©1999 Timothy G. Standish Mutation Timothy G. Standish, Ph. D.

©1999 Timothy G. Standish

MutationMutation

Timothy G. Standish, Ph. D.


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.


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.


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


Macromutation - DeletionMacromutation - DeletionChromosome

Centromere

A B C D E F G H

Genes

E F

A B C D G H


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


Macromutation - InversionMacromutation - InversionChromosome

Centromere

A B C D F E G H

Genes

A B C D E F G H

Inversion


Macromutation - TranslocationMacromutation - Translocation

A B E F C D G H

ChromosomeCentromere Genes

A B C D E F G H


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.


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.


Purine to Pyrimidine

Transversion

Pyrimidine to Pyrimidine

Transition

Substitution MutationsSubstitution Mutations

3’AGTTCAG-TAC-TGA-ATA-CCA-TCA-ACT-GATCATC5’



Met Thr Cys Gly Ser

3’AGTTCAG-TAC-TGA-AAA-CCA-TCA-ACT-GATCATC5’



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


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


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


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


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.


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.


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”


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.


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


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.


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


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


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©1999 Timothy G. Standish Mutation Timothy G. Standish, Ph. D.

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