1. Lecture 18: Mutation October 30, 2015

2. Last Time uExam to be returned Monday. Answer key is posted uEffects of population structure, admixture, selection, and mutation on LD uAdmixture calculation uSelective sweeps

3. Today uMutation introduction uMutation-reversion equilibrium uMutation and selection

4. What Controls Genetic Diversity Within Populations? 4 major evolutionary forces Diversity Mutation + Drift - Selection +/- Migration +

5. Mutation uPrimary driver of genetic diversity  Main source of new variants within a reproductively isolated species uMutation often ignored because rates assumed to be extremely low relative to magnitude of other effects uAccumulation of mutations in population primarily a function of drift and selection PLUS rate of back- mutation uMutation rates are tough to estimate!

6. Spontaneous mutation rates uSchlager and Dickie (1967) tracked spontaneous mutation at 5 loci controlling coat color in 17 million house mice uForward > Backward mutation http://www.gsc.riken.go.jp http://jaxmice.jax.org

7. Mutation Rates can Vary Tremendously Among Loci uLength mutations occur much more frequently than point mutations in repetitive regions uMicrosatellite mutation rates as high as 10 -2 Source: SilkSatDB

8. Reverse Mutations uMost mutations are “reversible” such that original allele can be reconstituted uProbability of reversion is generally lower than probability of mutation to a new state Possible States for Second Mutation at a Locus Thr Tyr Leu Leu ACC TAT TTG CTG Reversion ACC TGT TTG CTG Thr Phe Leu Leu C G ACC TCT TTG CTG Thr Ser Leu Leu A C ACC TTT TTG CTG Thr Cys Leu Leu C T

9. Allele Frequency Change Through Time uWith no back-mutation: uHow long would it take to reduce A 1 allele frequency by 50% if μ=10 -5 ?

10. Two-Allele System with Forward and Reverse Mutation where μ is forward mutation rate, and ν is reverse mutation rate A 1 A 2 µ ν uExpected change in mutant allele:

11. Allele Frequency Change Driven By Mutation uEquilibrium between forward and reverse mutations:

12. Allele Frequency Change Through Time with Reverse mutation Forward Mutation (µ) Reverse Mutation (ν) Allele Frequency (p) Mutant Alleles (q)

13. Equilibrium Occurs between Forward and Reverse Mutation uForward mutation 10 -5 uLower rate of reverse mutation means higher q eq Is this equilibrium stable or unstable? μ=10 -5

14. Mutation-Reversion Equilibrium where µ=forward mutation rate (0.00001) and ν is reverse mutation rate (0.000005)

15. What if the population is not infinite?

16. Fate of Alleles in Mutation-Drift Balance uTime to fixation of a new mutation is much longer than time to loss u(p) is probability of fixation u(q) is probability of loss uAn equilibrium occurs between creation of new mutants, and loss by drift p=frequency of new mutant allele in small population

17. Infinite Alleles Model (Crow and Kimura Model) uEach mutation creates a completely new allele uAlleles are lost by drift and gained by mutation: a balance occurs uIs this realistic? uAverage human protein contains about 300 amino acids (900 nucleotides) uNumber of possible mutant forms of a gene: If all mutations are equally probable, what is the chance of getting same mutation twice?

18. Fate of Alleles in Mutation-Drift Balance uTime to fixation of a new mutation is much longer than time to loss u(p) is probability of fixation u(q) is probability of loss uAn equilibrium occurs between creation of new mutants, and loss by drift p=frequency of new mutant allele in small population

19. M utation & M ating Simulation 1.Select two gametes from the gamete pool (brown is wild=type, green=mutant 2.Find a mate using the Excel sheet (e.g., see below) 3.Pass a random allele down to each of 2 offspring. One of these offspring will become you for the next generation. 4.Mutate an offspring allele if indicated by the Excel sheet by choosing a new random allele from the pool (cup of candy) (rate = 1x10 -2 ) 5.Repeat for the next generation. x ApoorvaMargo

20. Results of M utation & M ating Simulation The forward mutation rate was quite high (1x10 -2 ), and the reverse mutation rate was at least an order of magnitude lower (based on the freqency of brown M&M’s in the mutant pool), so the frequency of mutant alleles increased fairly dramatically even with substantial potential for genetic drift.