©1999 Timothy G. Standish
MutationMutation
Timothy G. Standish, Ph. D.
©1999 Timothy G. Standish
The Modern SynthesisThe 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.
©1999 Timothy G. Standish
MutationMutation 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.
©1999 Timothy G. Standish
MacromutationsMacromutations Four major types of Macromutations are
recognized:1 Deletions - Loss of chromosome sections2 Duplications - Duplication of chromosome
sections3 Inversions - Flipping of parts of chromosomes4 Translocations - Movement of one part of a
chromosome to another part
©1999 Timothy G. Standish
Macromutation - DeletionMacromutation - DeletionChromosome
Centromere
A B C D E F G H
Genes
E F
A B C D G H
©1999 Timothy G. Standish
Macromutation - DuplicationMacromutation - Duplication
A B C D E F E F G H
ChromosomeCentromere
A B C D E F G H
Genes
E F
Duplication
©1999 Timothy G. Standish
Macromutation - InversionMacromutation - InversionChromosome
Centromere
A B C D F E G H
Genes
A B C D E F G H
Inversion
©1999 Timothy G. Standish
Macromutation - TranslocationMacromutation - Translocation
A B E F C D G H
ChromosomeCentromere Genes
A B C D E F G H
©1999 Timothy G. Standish
Micro or Point MutationsMicro or Point Mutations Two major types of Macromutations are recognized:1 Frame Shift - Loss or addition of one or two
nucleotides2 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.
©1999 Timothy G. Standish
Frame Shift MutationsFrame Shift Mutations
5’AGUC-AUG-ACU-UUG-GUA-GUU-GAC-UAG-AAA3’
3’AGTTCAG-TAC-TGA-AAC-CAT-CAA-CTG-ATCATC5’
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Met Thr Cys Gly Ser
Met Thr ValVal ValLeu
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.
©1999 Timothy G. Standish
Purine to Pyrimidine
Transversion
Pyrimidine to Pyrimidine
Transition
Substitution MutationsSubstitution Mutations
3’AGTTCAG-TAC-TGA-ATA-CCA-TCA-ACT-GATCATC5’
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Met Thr Cys Gly Ser
3’AGTTCAG-TAC-TGA-AAA-CCA-TCA-ACT-GATCATC5’
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Met Thr Cys Gly Ser
5’AGUC-AUG-ACU-UAU-GGU-AGU-UGA-CUAGAAA3’
Met Thr Gly SerTyr
5’AGUC-AUG-ACU-UUU-GGU-AGU-UGA-CUAGAAA3’
Met Thr Gly SerPhe
©1999 Timothy G. Standish
Transitions Vs TransversionsTransitions 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
©1999 Timothy G. Standish
S E C O N D B A S E
AGGUGGCGGAGGG
Gly*
AGUAGCAGAAGG
Arg
G
CGUCGCCGACGG
Arg
GUGUUGCUGAUGG
C
GAUGACGAAGAG
AAUAACAAAAAG
Glu
CAUCACCAACAG
AUAUUACUAAUAG
StopTyr
GUUGUCGUAGUG
Val
AUUAUCAUAAUG start
Ile
CUUCUCCUACUG
Leu
UUUUUUCUUAUUG
Leu
Phe
Met/
GCUGCCGCAGCG
Ala
ACUACCACAACG
Thr
CCUCCCCCACCG
Pro
CUCUUCCUCAUCG
Ser
UCAG
U
UCAG
UCAG
UCAG
Gln†His
Trp
Cys THIRD
BASE
FIRST
BASE
The Genetic CodeThe Genetic Code
Asp
Lys
Asn†
Stop
Ser
Neutral Non-polarPolarBasicAcidic
†Have aminegroups
*Listed as non-polar bysome texts
ValMutant -globin
H2NOH
OH
CO
H2CH
CCH2
CO Acid
GluNormal -globin
TC TNormal -globin DNA
H2NOH
CO
H3CH
CCH
CH3
Neutral Non-polar
AG AmRNA
TC AMutant -globin DNA
AG UmRNA
The Sickle Cell Anemia MutationThe Sickle Cell Anemia Mutation
©1999 Timothy G. Standish
Weakness
Tower skull
Impairedmental function
Infectionsespecially
pneumoniaParalysis Kidney
failureRheumatism
Sickle Cell Anemia:Sickle Cell Anemia:A Pleiotropic TraitA Pleiotropic TraitMutation 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 andfever
Braindamage
Damage to other organs
Spleen damage
Anemia
Accumulation of sickledcells in the spleen
Clogging of smallblood vessels
Breakdown ofred blood cells
©1999 Timothy G. Standish
The Likely and the UnlikelyThe 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.
©1999 Timothy G. Standish
In a Long Time In a Long Time and Big Universeand 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.
©1999 Timothy G. Standish
Little or Big Changes?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”
©1999 Timothy G. Standish
Understanding Complexity Understanding Complexity Allows Better Estimates of Allows Better Estimates of
ProbabilityProbability 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.
©1999 Timothy G. Standish
Board
Behe’s InsightBehe’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:
SpringHammer
TriggerStaple Cheese
Bait holder
©1999 Timothy G. Standish
Irreducibly Complex Protein Irreducibly Complex Protein MachinesMachines
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.
©1999 Timothy G. Standish
How Can Irreducibly Complex How Can Irreducibly Complex Protein Machines be Made?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
©1999 Timothy G. Standish
What If Proteins Have No What If Proteins Have No Independent Function?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
©1999 Timothy G. Standish