Mutations Timothy G. Standish, Ph. D.

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.

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

Mutation 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.

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

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

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

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

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

Micro or Point Mutations Two major types of Macromutations are recognized: 1 Frame Shift - Loss or addition of one or two nucleotides 2 Substitutions - 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.

Frame Shift Mutations 3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’ 3’AGTTCAG-TAC-TGA-AAC-CAT-CAA-CTG-ATCATC5’ 5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’ Met Thr Cys Gly Ser 5’AGUC-AUG-ACU-UUG-GUA-GUU-GAC-UAG-AAA3’ Met Thr Val 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.

Substitution Mutations Transition 3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’ 5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’ Met Thr Cys Gly Ser Pyrimidine to Pyrimidine 3’AGTTCAG-TAC-TGA-ATA-CCA-TCA-ACT-GATCATC5’ 5’AGUC-AUG-ACU-UAU-GGU-AGU-UGA-CUAGAAA3’ Met Thr Gly Ser Tyr Transversion 3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’ 5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’ Met Thr Cys Gly Ser Purine to Pyrimidine 3’AGTTCAG-TAC-TGA-AAA-CCA-TCA-ACT-GATCATC5’ 5’AGUC-AUG-ACU-UUU-GGU-AGU-UGA-CUAGAAA3’ Met Thr Gly Ser Phe

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

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

The Sickle Cell Anemia Mutation Normal b-globin DNA T C A Mutant b-globin DNA G U mRNA A G mRNA Glu Normal b-globin Val Mutant b-globin H2N OH C O H2C H CH2 Acid H2N OH C O H3C H CH CH3 Neutral Non-polar

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

The End