©2000 Timothy G. Standish

MutationsMutations

Timothy G. Standish, Ph. D.

©2000 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 of individuals in populations to produce new species.

DNA

mRNA

Transcription

IntroductionIntroduction

The Central Dogma The Central Dogma of Molecular Biologyof Molecular Biology

Cell

Polypeptide(protein)

TranslationRibosome

©1998 Timothy G. Standish

©2000 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

aberations. Involve changes in large amounts of DNA. Micromutations - Commonly called point mutations and

microlesions.

©2000 Timothy G. Standish

MacromutationsMacromutations 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

©2000 Timothy G. Standish

Macromutation - DeletionMacromutation - Deletion

ChromosomeCentromere

A B C D E F G H

Genes

E F

A B C D G H

©2000 Timothy G. Standish

Macromutation - DuplicationMacromutation - DuplicationChromosome

Centromere

A B C D E F G H

Genes

A B C D E F E F G HE F

Duplication

©2000 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

©2000 Timothy G. Standish

Macromutation - TranslocationMacromutation - Translocation

A B E F C D G H

ChromosomeCentromere Genes

A B C D E F G H

©2000 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 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.

©2000 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.

©2000 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

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

©2000 Timothy G. Standish

S E C O N D B A S E

A

GGUGGCGGAGGG

Gly*

AGUAGCAGAAGG

Arg

G

CGUCGCCGACGG

Arg

GUGUUGCUGAUGG

C

GAUGACGAAGAG

AAUAACAAAAAG

Glu

CAUCACCAACAG

AUAUUACUAAUAG

Stop

Tyr

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

C

O Acid

GluNormal -globin

TC T

Normal -globin DNA

H2NOH

CO

H3CH

CCH

CH3

Neutral Non-polar

AG AmRNA

TC A

Mutant -globin DNA

AG UmRNA

The Sickle Cell Anemia MutationThe Sickle Cell Anemia Mutation

©2000 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

©2000 Timothy G. Standish