1. Gene Mutations and DNA Repair
Benjamin A. Pierce
GENETICS
A Conceptual Approach
FIFTH EDITION
CHAPTER 18
Gene Mutations and DNA Repair
© 2014 W. H. Freeman and Company 1

2. People with a mutation in the tinman gene, named after Tin Man, in The Wizard of Oz, often have congenital heart defects. [Mary Evans Picture Library/Alamy.]

3. 18.1 Mutations Are Inherited Alterations in the DNA Sequence
The Importance of Mutations
Categories of Mutations
Types of Genetic Mutations
Phenotypic Effects of Mutations
Suppressor Mutations

4. The Importance of Mutations
Mutations: sustainer of life and cause of great suffering
Source of all genetic variation, which further provides the raw material for evolution
Source of many diseases and disorders
Useful for probing fundamental biological processes

5. Categories of Mutations
Somatic mutations
Germ-line mutations
Gene vs. chromosomal mutations

6. Figure 18.1 The two basic classes of mutations are somatic mutations and germ-line mutations.

7. Types of Gene Mutations (based on their molecular nature)
Base substitutions
Transition
Transversion
Insertions and deletions
Frameshift mutations
In-frame insertions and deletions
Expanding nucleotide repeats
Increase in the number of a copies of
a set of nucleotides

8. Figure 18.2 Three basic types of gene mutations are base substitutions, insertions, and deletions.

9. Figure A transition is the substitution of a purine for a purine or of a pyrimidine for a pyrimidine; a transversion is the substitution of a pyrimidine for a purine or of a purine for a pyrimidine.

10. Figure The fragile-X chromosome is associated with a characteristic constriction (fragile site) on the long arm. [Visuals Unlimited.]

12. Figure 18.5 A model of how the number of copies of a nucleotide repeat may increase in replication.

13. Concept Check 1
Which of the following changes is a transition base substitution?
Adenine is replaced by thymine.
Cytosine is replaced by adenine.
Guanine is replaced by adenine.
Three nucleotide pairs are inserted into DNA.

14. Concept Check 1
Which of the following changes is a transition base substitution?
Adenine is replaced by thymine.
Cytosine is replaced by adenine.
Guanine is replaced by adenine.
Three nucleotide pairs are inserted into DNA.

15. Phenotypic Effects of Mutations
Forward mutation: wild type  mutant type
Reverse mutation: mutant type  wild type
Missense mutation: amino aciddifferent amino acid
Nonsense mutation: sense codon nonsense codon
Silent mutation: codonsynonymous codon
Neutral mutation: no change in function

16. Figure 18.6 Base substitutions can cause (a) missense, (b) nonsense, and (c) silent mutations.

17. Phenotypic Effects of Mutations
Loss-of-function mutations
Gain-of-function mutations
Conditional mutation
Lethal mutation

18. Suppressor Mutations
Suppressor mutation: a mutation that hides or suppresses the effect of another mutation
Intragenic
Intergenic

19. Figure 18.7 Relation of forward, reverse, and suppressor mutations.

20. Figure An intragenic suppressor mutation occurs in the gene containing the mutation being suppressed.

21. Figure An intergenic suppressor mutation occurs in a gene other than the one bearing the original mutation. (a) The wild-type sequence produces a full-length, functional protein. (b) A base substitution at a site in the same gene produces a premature stop codon, resulting in a shortened, nonfunctional protein. (c) A base substitution at a site in another gene, which in this case encodes tRNA, alters the anticodon of tRNATyr; tRNATyr can pair with the stop codon produced by the original mutation, allowing tyrosine to be incorporated into the protein and translation to continue.

23. Mutation Rates Factors affecting mutation rates
Variation in mutation rates
Adaptive mutations

24. Factors Affecting Mutation Rates
Frequency with which a change takes place in DNA
The probability that when a change takes place, that change will be repaired
The probability that a mutation will be detected

26. Adaptive Mutation
Genetic variation critical for evolutionary change that brings about adaptation to new environments
Stressful conditions, where adaptation might be necessary to survive, induces increased mutation in bacteria

27. 18.2 Mutations Are Potentially Caused by a Number of Different Factors
Spontaneous replication errors
Spontaneous chemical changes
Chemically induced mutations
Radiation

28. Spontaneous Replication Errors
Tautomeric shifts
Mispairing due to other structures
Incorporation errors and replication errors
Causes of deletion and insertions
Strand slippage
Unequal crossing over

29. Figure 18.10 Nonstandard base pairings can occur as a result of the flexibility in DNA structure.

30. Figure 18.11 Wobble base pairing leads to a replicated error.

31. Figure 18.12 Insertions and deletions may result from strand slippage.

32. Figure 18.13 Unequal crossing over produces insertions and deletions.

33. Spontaneous Chemical Changes
Depurination: loss of purine
Deamination: loss of an amino group

34. Figure 18.14 Depurination (the loss of a purine base from a nucleotide) produces an apurinic site.

35. Figure 18.15 Deamination alters DNA bases.

36. Chemically Induced Mutations
Mutagen
Base analogs

37. Figure bromouracil (a base analog) resembles thymine, except that it has a bromine atom in place of a methyl group on the 5-carbon atom. Because of the similarity in their structures, 5-bromouracil may be incorporated into DNA in place of thymine. Like thymine, 5-bromouracil normally pairs with adenine but, when ionized, it may pair with guanine through wobble.

38. Figure 18.17 5-bromouracil can lead to a replicated error.

39. Chemically Induced Mutations
Alkylating agents: donate alkyl group
Ethylmethylsulfonate EMS
Mustard gas
Deamination: nitrous acid
Hydroxylamine: add hydroxyl group

40. Figure 18.18 Chemicals may alter DNA bases.

41. Chemically Induced Mutations
Oxidative reaction: superoxide radicals
Hydrogen peroxide
Intercalating agents: proflavin, acridine orange, and ethidium bromide

42. Figure 18.19 Oxidative radicals convert guanine into 8-oxy-7, 8-dihydrodeoxyguanine.

43. Figure 18. 20 Intercalating agents
Figure Intercalating agents. Proflavin and acridine orange (a) insert themselves between adjacent bases in DNA, distorting the three-dimensional structure of the helix (b).

44. Concept Check 2
Base analogs are mutagenic because of which characteristic?
They produce changes in DNA polymerase that cause it to malfunction.
They distort the structure of DNA.
They are similar in structure to the normal bases.
They chemically modify the normal bases.

45. Concept Check 2
Base analogs are mutagenic because of which characteristic?
They produce changes in DNA polymerase that cause it to malfunction.
They distort the structure of DNA.
They are similar in structure to the normal bases.
They chemically modify the normal bases.

46. Radiation Radiation greatly increases mutation rates in all organisms
Pyrimidine dimer: two thymine bases block replication.
SOS system in bacteria: SOS system allows bacteria cells to bypass the replication block with a mutation-prone pathway.

47. Figure 18. 21 Pyrimidine dimers result from ultraviolet light
Figure Pyrimidine dimers result from ultraviolet light. (a) Formation of thymine dimer. (b) Distorted DNA.

48. 18.3 Mutations Are the Focus of Intense Study by Geneticists
Detecting Mutations with the Ames Test
Radiation Exposure in Humans

49. Figure 18.22 The Ames test is used to identify chemical mutagens.

50. Figure 18.23 Hiroshima was destroyed by an atomic bomb on August 6, 1945.

51. 18.4 Transposable Elements Cause Mutations
Transposable elements: sequences that can move about the genome
Transposition: movement of the transposons
Features:
Flanking direct repeats
Terminal inverted repeats

52. Figure 18.24 Flanking direct repeats are generated when a transposable element inserts into DNA.

53. Figure 18. 25 Many transposable elements have common characteristics
Figure Many transposable elements have common characteristics. (a) Most transposable elements generate flanking direct repeats on each side of the point of insertion into target DNA. Many transposable elements also possess terminal inverted repeats. (b) These representations of direct and indirect repeats are used in illustrations throughout this chapter.

54. 18.4 Transposable Elements Cause Mutations
Transposons cause mutations by:
Inserting into another gene
Promoting DNA rearrangements
Examples:
Approximately half of spontaneous mutations in Drosophila
Human genetic diseases
The color of grapes

55. Figure Red and white grape color in grapes resulted from insertion and deletion of a retrotransposon.

56. Figure 18.27 Many chromosomal rearrangements are generated by transposition.

57. Transposable Elements in Bacteria
DNA transposons constitute two major groups:
Insertion sequences
Composite transposons

58. Figure 18.27 Many chromosomal rearrangements are generated by transposition.

59. Figure 18.28 Insertion sequences are simple transposable elements found in bacteria.

60. Figure 18.29 Tn10 is a composite transposon in bacteria.

61. Figure 18.30 Mu is a transposing bacteriophage.

62. Transposable Elements in Eukaryotes
Two primary groups:
Similar to transposable elements in bacteria
short inverted repeats
P elements in Drosophila
Ac and Ds elements
Retrotransposons
Ty elements in yeast
Copia elements in Drosophila
Alu sequences in humans

63. Figure 18.32 Variegated (multicolored) kernels in corn are caused by mobile genes.

64. Figure 18.33 Ac and Ds are transposable elements in maize.

65. Figure 18.34 Transposition results in variegated maize kernels.

66. Figure 18.35 Hybrid dysgenesis in Drosophila is caused by the transposition of P elements.

68. 18.5 A Number of Pathways Repair Changes in DNA
Mismatch Repair
Direct Repair
Base-Excision Repair
Nucleotide-Excision Repair

69. Figure Many incorrectly inserted nucleotides that escape proofreading are corrected by mismatch repair.

70. Figure 18.37 Direct repair changes nucleotides back into their original structures.

71. Concept Check 3
Mismatch repair in bacteria distinguishes between old and new strands of DNA on the basis of __________.
differences in base composition of the two strands
modification of histone proteins
base analogs on the new strand
methyl groups on the old strand

72. Concept Check 3
Mismatch repair in bacteria distinguishes between old and new strands of DNA on the basis of __________.
differences in base composition of the two strands
modification of histone proteins
base analogs on the new strand
methyl groups on the old strand

73. Figure 18.38 Base-excision repair excises modified bases and then replaces one or more nucleotides.

74. Figure 18.39 Nucleotide-excision repair removes bulky DNA lesions that distort the double helix.

75. 18.5 A Number of Pathways Repair Changes in DNA
Repair of Double-Strand Breaks
Translesion DNA Polymerases
Genetics Diseases and Faulty DNA Repair