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Download F. Mutation and Repair 1. Background on DNA Mutations
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Transcript
___________________________________ F. Mutation and Repair ___________________________________ 1. Background on DNA Mutations 2. Common Types and Mechanisms of DNA Damage, Mutation and Repair ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 1. Background on DNA Mutations ___________________________________ a. Mutation rates are extremely low but are an essential component of evolutionary change ___________________________________ b. The most common source of DNA mutation is error during replication ___________________________________ c. Environmental damage to the DNA is independent of DNA mutation but can also be the underlying cause ___________________________________ ___________________________________ ___________________________________ a. Mutation rates are extremely low but are an essential component of evolutionary change • Mutations that become part of the multicellular genome must occur in the cells of the germ line • Somatic mutations may or may not affect the individual but cannot affect the population • Low rates of mutation can result in high rates of evolution in single-celled organisms ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-1 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ b. The most common source of DNA mutation is error during replication • There is an average mistake of 1 base pair every 10,000 • Due to proofreading and repair mechanisms this rate declines to 1 every 1,000,000,000 • Inherent in meiosis are assortment and crossover events that lead to highly significant changes in germ line DNA sequences ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Independent Assortment of Chromosomes ___________________________________ • Homologous pairs of chromosomes orient randomly at metaphase I of meiosis ___________________________________ • In independent assortment, each pair of chromosomes sorts maternal and paternal homologues into daughter cells independently of the other pairs ___________________________________ • The number of combinations possible when chromosomes assort independently into gametes is 2n, where n is the haploid number ___________________________________ • For humans (n = 23), there are more than 8 million (223) possible combinations of chromosomes ___________________________________ ___________________________________ Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings ___________________________________ Random Fertilization ___________________________________ • Random fertilization adds to genetic variation because any sperm can fuse with any ovum (unfertilized egg) ___________________________________ • The fusion of two gametes (each with 8.4 million possible chromosome combinations from independent assortment) produces a zygote with any of about 70 trillion diploid combinations ___________________________________ ___________________________________ ___________________________________ ___________________________________ Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings ___________________________________ Fig. 13-12-5 Prophase I of meiosis Pair of homologs Nonsister chromatids held together during synapsis ___________________________________ Chiasma Centromere ___________________________________ Crossing over ___________________________________ TEM Anaphase I ___________________________________ Anaphase II ___________________________________ Daughter cells Recombinant chromosomes ___________________________________ ___________________________________ Crossing Over ___________________________________ • Crossing over produces recombinant chromosomes, which combine genes inherited from each parent ___________________________________ • Crossing over begins very early in prophase I, as homologous chromosomes pair up gene by gene ___________________________________ • In crossing over, homologous portions of two nonsister chromatids trade places ___________________________________ • Crossing over contributes to genetic variation by combining DNA from two parents into a single chromosome ___________________________________ ___________________________________ Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings ___________________________________ c. Environmental damage to the DNA is independent of DNA mutation but can also be the underlying cause ___________________________________ 1. DNA damage is simply a chemical alteration to DNA, whereas DNA mutation is a change in one or more base pairs ___________________________________ 2. DNA damage becomes DNA mutation when DNA replication proceeds without repairing the damage or by means of error-prone DNA repair systems ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Sites susceptible to reactive oxygen attack Sites susceptible to uncontrolled methylation ___________________________________ Sites susceptible to hydrolytic attack ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-44 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ ___________________________________ UV radiation can lead to dimerization between adjacent pyrimidine bases ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-46 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ Fig. 17-22 Example Mutation: Sickle Cell Anemia 3’ 5’ Wild-type hemoglobin DNA Mutant hemoglobin DNA C T T C A T 5’ 3’ G T A G A A 3’ 5’ 5’ 3’ ___________________________________ ___________________________________ mRNA 5’ mRNA G A A 3’ 5’ G U A 3’ ___________________________________ Normal hemoglobin Glu Sickle-cell hemoglobin Val ___________________________________ ___________________________________ ___________________________________ 2. Common Types and Mechanisms of DNA Damage, Mutation and Repair a. The alteration of a single base pair (point mutation) can result from chemical damage followed by copying error b. The insertion or deletion of a single base pair (point mutation) during DNA replication c. Single-stranded and double-stranded breaks can result from electrophilic attack from reactive oxygen species ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ a. The alteration of a single base pair (point mutation) can result from chemical damage followed by copying error ___________________________________ ___________________________________ 1. DNA damage leading to structural distortion of the base pair chemistry ___________________________________ 2. DNA base pair changes (mutations) that result from structural distortion can include transitions and transversions ___________________________________ 3. Potential outcomes in protein expression and phenotype ___________________________________ 4. Several DNA repair systems can remove these mutations ___________________________________ ___________________________________ ___________________________________ 1. DNA damage leading to structural distortion a. Alkylation of nitrogen in bases b. Deamination of cytosine to form uracil c. Formation of pyrimidine dimers ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Sites susceptible to reactive oxygen attack Sites susceptible to uncontrolled methylation Sites susceptible to hydrolytic attack ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-44 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-50a Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-50b Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ ___________________________________ UV radiation can lead to dimerization between adjacent pyrimidine bases ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-46 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ 2. DNA base pair changes (mutations) that result from structural distortion ___________________________________ ___________________________________ a. Transitions: Change from a pyrimidine to another pyrimidine or change from a purine to another purine. Causes mismatch. b. Transversion: change from a purine to a pyrimidine or a pyrimidine to a purine. Also causes mismatch. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-47 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ 3. Potential outcomes in protein expression and phenotype ___________________________________ ___________________________________ a. Silent mutations have no effect on the amino acid produced because of redundancy b. Missense mutations still code for an amino acid, but not necessarily the right amino acid c. Nonsense mutations change an amino acid codon into a stop codon, nearly always leading to a nonfunctional protein d. Insertion or deletion of nucleotides may alter the reading frame, producing a frameshift mutation Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 4. Several DNA repair systems can remove these mutations ___________________________________ ___________________________________ a. Mismatch repair b. Base excision repair ___________________________________ c. Nuclear excision repair ___________________________________ ___________________________________ ___________________________________ ___________________________________ Mismatch Repair ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-48 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ b. The insertion or deletion of a single base pair (point mutation) during DNA replication ___________________________________ ___________________________________ 1. One of two steps in replication can produce error: mistaken reading of template and/or addition of base to daughter strand by DNA Polymerase 2. Frame shift mutation is the result 3. Potential outcomes in protein expression and phenotype 4. Several DNA repair systems can remove these mutations ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 1. One of two steps in replication can produce error: mistaken reading of template and/or addition of base to daughter strand by DNA Polymerase ___________________________________ ___________________________________ ___________________________________ ___________________________________ deletion insertion ___________________________________ ___________________________________ ___________________________________ 2. Frame shift mutation is the result ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 3. Potential outcomes in protein expression and phenotype ___________________________________ ___________________________________ a. Silent mutations if out of reading frame b. Functions lost downstream ___________________________________ c. Nonsense mutations change an amino acid codon into a stop codon, nearly always leading to a nonfunctional protein ___________________________________ ___________________________________ ___________________________________ ___________________________________ 4. Several DNA repair systems can remove these mutations ___________________________________ ___________________________________ a. Mismatch repair b. Base excision repair c. Nuclear excision repair ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-48 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ c. Single-stranded and double-stranded breaks can result from reactive oxygen species activity ___________________________________ ___________________________________ 1. ROS are generated by either endogenous metabolic processes or exogenous ionizing radiation (like gamma and X-rays) ___________________________________ 2. DNA mutation is the loss or gain of significant amounts of DNA, including chromosomal deletions, additions ___________________________________ 3. Potential outcomes range from gene shuffling in or across chromosomes, gene inactivation, altered gene regulation, gene duplication ___________________________________ 4. DNA repair system that can remove these mutations ___________________________________ ___________________________________ 1. ROS are generated by either endogenous metabolic processes or exogenous ionizing radiation (like gamma and X-rays) ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 2. DNA mutation is the loss or gain of significant amounts of DNA, including chromosomal deletions, additions ___________________________________ ___________________________________ a. Insertion: addition of variable sized nucleotide fragment b. Deletion: deletion of variable sized nucleotide fragment ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ 3. Potential outcomes range from gene shuffling in or across chromosomes, gene inactivation, altered gene regulation, gene duplication ___________________________________ ___________________________________ a. Double stranded breaks can drift apart and religate with other chromosomes b. Regions of microhomology can match up and reanneal to rejoin the two broken ends. This causes hypermutation because some DNA is lost. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings ___________________________________ 4. DNA repair system that can remove these mutations ___________________________________ ___________________________________ a. Nonhomologous End-Joining b. Homologous End-Joining ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Figure 5-51 Molecular Biology of the Cell (© Garland Science 2008) ___________________________________ ___________________________________ ___________________________________ Gene conservation is the maintenance of DNA sequences across species. If the function is essential and unchanged, the structure (sequence) is unchanged. If it’s a protein function you’ve got to have, you must repair any mutations or you’re toast Fundamental activities, such as sequences for ribosome expression, are much the same in all cells ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Gene duplication and gene families define the advancing complexity of living organisms. ___________________________________ ___________________________________ 1. The idea is that during meiosis in sexually reproducing organisms, crossover mutations can form multiple copies of a gene, a chromosome or the entire genome. 2. The organism survived just fine with one copy so it only repairs damages (mutations) to one copy, leaving the other to freely mutate. 3. Once in a blue moon the mutated copy develops new, advantageous functions. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________
