CHAPTER 14 GENE MUTATION DNA REPAIR AND TRANSPOSITION 14 1 Gene Mutations Are Classified in Various Ways A Mutation is an alteration in DNA sequence Mutations may be o Single base pair substitutions o Deletions or insertions of one or more base pairs o Major alterations in chromosomal structure Mutations may occur within the coding or noncoding region of a gene Spontaneous mutations happen naturally and randomly and are usually linked to normal biological or chemical processes in the organism that alters the structure of nitrogenous bases o Often occur during the enzymatic process of DNA replication Induced mutations result from the influence of an extraneous factor either natural or artificial o Radiation o UV light o Natural and synthetic chemical Somatic mutations occur in any cell except germ cells and are not heritable Germ line mutations occur in gametes and are inherited Autosomal mutations occur within genes located on the autosomes X linked and Y linked mutations occur within genes located on the X and Y chromosome respectively Mutations can be classified based on type of nucleotide change Point mutation or base substitution is a change of one base pair to another o May result in a new triplet code for a different amino acid missense mutation o May result in a triplet code for a stop codon resulting in the termination of translation of the protein early nonsense mutation o New triplet code still codes for the same amino acid silent mutation Base substitutions can be classified as o Transitions a pyrimidine replaces a pyrimidine or a purine replaces a purine o Tansversions a purine and a pyrimidine are interchanged Frameshift mutations result from insertions or deletions of a base pair altering the triplet reading frame FIGURE o Can be very severe especially if they occur early in the coding sequence and especially if one of the many altered triplets will be UAA UAG or UGA the translation termination codons o Except multiples of three which would reestablish the initial frame of reading Mutations can be classified according to their phenotypic effects as o Loss of function mutations null mutations Reduce eliminate function of gene product Null mutations are those that result in complete loss of function o Gain of function mutations Result in a gene product with enhanced new function o Visible morphological mutations Alter normal wild type visible phenotype o Nutritional biochemical mutations Cause loss in ability to synthesize an amino acid or vitamin o Biochemical mutations Can have an effect on the well being and survival of the affected individual Sickle cell anemia and hemophilia are examples of diseases resulting from biochemical mutation o Behavioral mutations Affect behavior patterns of organisms For example the mating behavior of a fruit fly may be impaired if it cannot beat its wings Affect regulation of gene expression can activate or inactivate o Regulatory mutations expression of a gene o Lethal mutations Interrupt an essential process and result in death Various inherited biochemical disorders Tay Sachs Huntington The expression of conditional mutations depends on the environment in which the organism finds itself o Temperature sensitive mutation Gene product functions at one temperature but not another temperature sensitive coat color variations in Siamese cats and Himalayan rabbits A neutral mutation can occur either in a protein coding region or in any part of the genome o The vast majority of mutations are likely to occur in the large portions of the genome that do not contain genes o They do not affect gene products or gene expression o Their effect on the genetic fitness of the organism is neutral 14 2 Spontaneous Mutations Arise from Replication Errors and Base Modifications During DNA replication DNA polymerase occasionally inserts incorrect nucleotides mutations o DNA polymerases can proofread and correct these errors but they may persist if not detected and corrected These types of errors due to mispairing predominantly lead to point o Bases can take several forms tautomers which increase their chance of mispairing during DNA replication If a DNA strand loops out and becomes displaced or if DNA polymerase slips small insertions and deletions can occur Insertions and deletions can lead to frameshift mutations or amino acid insertions or deletion in the gene product o Replication slippage can occur anywhere in the DNA but is more common in repeated sequences Hot spots for DNA mutation and in some cases contribute to hereditary diseases Fragile X Huntington disease Purines and pyrimidines can exist in tautomeric forms alternate chemical forms that differ by a single proton shift in the molecule Tautomeric shifts can change the bonding structure allowing noncomplementary base pairing o May lead to permanent base pair changes and mutations FIGURE o Result in a point mutation shift in C at point of synthesis o Requires Failure to recognize repair Another round of DNA sythesis Depurination and Deamination DNA base damage by depurination and deamination is the most common cause of spontaneous mutation o Depurination loss of one of the nitrogenous bases usually a purine G or A in an intact double helical DNA molecule If apurinic sites are not repaired there will be no base at that position during DNA replication and DNA polymerase may introduce a nucleotide at random at that site o Deamination amino group in cytosine converted to uracil adenine converted to hypoxanthine o Results in change in base pairing of the original bases G C converted to A T DNA may suffer oxidative damage by the by products of normal cellular processes and exposure to high energy radiation Resulting in modifications to bases Loss of bases and single strand breaks o Superoxides O2 o Hydroxyl radicals OH o Hydrogen peroxide H2O2 14 3 Induced Mutations Arise from DNA Damage Caused by Chemicals and Radiation Induced mutations are those that increase the rate of mutation above spontaneous background Mutagens are natural or artificial agents that induce mutations o Fungal toxins o Cosmic rays o Ultraviolet light o Industrial pollutants o Medical X rays o Chemicals in tobacco smoke Smoke organic Base analogs mutagenic chemicals can substitute for purines or pyrimidines during nucleic acid replication FIGURE o For example 5 bromouracil 5 BU behaves as a thymine analog Increases tautomeric shifts Increases sensitivity to UV light which is also mutagenic o If 5 BU is linked to Deoxyribose the
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