1. Lecture 19: Mutation November 2, 2012

2. Last Time  Human origins  Human population structure  Signatures of selection in human populations  Neanderthals, Denisovans and Homo sapiens

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 7.5 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. Question: Do most mutations cause reduced fitness?

9. Relative Abundance of Mutation Types uMost mutations are neutral or ‘Nearly Neutral’ uA smaller fraction are lethal or slightly deleterious (reducing fitness) uA small minority are advantageous

10. Types of Mutations (Polymorphisms)

11. uFirst and second position SNP often changes amino acid  UCA, UCU, UCG, and UCC all code for Serine uThird position SNP often synonymous uMajority of positions are nonsynonymous uNot all amino acid changes affect fitness: allozymes Synonymous versus Nonsynonymous SNP

12. Nuclear Genome Size uSize of nuclear genomes varies tremendously among organisms uWeak association with organismal complexity, especially within kingdoms Arabidopsis thaliana 120 Mbp Poplar460 Mbp Rice 450 Mbp Maize 2,500 Mbp Barley5,000 Mbp Hexaploid wheat16,000 Mbp Fritillaria (lilly family) >87,000 Mbp

13. Noncoding DNA accounts for majority of genome in many eukaryotes uIntergenic space is larger uTransposable element insertions (Alu in humans)

14. Noncoding DNA accounts for majority of genome in many eukaryotes Genic Fraction (%) Genome Size (x10 9 bp)

15. Intron Size Partly Accounts for Genome Size Differences Fugu: 365 Mbp Human: 3500 Mbp log(number of introns) Intron Size (bp) Aparicio et al. 2002, Science 297:1301

16. What is the probability of a mutation hitting a coding region? Lynch (2007) Origins of Genome Architecture Composition of the Human Genome

17. 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

18. 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 ?

19. 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:

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

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

22. 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

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

24. Mutation-Selection Balance uEquilibrium occurs when creation of mutant allele is balanced by selection against that allele uFor a recessive mutation: uAt equilibrium: assuming: 1-sq 2  1

25. What is the equilibrium allele frequency of a recessive lethal with no mutation in a large (but finite) population? uWhat happens with increased forward mutation rate from wild-type allele? uHow about reduced selection?

26. Balance Between Mutation and Selection Recessive lethal allele with s=0.2 and μ=10 -5

27. Muller’s Ratchet uDeleterious mutations accumulate in haploid or asexual lineages uDriving force for evolution of recombination and sex

28. Mutation-Selection Balance with Dominance uDominance exposes alleles to selection, and therefore acts to decrease equilibrium allele frequencies for h>>0 uComplete Dominance of A 2 : uRecessive Case: Which q eq is larger? Why?

29. Effect of dominance and selection on allele frequency in mutation-selection balance (μ=10 -5 ) uDrastic effect of dominance on equilibrium frequencies of deleterious alleles uExposure to selection in heterozygotes recessive case

30. What if the population is not infinite?

31. 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

32. 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?

33. Infinite Alleles Model (IAM: Crow and Kimura Model) uHomozygosity will be a function of mutation and probability of fixation of new mutants Probability of sampling same allele twice Probability of sampling two alleles identical by descent due to inbreeding in ancestors Probability neither allele mutates

34. Expected Heterozygosity with Mutation-Drift Equilibrium under IAM uAt equilibrium f t = f t-1 =f eq uPrevious equation reduces to: Ignoring μ 2 uRemembering that H=1-f: 4N e μ is called the population mutation rate Ignoring 2μ

35. Equilibrium Heterozygosity under IAM uFrequencies of individual alleles are constantly changing uBalance between loss and gain is maintained u4N e μ>>1: mutation predominates, new mutants persist, H is high u4N e μ<<1: drift dominates: new mutants quickly eliminated, H is low

36. Effects of Population Size on Expected Heterozgyosity Under Infinite Alleles Model (μ=10 -5 ) uRapid approach to equilibrium in small populations uHigher heterozygosity with less drift