1. ©2000 Timothy G. Standish Mutations Timothy G. Standish, Ph. D.

2. ©2000 Timothy G. Standish The Modern Synthesis Charles Darwin recognized that variation existed in populations and suggested natural selection as a mechanism for choosing some variants over others resulting in survival of the fittest and gradual changes in populations of organisms. Without a mechanism for generation of new variation, populations would be selected into a corner where only one variation would survive and new species could never arise. The Modern Synthesis combines the mechanism of mutation in DNA to generate variation with natural selection of individuals in populations to produce new species.

3. DNA mRNA Transcription Introduction The Central Dogma of Molecular Biology Cell Polypeptide (protein) Translation Ribosome ©1998 Timothy G. Standish

4. ©2000 Timothy G. StandishMutation Mutation = Change Biologists use the term “mutation” when talking about any change in the genetic material. Not all result in a change in phenotype. There are two major types of mutations: Macromutations - Also called macrolesions and chromosomal aberations. Involve changes in large amounts of DNA. Micromutations - Commonly called point mutations and microlesions.

5. ©2000 Timothy G. StandishMacromutations 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

6. ©2000 Timothy G. Standish Macromutation - Deletion Chromosome Centromere A B C D E F G H Genes E F A B C D G H

7. ©2000 Timothy G. Standish Macromutation - Duplication Chromosome Centromere A B C D E F G H Genes A B C D E F E F G H E F Duplication

8. ©2000 Timothy G. Standish Macromutation - Inversion Chromosome Centromere A B C D F E G H Genes A B C D E F G H Inversion

9. ©2000 Timothy G. Standish Macromutation - Translocation A B E F C D G H Chromosome Centromere Genes A B C D E F G H

10. ©2000 Timothy G. Standish Micro or Point Mutations Two major types of Macromutations 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: –Transition - Substitution of one purine for another purine, or one pyrimidine for another pyrimidine. –Transversion - Replacement of a purine with a pyrimidine or vice versa.

11. ©2000 Timothy G. Standish 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 downstream 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.

12. ©2000 Timothy G. Standish 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

13. Transitions Vs Transversions Cells have many different mechanisms for preventing mutations These mechanisms make mutations very uncommon Even when point mutations occur in the DNA, there may be no change in the protein coded for Because of the way these mechanisms work, transversions are less likely than transitions Tranversions tend to cause greater change in proteins than transitions

14. ©2000 Timothy G. Standish S E C O N D B A S E A GGU GGC GGA GGG Gly* AGU AGC AGA AGG Arg G CGU CGC CGA CGG Arg G UGU UGC UGA UGG C GAU GAC GAA GAG AAU AAC AAA AAG Glu CAU CAC CAA CAG A UAU UAC UAA UAG Stop Tyr GUU GUC GUA GUG Val AUU AUC AUA AUG start Ile CUU CUC CUA CUG Leu U UUU UUC UUA UUG Leu Phe Met/ GCU GCC GCA GCG Ala ACU ACC ACA ACG Thr CCU CCC CCA CCG Pro C UCU UCC UCA UCG Ser UCAGUCAG U UCAGUCAG UCAGUCAG UCAGUCAG Gln † His Trp Cys THIRDBASETHIRDBASE FIRSTBASEFIRSTBASE The Genetic Code Asp Lys Asn † Stop Ser Neutral Non-polar Polar Basic Acidic †Have amine groups *Listed as non-polar by some texts

15. 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

16. ©2000 Timothy G. Standish 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

17. ©2000 Timothy G. Standish