When Darwin wrote the Origin , he imagined that . . . A grand and almost untrodden field of inquiry will be opened, on

2. The capacity to blunder slightly is the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and there would be no music. Lewis Thomas, 1979 The Medusa and the Snail

3. When Darwin wrote the Origin, he imagined that . . . A grand and almost untrodden field of inquiry will be opened, on the causes and laws of variation. Charles Darwin, 1859 On the Origin of Species

4. Today we shall visit that field of inquiry. Why do mutations happen?

5. There are two classical answers. 1. 2.

6. There are two classical answers. 1. Mutations are accidents, and “accidents will happen.” 2.

7. There are two classical answers. 1. Mutations are accidents, and “accidents will happen.” 2. Mutations are necessary, “for the good of the species.”

8. Here are the basic facts. ● ● ● ●

9. Here are the basic facts. ● Most mutations are deleterious. ● ● ●

10. Here are the basic facts. ● Most mutations are deleterious. ● Organisms differ widely, in their susceptibility to mutation. ● ●

11. Here are the basic facts. ● Most mutations are deleterious. ● Organisms differ widely, in their susceptibility to mutation. ● Genes coding enzymes for DNA replication, proofreading, and correction come in various alleles, with varying degrees of accuracy. ●

12. Here are the basic facts. ● Most mutations are deleterious. ● Organisms differ widely, in their susceptibility to mutation. ● Genes coding enzymes for DNA replication, proofreading, and correction come in various alleles, with varying degrees of accuracy. ● Mutation rates could be much lower than they are.

13. Why has natural selection not reduced the mutation rate even more?

14. Why are mutation rates not much lower? Natural selection usually involves compromise.What advantages and costs are being compromised?

15. Why are mutation rates not much lower? Is the advantage of accurate replicationbeing balanced by selection . . . ● ●

16. Why are mutation rates not much lower? Is the advantage of accurate replicationbeing balanced by selection . . . ● against the immediate expense of accurate replication? ●

17. Why are mutation rates not much lower? Is the advantage of accurate replicationbeing balanced by selection . . . ● against the immediate expense of accurate replication? or ● against the occasional benefit of inaccurate replication?

18. Two hypotheses . . . 1. 2.

19. Two hypotheses . . . 1. “Accidents will happen.”Error-free reproduction is simply too expensive to be practical. 2.

20. Two hypotheses . . . 1. “Accidents will happen.”Error-free reproduction is simply too expensive to be practical. 2. “For the good of the species.”A low level of mutation is needed as a hedge against extinction.

21. Is the immediate hazard of mutationbalanced by . . . Immediate expense of accuracy? __________ Long-term benefit for adaptation? __________ OR

22. Is the immediate hazard of mutationbalanced by . . . Immediate expense of accuracy? __________ Do mutations happen only as accidental errors? Long-term benefit for adaptation? __________ Is a low but positive mutation rate selected because some mutations will be beneficial? OR

23. Is a low but positive rate of mutation . . . Accidental? OR Selected?

24. Accidental? Selected? Mutations are accidents, and accidents will happen. A.H. Sturtevant, 1937 Mistakes in the copying of genetic information produce mutations. D. Futuyma, 1979 Evolutionary Biology (Classic textbook)

25. Accidental? Selected? . . . The cost of fidelity is the generally accepted explanation for non-zero mutation rates in multicellular eukaryotes. Direct selection almost always favours a decrease in the mutation rate to reduce the frequency of deleterious mutations. However, selection to reduce the cellular resources that are devoted to maintaining replication fidelity and/or selection to increase the speed of replication lead to indirect selection to increase the mutation rate. The optimum is established when the cumulative direct and indirect effects cancel each other out. C.F. Baer, et al. 2007 Nature Reviews Genetics Cells have evolved several enzymatic systems that either prevent mutations from forming or eliminate those that do. These safeguards enable organisms to keep mutations to a low level that balances their need to evolve with their need to avoid damage to their genomes. L.H. Hartwell, et al., 2008 Genetics: From Genes to Organisms (current textbook for ZOOL 305)

26. Accidental? Selected? Mutations are accidents, and accidents will happen. A.H. Sturtevant, 1937 Cells have evolved several enzymatic systems that either prevent mutations from forming or eliminate those that do. These safeguards enable organisms to keep mutations to a low level that balances their need to evolve with their need to avoid damage to their genomes. L.H. Hartwell, et al., 2008 Genetics: From Genes to Organisms (current textbook for ZOOL 305) Mistakes in the copying of genetic information produce mutations. D. Futuyma, 1979 Evolutionary Biology (Classic textbook)

27. Mutations are accidents. This is the most widely accepted answer to the question, “Why do mutations happen.” _________________________ Mutations are the unavoidable side effect of compromising accuracy with speed and efficiency. A strong argument supports this position.

28. Mutations are accidents. This is the most widely accepted answer to the question, “Why do mutations happen.” _________________________ Mutations are the unavoidable side effect of compromising accuracy with speed and efficiency. A strong argument supports this position.

29. Mutations are accidents. _________________________ Point mutation rates are governed by genes that make enzymes which replicate, proofread, and correct DNA. Allelic variation in these genes determines replication speed and fidelity.

30. Mutations are accidents. _________________________ Point mutation rates are governed by genes that make enzymes which replicate, proofread, and correct DNA. Allelic variation in these genes determines replication speed and fidelity. Since most point mutations are deleterious, “mutator” alleles which decrease replication fidelity will be selected against (unless there is a compensating increase in replication rate).

31. Mutations are accidents. _________________________ Point mutation rates are governed by genes that make enzymes which replicate, proofread, and correct DNA. Allelic variation in these genes determines replication speed and fidelity. Since most point mutations are deleterious, “mutator” alleles which decrease replication fidelity will be selected against (unless there is a compensating increase in replication rate). A “mutator” allele might hitchhike by linkage with a (rare) beneficial allele, but recombination will eventually separate the two.

32. Mutations are accidents. _________________________ Natural selection cannot be caused by a “need to evolve.”

33. Mutations are accidents. _________________________ Natural selection cannot be caused by a “need to evolve.” Selection cannot see into the future.

34. Mutations are accidents. _________________________ Natural selection cannot be caused by a “need to evolve.” Selection cannot see into the future. Selection is blind to “the good of the species.”

35. This argument supports a strong conclusion: Natural selection of mutation rates has only one possible direction, that of reducing the frequency of mutation to zero. That mutations should continue to occur . . . is merely a reflection of the unquestionable principle that natural selection can often produce mechanisms of extreme precision, but never of perfection. George Williams, 1966 Adaptation and Natural Selection

36. The cost of fidelity is the generally accepted explanation for non-zero mutation rates in multicellular eukaryotes. C.F. Baer, et al. 2007 Nature Reviews Genetics

37. Evolution has probably reduced the mutation rates to far below species optima, as the result of unrelenting selection for zero mutation rate in every population. Mutation is, of course, a necessary precondition to continued evolutionary change. So evolution takes place, not so much because of natural selection, but to a large degree in spite of it. George Williams, 1966 Adaptation and Natural Selection

38. A low but positive rate of mutation is . . . Accidental. Selected? OR

39. A low but positive rate of mutation is . . . Accidental. Mutations are the errors which remain after selection has optimized replication fidelity against metabolic cost and speed of replication. Selected? OR

41. The preceding argument that “mutations are accidents” is based on our understanding of point mutations within classical genes. This argument is probably correct regarding point mutations in protein-coding sequences. ● Point mutations probably are mostly deleterious ● Point mutations probably do occur at random sites within genomes. ●Rates for point mutation probably are determined by genes for replication fidelity. ● If these are true, the conclusion does follow: Mutations are accidents.

42. The preceding argument that “mutations are accidents” is based on our understanding of point mutations within classical genes. This argument is probably correct regarding point mutations in protein-coding sequences. ● Point mutations probably are mostly deleterious. ● Point mutations probably do occur at random sites within genomes. ●Rates for point mutation probably are determined by genes for replication fidelity. ● If these are true, the conclusion does follow: Mutations are accidents.

43. The preceding argument that “mutations are accidents” is based on our understanding of point mutations within classical genes. This argument is probably correct regarding point mutations in protein-coding sequences. ● Point mutations probably are mostly deleterious. ● Point mutations probably do occur at random sites within genomes. ●Rates for point mutation probably are determined by genes for replication fidelity. ● If these are true, the conclusion does follow: Mutations are accidents.

44. The preceding argument that “mutations are accidents” is based on our understanding of point mutations within classical genes. This argument is probably correct regarding point mutations in protein-coding sequences. ● Point mutations probably are mostly deleterious. ● Point mutations probably do occur at random sites within genomes. ● Rates for point mutation probably are determined by genes for replication fidelity. ● If these are true, the conclusion does follow: Mutations are accidents.

45. The preceding argument that “mutations are accidents” is based on our understanding of point mutations within classical genes. This argument is probably correct regarding point mutations in protein-coding sequences. ● Point mutations probably are mostly deleterious. ● Point mutations probably do occur at random sites within genomes. ● Rates for point mutation probably are determined by genes for replication fidelity. ● If these assumptions are true, the conclusion does follow: Mutations are accidents.

46. However . . . This argument is also fundamentally misleading.

47. Several other styles of mutation are also known, besides point mutations.

48. Several other styles of mutation are also known, besides point mutations. ● programmed gene rearrangements ● transposable elements ● gene duplications ● repeat-based mutability

49. Several other styles of mutation are also known, besides point mutations. ● programmed gene rearrangements ● transposable elements ● gene duplications ● repeat-based mutability All of these were unexpected when first discovered. Although some of these are commonly dismissed as “selfish” or “junk” DNA, their implications have yet to be fully integrated into evolutionary theory.

50. Can unconventional mutational mechanismsbe positively selected?