1. Chapter 13 Mutation, DNA Repair, and Recombination
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2. Chapter Outline
Mutation: Source of the Genetic Variability Required for Evolution
Mutation: Basic Features of the Process
Mutation: Phenotypic Effects
The Molecular Basis of Mutation
Screening Chemicals for Mutagenicity: The Ames Test
DNA Repair Mechanisms
Inherited Human Diseases with Defects in DNA Repair

3. Mutation: Source of the Genetic Variability Required for Evolution
Mutations—inherited changes in the genetic material—provide new genetic variation that allows organisms to evolve.

4. Mutation Mutation Mutant—an organism that exhibits a novel phenotype
A change in the genetic material
The process by which the change occurs
Mutant—an organism that exhibits a novel phenotype
Types of Mutations
Changes in chromosome number and structure
Point mutations—changes at specific sites in a gene (substitution, insertion, or deletion)

5. Mutation and Evolution
Mutation is the source of all genetic variation.
Recombination mechanisms rearrange genetic variability into new combinations.
Natural selection preserves the combinations best adapted to the existing environment.

6. Key Point
Mutations are heritable changes in the genetic material that provide the raw material for evolution.

7. Mutation: Basic Features of the Process
Mutations occur in all organisms from viruses to humans. They can occur spontaneously or be induced by mutagenic agents. Mutation is usually a random, nonadaptive process.

8. Mutation: Somatic or Germinal
Germinal mutations occur in germ-line cells and will be transmitted through the gametes to the progeny.
Somatic mutations occur in somatic cells; the mutant phenotype will occur only in the descendants of that cell and will not be transmitted to the progeny.

9. Mutation: Spontaneous or Induced
Spontaneous mutations occur without a known cause due to inherent metabolic errors or unknown agents in the environment.
Induced mutations result from exposure or organisms to mutagens, physical and chemical agents that cause changes in DNA, such as ionizing irradiation, ultraviolet light, or certain chemicals.

10. Mutation: A Reversible Process
Forward mutation—mutation of a wild-type allele to a mutant allele.
Reverse mutation (reversion)—a second mutation that restores the original phenotype.
Back mutation—a second mutation at the same site.
Suppressor mutation—a second mutation at a different location in the genome.

11. Key Points
Mutations occur in both germ-line and somatic cells, but only germ-line mutations are transmitted to progeny.
Mutations can occur spontaneously or be induced by mutagenic agents in the environment.
Mutation usually is a nonadaptive process in which an environmental stress simply selects organisms with preexisting, randomly occurring mutations.

12. Key Points
Adaptive, or stationary-phase, mutagenesis occurs in bacteria that have been exposed to an environmental stress such as starvation.
Restoration of the wild-type phenotype in a mutant organism can result from either back mutation or a suppressor mutation.

13. Mutation: Phenotypic Effects
The effects of mutations on phenotype range from no observable change to lethality.

14. Types of Mutations
Isoalleles have no effect on phenotype or small effects that can be recognized only by special techniques.
Null alleles result in no gene product or totally nonfunctional gene products.
Recessive lethal mutations affect genes required for growth of the organisms and are lethal in the homozygous state.
Mutations may be dominant or recessive.

15. Recessive Mutations Often Block Metabolic Pathways

16. Neutral Mutations
Because of the degeneracy and order in the genetic code, man mutations have no effect on the phenotype of the organism. These are called neutral mutations.

17. Mutations in Human Globin Genes
Adult hemoglobin (Hemoglobin A) contains two  chains and two  chains.
Hemoglobin in patients with sickle-cell anemia (Hemoglobin S) differs from Hemoglobin A at only one position.
The sixth amino acid in the  chain is glutamic acid in Hemoglobin A and is valine in Hemoglobin S. This substitution is caused by mutation of a single base pair.

18. Tay-Sachs Disease Tay-Sachs disease is an autosomal recessive disease.
The mutation causing Tay-Sachs disease is in the gene encoding hexosaminidase A.

19. Mutations Affecting Metabolism of Phenylalanine and Tyrosine
Phenylketonuria is caused by a mutation in phenylalanine hydroxylase.
Albinism is caused by a mutation in tyrosinase
Alkaptonuria is caused by a mutation homogentisic acid oxidase.
Tyrosinosis is caused by a mutation in tyrosine transaminase.
Tyrosinemia is caused by a mutation in p-hydroxyphenylpyruvic acid oxidase.

20. Key Points
The effects of mutations on the phenotypes of living organisms range from minor to lethal changes.
Most mutations exert their effects on the phenotype by altering the amino acid sequences of polypeptides, the primary gene products.

21. Key Points
The mutant polypeptides, in turn, cause blocks in metabolic pathways.
Conditional lethal mutations provide powerful tools with which to dissect biological processes.

22. The Molecular Basis of Mutation
Mutations alter the nucleotide sequences of genes in several ways, for example the substitution of one base pair for another or the deletion or addition or one or a few base pairs.

23. Tautomeric Shifts

24. Tautomeric Shifts Affect Base-Pairing

25. Mutation Caused by Tautomeric Shifts

26. Base Substitutions
A transition replaces a pyrimidine with another pyrimidine or a purine for another purine.
A transversion replaces a pyrimidine with a purine or a purine with a pyrimidine.

27. Frameshift Mutations

28. Factors Influencing the Rate of Spontaneous Mutations
Accuracy of the DNA replication machinery
Efficiency of the mechanisms for the repair of damaged DNA
Degree of exposure to mutagenic agents in the environment

29. Induced Mutations
Induced mutations occur upon exposure to physical or chemical mutagens.
Hermann J. Muller and Edgar Alternburg measured the frequency of X-linked recessive lethal mutations in Drosophila.
Muller demonstrated that exposing Drosophila sperm to X-rays increased the mutation frequency.

30. Mutagenesis by Ultraviolet Irradiation
Hydrolysis of cytosine to a hydrate may cause mispairing during replication
Cross-linking of adjacent thymine forms thymidine dimers, which block DNA replication and activate error-prone DNA repair mechanisms.

31. Mutations Induced by Transposons

32. Expansion of Trinucleotide Repeats
Simple tandem repeats are repeated sequence of one to six nucleotide pairs.
Trinucleotide repeats can increase in copy number and cause inherited diseases.
Examples: Fragile X Syndrome, Huntington disease, spinocerebellar ataxia
These diseases are characterized by anticipation, the increased severity of disease or earlier age of onset in successive generations as the trinucleotide copy number increases.

33. Key Points
Mutations are induced by chemicals, ionizing irradiation, ultraviolet light, and endogenous transposable genetic elements.
Point mutations are of three types:
Transitions—purine for purine and pyrimidine for pyrimidine substitutions,
Transversions—purine for pyrimidine and pyrimidine for purine substitutions, and
Frameshift mutations—additions or deletions of one or two nucleotide pairs, which alter the reading frame of the gene distal to the site of the mutation.

34. Key Points
Several inherited human diseases are caused by expanded trinucleotide repeats.

35. Screening Chemicals for Mutagenicity: The Ames Test
The Ames test provides a simple and inexpensive method for detecting the mutagenicity of chemicals.

37. Key Points
Bruce Ames and coworkers developed an inexpensive and sensitive method for testing the mutagenicity of chemicals with histidine auxotrophic mutants of Salmonella.

38. DNA Repair Mechanisms
Living organisms contain many enzymes that scan their DNA for damage and initiate repair processes when damage is detected.

39. DNA Repair Mechanisms in E. coli
Light-dependent repair (photoreactivation)
Excision repair
Mismatch repair
Postreplication repair
Error-prone repair system (SOS response)

40. Light-Dependent Repair: Photolyase Cleaves Thymine Dimers

41. Excision Repair
A DNA repair endonuclease or endonuclease-containing complex recognizes, binds to, and excised the damaged base or bases.
A DNA Polymerase fills in the gap, using the undamaged complementary strand of DNA as a template.
DNA ligase seals the break left by DNA polymerase.

42. Types of Excision Repair
Base excision repair pathways remove abnormal or chemically modified bases.
Nucleotide excision repair pathways remove larger defects, such as thymine dimers.

43. Base Excision Repair

45. Nucleotide Excision Repair

47. Key Points
Multiple DNA repair systems have evolved to safeguard the integrity of genetic information in living organisms.
Each repair pathway corrects a specific type of damage in DNA.

48. Inherited Human Diseases with Defects in DNA Repair
Several inherited human disorders result from defects in DNA repair pathways.

49. Xeroderma Pigmentosum (XP)
Individuals with XP are sensitive to sunlight.
The cells of individuals with XP are deficient in the repair of UV-induced damage to DNA.
Individuals with XP may develop skin cancer or neurological abnormalities.

51. Key Points
The importance of DNA repair pathways is documented convincingly by inherited human disorders that result from defects in DNA repair.
Certain types of cancer are also associated with defects in DNA repair pathways.

52. DNA Recombination Mechanisms
Recombination between homologous DNA molecules involves the activity of numerous enzymes that cleave, unwind, stimulate single-strand invasions of double helices, repair, and join strands of DNA.

53. Recombination
In eukaryotes, crossing over is associated with the formation of the synaptonemal complex during prophase of meiosis I.
Crossing over involves the breakage of parental chromosomes and rejoining of the parts in new combinations.
The Holliday model and the double-strand break model are two explanations of the molecular basis of recombination.

54. The Holliday Model