MutationsMutations

DNA

mRNA

Transcription

IntroductionIntroductionof Molecular Biologyof Molecular Biology

Cell

Polypeptide(protein)

TranslationRibosome

MutationMutation1. Mutation = Change2. Biologists use the term “mutation” when talking

about any change in the genetic material. Not all result in a change in phenotype.

3. There are two major types of mutations:4. Macromutations - Also called macrolesions and

chromosomal aberations. Involve changes in large amounts of DNA.

5. Micromutations - Commonly called point mutations and microlesions.

MacromutationsMacromutations1. 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 - Deletion

ChromosomeCentromere

A B C D E F G H

Genes

E F

A B C D G H

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

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 Mutations1. 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 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 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.

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

1. Cells have many different mechanisms for preventing mutations

2. These mechanisms make mutations very uncommon3. Even when point mutations occur in the DNA, there

may be no change in the protein coded for4. Because of the way these mechanisms work,

transversions are less likely than transitions5. Tranversions tend to cause greater change in proteins

than transitions

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

Weakness

Tower skull

Impairedmental function

InfectionsEspeciallyPneumonia

Paralysis Kidneyfailure

Rheumatism

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