16 Mutation

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FACULTY OF MEDICINE

InternationalProgramme

ENE

ENE

MUTATIONUTATION

M. Mansyur RomiM. Mansyur Romi

Dept. o Anatomy! Em"ryology #Dept. o Anatomy! Em"ryology #Ant$ropologyAnt$ropology

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Mutation: Mutation:

any heritable change in the nucleotideany heritable change in the nucleotidesequence of genomic DNAsequence of genomic DNA caused by areplication error or by a mutagen.

Mutagen a chemical or physical agent

that can cause a mutation in a DNA

molecule

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Type of m utations

ype of m utations

%$ere o&&ur'%$ere o&&ur'

( )ameti& or germinal mutation( )ameti& or germinal mutation

( *omati& mutation( *omati& mutation

+o, o&&ur'+o, o&&ur'

( *pontaneous mutation( *pontaneous mutation

( In-u&e- mutation( In-u&e- mutation

(( Directed (adaptive) mutationDirected (adaptive) mutation

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Germinal Mutation Germinal Mutation

O&&urs in a &ell t$at is -estine- toO&&urs in a &ell t$at is -estine- to"e&ome an egg or sperm"e&ome an egg or sperm

Is transmitte- to uture generationsIs transmitte- to uture generations

Som atic Mutation

om atic M utation

O&&urs in a "o-y &ell li/er! "oneO&&urs in a "o-y &ell li/er! "oneet&0 not an&estral to gametes.et&0 not an&estral to gametes.

Can a1e&t to p$enotype o its &arrierCan a1e&t to p$enotype o its &arrier

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Spontaneous Mutation

pontaneous Mutation

Arise as a natural errors in replication that Arise as a natural errors in replication thatevade proofreading function of the DNApolymerases that synthesize newpolynucleotide mismatches

Result from random thermal motions ofResult from random thermal motions ofatoms and molecules in and near the DNAatoms and molecules in and near the DNA

Small portion and due to foreign chemicalsSmall portion and due to foreign chemicals

or radiation that get inside cells and nearor radiation that get inside cells and nearthe DNAthe DNA

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1. Error in replication

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Mutation rate (Mutation rate ( ))

T$e re2uen&y o mutation e3presse-T$e re2uen&y o mutation e3presse-

as t$e num"er o mutation per lo&usas t$e num"er o mutation per lo&us

per gamete per generationper gamete per generation

E. coli ~E. coli ~ 454645467 ' 4 error in e/ery 467 repli&ation

+umans 8 45469 : 4546; ' -ue to a$ig$er &omple3ity o $umanrepli&ation

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Induced M utation

nduced Mutation

Follo,ing e3posure to an agent! aFollo,ing e3posure to an agent! a

mutagenmutagen! <no,n to pro-u&e! <no,n to pro-u&e

mutation a"o/e t$e rate at ,$i&$mutation a"o/e t$e rate at ,$i&$

t$ey o&&urs spontaneously.t$ey o&&urs spontaneously.Mutagens 'Mutagens '

In-ustrial &$emi&als! pesti&i-esIn-ustrial &$emi&als! pesti&i-es

*u"stan&es in ,aste lan-=lls*u"stan&es in ,aste lan-=lls Cigarette smo<e &omponents!Cigarette smo<e &omponents!

-rugs-rugs

Ra-iation rom atomi& ,arare #Ra-iation rom atomi& ,arare #

nu&lear po,er in-ustry! et&nu&lear po,er in-ustry! et&

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2. Effect of mutagen

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Directed (Adaptive)Directed (Adaptive)

MutationMutation Arises not as a result of blind variation on the Arises not as a result of blind variation on the

genetical level and consequent selection, butgenetical level and consequent selection, but

by some sort of purposeful behavior of theby some sort of purposeful behavior of the

cell as a wholecell as a whole

he cell is able to mutate favorably underhe cell is able to mutate favorably under

conditions that would select for that new traitconditions that would select for that new trait

!ontradicts the darwinian theory of evolution!ontradicts the darwinian theory of evolution

and the central dogma of molecular biologyand the central dogma of molecular biology

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Size of Material Size of Material Point mutationPoint mutation

single nu&leoti-e &$ange notsingle nu&leoti-e &$ange not

/isi"le un-er a mi&ros&ope/isi"le un-er a mi&ros&ope

>roa- mutation>roa- mutation

mi&ros&opi&ally /isi"le a"errationmi&ros&opi&ally /isi"le a"erration

me&$anism'me&$anism'-eletion-eletion

insertioninsertion

su"stitution trans/ersion! transition0 et&su"stitution trans/ersion! transition0 et&

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Point mutation common

"single site mutation# $ replace one nucleotide

with another

Divided into two categories:

1. Transitions $ are purine%to purine or pyrimidine%to%

pyrimidine changes $ A&, & A, !, or !.

2. Transversions $ are purine%to%pyrimidine or

pyrimidine%to%purine changes$ A!, A, &!,

&, ! A, !&, A or &

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In-frame mutation maintain reading

frame "codon is intact#

Out of frame/frame-shift mutation

disrupt reading frame

&oint 'utation( Sin)le nucleotide chan)e

* deletion

* insertion* 'issense

* nonsense +create a sto, codon-

* silent +no a'ino acid alteration-

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Point mutation :

Silent

Missense

Missense

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In-frame

Out of frame

Deletion mutation:

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'ffects of mutation'ffects of mutation

!hange in a morphological trait!hange in a morphological trait

Nutritional or biochemical variationNutritional or biochemical variation

!hange in behavior !hange in behavior !hanges in gene regulation!hanges in gene regulation

(ethality(ethality

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!em ical Muta"enesis

!em ical Muta"enesis

Pro?a/ine! &auses a--ition or -eletion oPro?a/ine! &auses a--ition or -eletion o

single "ases -uring synt$esis o ne, DNAsingle "ases -uring synt$esis o ne, DNA

stran-s.stran-s.

Nitrous a&i-! repla&ing amino groups ,it$Nitrous a&i-! repla&ing amino groups ,it$<eto groups. DNA treate- ,it$ nitrous<eto groups. DNA treate- ,it$ nitrous

a&i- pro-u&es errors -uring su"se2uenta&i- pro-u&es errors -uring su"se2uent

repli&ations.repli&ations.

;@"romoura&il! resem"le t$e natural;@"romoura&il! resem"le t$e natural"ases t$at t$ey &an "e mista<enly"ases t$at t$ey &an "e mista<enly

in&orporate- into DNA at t$e time oin&orporate- into DNA at t$e time o

repli&ation.repli&ation.

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Screenin" system Screenin" system

T$e Ames testT$e Ames test

to suggest ,$et$er a &ompoun- isto suggest ,$et$er a &ompoun- ismutageni& or &ar&inogeni& in animalsmutageni& or &ar&inogeni& in animals

"y -etermining ,$et$er it is"y -etermining ,$et$er it ismutageni& in "a&teria.mutageni& in "a&teria.

*ister &$romati- e3&$ange*ister &$romati- e3&$ange

ater e3posing t$e &ells in /itro toater e3posing t$e &ells in /itro to

t$e test &$emi&al! resear&$er loo< att$e test &$emi&al! resear&$er loo< atmetap$ase or &$romosomal -ee&tsmetap$ase or &$romosomal -ee&tso /arious type.o /arious type.

>lue mouse test>lue mouse test

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#adiation Muta"enesis #adiation Muta"enesis

To be mutagenic radiant energy must To be mutagenic radiant energy must

reach DNA directly or nearbyreach DNA directly or nearby

Radiation dose: the amount ofRadiation dose: the amount ofradiation absorbed by given amountradiation absorbed by given amount ofof

substancesubstance

> units : rontgent, rad, rem,> units : rontgent, rad, rem, graygray

Is there a threshold or “ safe dose!Is there a threshold or “ safe dose!

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#adiation Effects

adiation E ffects

Somatic 'ffectSomatic 'ffect %% respect to chronic or low%levelrespect to chronic or low%level

ionizing radiationionizing radiation

% possible induction of cancer % possible induction of cancer

&erminal effect&erminal effect

% possible induction of point mutation or % possible induction of point mutation or chromosomal aberrationschromosomal aberrations

% may cause harm to immediate off spring% may cause harm to immediate off spring

or later descendantsor later descendants

% 'stimation$ ) rad per generation produces% 'stimation$ ) rad per generation produces

) case of genetic disease per *+.+++ births in) case of genetic disease per *+.+++ births inthe children of those eposedthe children of those eposed

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-utation is the ey processes responsible forthe variability in the genome

-utation has various effects on genome

function

Some cells can modify their repair processes to

induce hypermutation and bacteria may be able to

carry out programmed mutations

Conclusions

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-ost mutations can be corrected by DNA repair

processes which include$

ecision procedures by removing damaged

nucleotides andmismatch repair systems for correcting

replication errors.

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Polymorphism:

Different nucleotide sequence that occurs in the populationas a whole

DeletionInsertion

Duplication

Missense

Silent

Patient (!"ontrol (-!

Patient (!"ontrol (!

Mutation

Polymorphism

Most polymorphism occurs in intronic sequence

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Biological system hierarchyBiological system hierarchy

supra individual !io-socio-culturalsupra individual !io-socio-cultural 'cosystem'cosystem environmental healthenvironmental health

SpeciesSpecies

international healthinternational healthSupranationalSupranational regional healthregional health

NationalNational public healthpublic health

!ommunity!ommunity community medicine/community medicine/

0amily0amily family medicinefamily medicine

1ndividual organism1ndividual organism personal medicinepersonal medicine

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Biological system hierarchyBiological system hierarchyinfra individual !io-physico-chemistryinfra individual !io-physico-chemistry

2rganism2rganism 3iomedical sciences3iomedical sciences$$

2rgan system2rgan system anatomy, physiology,anatomy, physiology,2rgan2rgan biochemistry,biochemistry,

issueissue histology, cell biology, histology, cell biology,

!ellular !ellular genetics,genetics,

-olecular -olecular medical chemistry,medical chemistry,

SubmolecularSubmolecular medical physics, etc. medical physics, etc.

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16 Mutation

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