1. 1 DNA Repair and Mutation

2. 2 Proofreading New DNA DNA polymerase initially makes about 1 in 10,000 base pairing errorsDNA polymerase initially makes about 1 in 10,000 base pairing errors Enzymes proofread and correct these mistakesEnzymes proofread and correct these mistakes The new error rate for DNA that has been proofread is 1 in 1 billion base pairing errorsThe new error rate for DNA that has been proofread is 1 in 1 billion base pairing errors Human’s 46 chromosome = 6 billion base pairsHuman’s 46 chromosome = 6 billion base pairs

3. 3 DNA Damage & Repair Chemicals, heat & ultraviolet radiation damage the DNA in our body cells Cells must continuously repair DAMAGED DNA Excision repair occurs when any of over 50 repair enzymes remove damaged parts of DNA As long as there is one good strand the other can repaired accurately (used as a template)

4. 4 Mutation And Repair Maintaining the integrity of genetic material is vital to the survival of organisms Somatic cell mutations are known to lead to cancers in multicelled eukaryotes Mutations in gametes are passed to offspring and most commonly will result in decreased fitness Elaborate systems for prevention and repair of mutations are known in prokaryotes and are believed to exist in eukaryotes although, in eukaryotes, these systems have not yet been well characterized

5. 5 Mutations Mutation = A random change in the genetic material of a cell Two major types of mutations: 1. Macro mutations: –Chromosome number mutations –Addition or deletion of large chunks of DNA –Movement of large chunks of DNA 2. Point mutations: –Changes in only one or two bases in a gene Not all mutations result in phenotypic change

6. 6 Macromutations Four major types of Macromutations are recognized: 1Deletions - Loss of chromosome sections 2Duplications - Duplication of chromosome sections 3Inversions - Flipping of parts of chromosomes 4Translocations - Movement of one part of a chromosome to another part

7. 7 Macromutation - Deletion Chromosome Centromere A B C D E F G H Genes E F A B C D G H

8. 8 Macromutation - Duplication A B C D E F E F G H Chromosome Centromere A B C D E F G H Genes E F Duplication

9. 9 Macromutation - Inversion Chromosome Centromere A B C D F E G H Genes A B C D E F G H Inversion

10. 10 Macromutation - Translocation A B E F C D G H Chromosome Centromere Genes A B C D E F G H

11. 11 Point Mutations Two major types of point mutations are recognized: 1Frame Shift - Loss or addition of one or two nucleotides 2Substitutions - Replacement of one nucleotide by another one. There are a number of different types

12. 12 Frame Shift Mutations 5’ AGUC-AUG-ACU-UUG-GUA-GUU-GAC-UAG-AAA 3’ 3’ AGTTCAG-TAC-TGA-AAC-CAT-CAA-CTG-ATCATC 5’ 3’ AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC 5’ 5’ AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA 3’ MetThrCys Gly Ser MetThrVal Leu Frame shift mutations tend to have a dramatic effect on proteins as all codons down stream from the mutation are changed and thus code for different amino acids. As a result of the frame shift, the length of the polypeptide may also be changed as a stop codon will probably come at a different spot than the original stop codon.

13. 13 Purine to Pyrimidine Transversion Pyrimidine to Pyrimidine Transition Substitution Mutations 3’ AGTTCAG-TAC-TGA-ATA-CCA-TCA-ACT-GATCATC 5’ 3’ AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC 5’ 5’ AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA 3’ MetThrCys Gly Ser 3’ AGTTCAG-TAC-TGA-AAA-CCA-TCA-ACT-GATCATC 5’ 3’ AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC 5’ 5’ AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA 3’ MetThrCys Gly Ser 5’ AGUC-AUG-ACU-UAU-GGU-AGU-UGA-CUAGAAA 3’ MetThr Gly Ser Tyr 5’ AGUC-AUG-ACU-UUU-GGU-AGU-UGA-CUAGAAA 3’ MetThr Gly Ser Phe

14. 14 Val Mutant  -globin H2NH2N OH C O H2CH2C H C CH 2 C O Acid Glu Normal  -globin TCT Normal  -globin DNA H2NH2N OH C O H3CH3C H C CH CH 3 Neutral Non-polar AGA mRNA TCA Mutant  -globin DNA AGU mRNA The Sickle Cell Anemia Mutation ©1998 Timothy G. Standish

15. 15 Weakness Tower skull Impaired mental function Infections Especially Pneumonia ParalysisKidney failure Rheumatism Sickle Cell Anemia: A Pleiotropic Trait Mutation of base 2 in  globin codon 6 from A to T causing a change in meaning from Glutamate to Valine Mutant  globin is produced Red blood cells sickle Heart failure Pain and Fever Brain damage Damage to other organs Spleen damage Anemia Accumulation of sickled Cells in the spleen Clogging of small Blood vessels Breakdown of Red blood cells