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Download Chapter 13 Mutation, DNA Repair, and Recombination
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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 Mutations—inherited changes in the genetic material— provide new genetic variation that allows organisms to evolve. Mutation 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) 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. Mutations are heritable changes in the genetic material that provide the raw material for evolution. 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. 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. 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. 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. 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. 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. The effects of mutations on phenotype range from no observable change to lethality. 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. 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. 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. Tay-Sachs disease is an autosomal recessive disease. The mutation causing Tay-Sachs disease is in the gene encoding hexosaminidase A. 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 phydroxyphenylpyruvic acid oxidase. 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. The mutant polypeptides, in turn, cause blocks in metabolic pathways. Conditional lethal mutations provide powerful tools with which to dissect biological processes. 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. 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. 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 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. 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. 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. Mutations are induced by chemicals, ionizing irradiation, ultraviolet light, and endogenous transposable genetic elements. Point mutations are of three types: (1) (2) (3) 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. Several inherited human diseases are caused by expanded trinucleotide repeats. The Ames test provides a simple and inexpensive method for detecting the mutagenicity of chemicals. Bruce Ames and coworkers developed an inexpensive and sensitive method for testing the mutagenicity of chemicals with histidine auxotrophic mutants of Salmonella. Living organisms contain many enzymes that scan their DNA for damage and initiate repair processes when damage is detected. Light-dependent repair (photoreactivation) Excision repair Mismatch repair Postreplication repair Error-prone repair system (SOS response) A DNA repair endonuclease or endonucleasecontaining 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. Base excision repair pathways remove abnormal or chemically modified bases. Nucleotide excision repair pathways remove larger defects, such as thymine dimers. 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. Several inherited human disorders result from defects in DNA repair pathways. 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. 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. 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. 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.