Mutation

1. Mutation Timothy G. Standish, Ph. D.

2. 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 to produce new species.

3. 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 aberrations. Involve changes in large amounts of DNA. • Micromutations - Commonly called point mutations and microlesions.

4. 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

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

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

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

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

9. 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.

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

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

12. 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

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

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

15. Mutant b globin is produced Breakdown of red blood cells Accumulation of sickled cells in the spleen Red blood cells sickle Anemia Clogging of small blood vessels Pain and fever Spleen damage Tower skull Heart failure Weakness Brain damage Damage to other organs Infections especially pneumonia Impaired mental function Paralysis Rheumatism Kidney failure 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

16. The Likely and the Unlikely • Arguments about evolution frequently revolve around probability. Meaningful complexity is unlikely to result from random events. Organisms are meaningfully complex. Some claim that natural selection overcomes much of this problem as, while change (mutation) may be random, selection is not. • Science is about predicting what is likely and what is unlikely. Everyone is in agreement that the events leading to production of living organisms are unlikely.

17. In a Long Time and Big Universe • It has been argued that given massive lengths of time and a universe to work in, the unlikely becomes likely: • Given infinite time, or infinite opportunities, anything is possible. The large numbers proverbially furnished by astronomy, and the large time spans characteristic of geology, combine to turn topsy-turvy our everyday estimates of what is expected and what is miraculous. Richard Dawkins. 1989. The Blind Watchmaker: Why the evidence of evolution reveals a universe without design. W.W. Norton and Co. NY, p 139.

18. Little or Big Changes? • Not all mutations improve fitness, they may: • Improve the fitness of an organism (very unlikely) • Be neutral, having no effect on fitness • Be detrimental, decreasing an organisms fitness (most likely) • The bigger the change the more likely it is to be significantly detrimental • Darwin argued that evolution is the accumulation of many small changes that improve fitness, big changes are unlikely to result in improved fitness. • “Many large groups of facts are intelligible only on the principle that species have been evolved by very small steps.” • The Origin of Species, Chapter VII, under “Reasons for disbelieving in great and abrupt modifications”

19. Understanding Complexity Allows Better Estimates of Probability • From Darwin’s time until the molecular revolution in biology, his explanation for the origin of organisms seemed reasonable as their complexity was not understood fully. • “First simple monera are formed by spontaneous generation, and from these arise unicellular protists . . .” The Riddle of the Universe at the Close of the Nineteenth Century by Ernst Haeckel, 1900.

20. Board Trigger Staple Cheese Bait holder Hammer Spring Behe’s Insight • Michael Behe contends that when we look at the protein machines that run cells, there is a point at which no parts can be removed and still have a functioning machine. He called these machines “irreducibly complex.” • We encounter irreducibly complex devices in everyday life. Behe used a simple mousetrap is an example of an irreducibly complex device:

21. Irreducibly Complex Protein Machines • Cells are full of irreducibly complex devices - Little protein machines that will only work if all the parts (proteins) are present and arranged together correctly. • Natural selection does not provide a plausible mechanism to get from nothing to the collection of parts necessary to run a number of irreducibly complex protein machines needed to have a living cell • Evolution of these protein machines must occur in single steps, not gradually, as to be selected a protein must be functional in some way. Each protein machine is fairly complex, thus evolution in a single step seems unlikely.

22. How Can Irreducibly Complex Protein Machines be Made? • The evolution model suggests two mechanisms: • Mechanism 1 • Random events produce proteins with some minimal function • These proteins mutate and less functional variants are removed by natural selection • Some of these proteins cooperate with one another to do tasks • From this, emergent properties of the system come about, these only occur when all the components are present • Note that this mechanism only works if each protein involved has individual properties conferring added fitness

23. What If Proteins Have No Independent Function? • Evolutionary Mechanism 2: • If the function of each protein in an irreducibly complex protein machine is completely dependent on the other proteins, then the only way to select them would be if the machine was already functional. • Getting a functional machine would require that all the components come together by chance • This seems unlikely

24. The End