T Think of microsatellites as repeat units: AT AT AT AT AT AT Highly polymorphic. Abundant in eukaryote genomes. Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 2 / 13

Slipped-strand mispairing Contraction During replication, a loop may form in the template strand leading to a decrease in the number of repeats in the new strand. Loop formed in Template Strand A T T A Template Strand A T A T A T A T A T A T T A T A T A T A T A T A New Strand Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 3 / 13

Slipped-strand mispairing Expansion Alternatively, a loop may form in the new strand, leading to an increase in repeat number relative to the template. Template Strand A T A T A T A T A T A T T A T A T A T A T A T A New Strand A T Loop formed in New Strand T A Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 4 / 13

Models for slipped-strand mispairing e.g. a symmetric random walk: λ i − 1 λ 1 λ i i − 1 i + 1 1 2 i . . . λ 2 λ i λ i +1 The main factors accounted for are: Length dependence of mutation rate. Bias towards contraction or expansion. Size of the mutation events. Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 5 / 13

Adelie vs Emperor AC distribution 0.5 Adelie Emperor 0.4 Model Frequency 0.3 0.2 0.1 0 6 8 10 12 14 16 18 20 Repeat # Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 6 / 13

Point Mutation Microsatellites also susceptible to point mutations. AT AT AT AC AT AT How to deal with this? AT AT AT AT AT Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 7 / 13

Point Mutation These models lose useful information, and may invalidate IID assumption. Loop forming around impure repeat. A C T A Template Strand A T A T A T A T A T A T New Strand T A T A T A T A T A T A Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 8 / 13

Our Model We move up a dimension in the state space. ( i , j ) # repeats # interruptions AT AT AT AC AT AT = (6 , 1) Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 9 / 13

Key Assumptions Effect of impurity is independent of location. = AT AT AT AC AT AT AT AT AT AC Each base pair is either ‘correct’ or ‘incorrect’. = = � = A T A C A G A A Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 10 / 13

Extra Assumptions A repeat unit is either pure or impure - binary. = = � = AT AX YT YX A sequence which is more than half impure is no longer a microsatellite. Slippage events of length 1 only. Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 11 / 13

Our Model (4 , 4) r m (4) 2 (2 , 2) (3 , 3) (4 , 2) r s (4 , 2) 4 r m (2) 2 r m (3) 3 r m (4) r m (4 , 1) 2 3 4 6 r s (2 , 1) r s (2 , 1) 2 2 (1 , 1) (2 , 1) r s (3 , 1) (3 , 1) 3 r s (4 , 1) (4 , 1) 3 8 r s (3 , 1) r s (4 , 1) 6 8 r s (2 , 1) r m (2) r m (3) r m (4) r m (1) r m (2) r m (3) r m (4) 4 6 9 12 r s (1 , 0) r s (2 , 0) r s (3 , 0) 2 2 2 (1 , 0) (2 , 0) (3 , 0) (4 , 0) r s (2 , 0) r s (3 , 0) r s (4 , 0) 2 2 2 Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 12 / 13

Acknowledgements Supervisors Dr Ma� lgorzata O’Reilly Dr Barbara Holland Dr Bennet McComish Tristan L. Stark (UTAS) Microsatellite Models November 7, 2013 13 / 13