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to Fa*sbm @
B.v stud.vingthis Factsheet.voushould gain a knowledge of:
a the nature and causesof'gene mutation: Remember: - DNAatul RNAarepoltmers oJ'rtucleotidas. clesigtrutedby
o the ef'f'ectsof gene mutations; tlu,lettersoJ'tlrcirtitt'oeetk)us bases,A (acleritrc I.T ( thtnitte). LI(w'acilt.
o genemutation as a sourceof variation which mav be of selective C (c't'tosirre) and G (guattittc). Tlrc bascs are an'anged into threcs
value. rtrukirtgtrp tlrccoclorts wlic'ltare rlrcwits of tlrcgetrcticcode.Particular
coclorrsceusatlrc irtsertiottof spcciJ'icantirto aciclsittto tlrcpolryeptides
This Factsheetassumes thatthe studenthasa basicknorvledseof thc nature so tlrut iJ the coclottsare altcrecl.tlrcut'ortganino aciclnrut'ba iusertctl.
of DNA. RNA. replication.the qeneticcode and proteinsvnthcsis.These Also rententbertlrutA is conrylemetrtartto T itt DliA ard to LI itt RIVA.
werecoveredin Factsheet I - nucleicacids imd Factsheet
22.Proteinsl,nthesis G is contplenrcnter'\' to C irtbcttltRNAarrclDNA.C onryslenrcntctt'\' nteens
49. ProteinsynthesisII - mechanisms. tlrut tlteyu'ill conbine togcrlterbr htdt'ogertltorrclirtg.

The nature of gene mutation In sicklecellanaemiathemutationaflectsthe aminoacidsequence of part

A mutationis a suddeninheritablechangein the geneticmaterial.Gene of the B-globinproteinchainof thehaemoglobin(Fig 2 ). Tliis resultsin the
mutationis sometimescalledpoint mutationbecausethe mutationmay' lormation of abnormalhaemogiobin-Swhich in conditionsof low oxyuen
only involvechangeof onenucleotide(base)inthecodonsequence ol tlie tensioncausesthe red bloodcellsto collapscinto sickleshapes.
gene. The replicationof DNA and transcriptionof messengerRNA
(mRNA) is not 100% etficient with the result that q_gg.rqqnql errors Fig 2. The mutation which results in Sickle Cell Anaemia
occur.Theseerrorsma)' causemutations.The mutationma)/ be due to
the insertion(addition)or deletionof a nucleotide.the substitution
ol one Anrino acid sequence Normal
nucleotidelor anotheror inversionof two nucleotides(Fis I ). of p-globin chain
of haemoglobin: p r ol i n e g l u t a m i ca c i d g l u t a m i c acid
Fig 1. Types of point mutation. +c o d e
+c o d e
+ code
A ;
l ' "
I t :
for tor
lfor I I lI F=

CorrespondingmRNA LICA GGG UUU GGU

r l
tI a
&t r .i =

Insertion of A as lburth nucleotide

l I ffi,
w ' i
B a s e so n D N A : CTT

Altered mRNA codons L ]C A U G G GU U U GG U Amino acid sequence Sickle Cell

of p-globin chain
Deletionof the third nucleotide.T of haemoglobin: proline valine g l u t a m i ca c i d a
+codes +codes t.^,-. Lt
If o r I | :"1.'
forI =
I lfor I
Altered mRNA codons UCG GGU UUG GU Codonson mRNA: CCA GUA GAA I i

tt tl tI

Substitution of fburth nucleotidewith T.

fgf i h: E
t l I f f !

B a s e so n D N A : GGT CAT CTT .j

Altered mRNA codons UCA AGG L]UU GGL' F

Inversion of secondandthird nucleotides The substitutionof A tor T sivesvaline insteadof clutamic acid
In sickle cell anaemia,the baseT marked(in the normaldiagram)with an
Altered mRNA codons UCG AGG UUU GGU arrow is substituted with a baseA. This meansthatthe resultantcodonon
the mRNA is GUA insteadof GAA and so the aminoacidvalineis inserted
into the protein in placeof glutamicacid. This resultsin the fbrmationof
Altering the base sequencesin the codclnsof the gene may alter the haemoglobin-S.This typeof genemutationis calleda 'missense'mutation
sequencein which aminoacidsare assembledinto the polypeptidemade and only changesone amino acid in the polypeptidechain.
by that gene.The alteredpolypeptidemay then havean alteredeftect or
function which in turn may alter one or more characteristicsof the Sometimesa basealterationin a codondoesnot altertheaminoacidsequence
organism.The resultingmutationis harmful,e.g. sickle cell anaemia, of thepolypeptidemadeby thegene.This is calleda'samesense'mutation.
or it may confer evolutionary/or survival benefit e.g. in industrial It occursbecausethe geneticcode is degenerate.Degeneratemeansthat
melanism which occursin many butterllies and moths. If the mutated someamino acidscan be codedfor by severalmRNA codonswhich vary in
allele is situatedon a sexchromosomethenthe mutatedcondition will be their third base.For instance.serineis codedfor by UCU, UCC, UCA and in haemophiliaand red-greencolour blindness.In these UCG. If the mutationchangedthe third basein UCA to make UCU, the
conditionsthe mutatedalleleis on the X-chromosome. new codon will still insertserineinto the polypeptide.
GeneMutations Bio Factsbeet

A 'nonsense'mutationchangesan amino-acicl-speciliing cocloninto a Naturalselection plavsa pmt whenheterozygous sicklecell traitindividuals

codon.For instance.if UCA. whichcodestor Iive in areasu'heremalariais prevalent.The maliuiai parasitelives in normal
ma-kingUGA. thenthis is a codonwhichhaltssvnthcsisof the red cells anclf-eedson haemoglobinA. It cannotfeed successlulhon
poll,peptide. haemoglohin-S andllnds difticultt,inenteringsickleclredcells.Thussickle-
cell carriersdo not suf-fertrom malaria in areasr.l,hercn-lauvnormal peclple
A 'fiameshift' mutationis a mutationiuisingtrorntheinsertionor deletion contractmalaria.The lrequencvof the sickle-cellalleleis raisedin these
of oneor morenucieotides (otherthanin multiplesof three)thatcausesthe malarialareasabove its frequencvin malaria-lreeareas.This could be
geneto be misreaclduring translationinto the polvpeptide.In this t1,peof becausethesurvivalrateandreprocluctive rate of sickle-celltrait carriersis
mutatictn.several or all of the codonsafterthc mutationare alteredand scr higherin malarialareasthanin non-malarialareas.or becausemore normal
scveralor all of the amino acids assernblecl togetherare incorrect.The pcopledie oi'maiariathansickie-celltrait carriersdo.
resultingpol-vpepticlewill probabll,becompletel\,inactivc andbiologicalll'
useless. A clcarerexampleol'naturalselectionoperatingon a mutatedgeneis shown
in theexampleof thc pcpperecl moth,Bistottbetularia.A sin-sle-eenelocus
Causesof mutation is involveclu'ith twc.rrnainalleles.The recessiveallele(c)determinesthe
l. Spontaneousmutations resultliom errorsin thereplicationo1'DNA. ' t 1 ' ' p i c a lp' h e n o t l , ' pien t h e
d o u b l e r e c e s s i v eh o m o z y g o t e s( c c ) . T h i s
Replicationof DNA is a complicatedprocessinvolvinsDNA poll,merase phenot.""pe is light coloureclmoths with a 'peppering' of black spotson
and a larse numberof other enzvmes.Theseenzvmesmake rare mistakes thc wings andbod"v'-. Thescwerethepredominantlbrms of themoth present
and these causebasechangesin the comrrositionof DNA. in Britainin thefirst half of thc nineteenthcentur),.In 18219 a dark-coloured
varietvcallecl'carbonarill'\\'asdiscoveredin Manchester.This phenotvpe
2. Induced mutations are chan-ees in the DNA causedb-vthe efl-ects
o1 was clueto a dominantmutationinto alleleC. The 'carbonaria'mothshad
ma1,be radiationclrchemicalin natureandcauscgenes the eenotypes CC or Cc. Between1849and 189,5the 'carbonaria'variety
to mutate at rates that are much hishcr than their spontaneousl'ate. increasecl in trequencl',lbrming 98% ol the populationin the Manchester
Examplesare: area.

ionising radiations. e.g. X-rays.cosmicrays lrom space.alpha(u) This increasein trequencv\\'asassociated with the IndustrialRevolution
rays(heliumnuclei).beta(F) ra1's(electrons
or positrons)andgamma in the nineteentl')
centurvandits associated pollution.The carbonparticles
(]) rays which are electromagnetic.
Alpha. betaand sammarays are andsulphurdioxidelalling out fiom tactorychimneyskilled thelight coloured
trom radioactivesources.The1,3c1bl,directlv breakingthe genetic lichenon treetruntrisandrocks.and tormed a black.sootycoatingon these
moleculesand by breakingup watermoleculesinto reactiveionised surlhces.The 'tvpical' torms of the moth were no longercamoullagedon
lragmentsthiit can damagetlie DNA indirectiy. thesesurfacesand so werc predatedon (bv birds such as robins and
thrushes)morcthanthe 'carbonaria'fbrms which were camoufla-sed. Thus
non-ionising radiations. The commonestexample is ultra-violet the lbrms survivedand were selectedbut the 'tvnical' lorms
Iight betweenwavelengths2-50to 170 pm. This is absorbedbi,,the were eatenandbecamescarce.
nitrogenousbasesin DNA and modifiesthem in variousways. One
rnain effect is tliat thymine dimers are produced- adjacentthvmine This phenomenonbecameknown as 'industrial melanism' and occurred
b a s e si n o n e D N A s t r a n d c o u p l e t o g e t h e rr a t h e r t h a n w i t h t h e in manl' speciesof did not occur in non-
complementaryadeninesin the other strand.Thus the DNA helix industrial.non-pollutedregionsof the country - herc the 'typical' forms
developsa bulgewhere it is not coupled.Luckily thereis a li-ehtrepair survived.
systemthat in the light usesrepairenzymesto make good the DNA
damage.However,somepeoplehavea genemutationwhich causes In 1956 the Clean Air Act u'as introducedwith the result that industrial
the repair enzyme to be damaged.These people are at risk lrom pollution bv sootand sulphurdioxide was greatlycurtailed.This resulted
developingskin cancer(xerodermapigmentosum) if they sunbathe. in a return of lichen qrowth and a lightning of the surf'aces
of trees and
rocks.The 'carbonaria'tbrmsareno longercamoullagedandnow geteaten
chemicals. Mustard gas is an alkylating agentr','liichadds a methvl while the 'typical' torms arecamouflagedand havean improvedchanceof
or similaralkyl group to guanine.alteringits ability to basepair.This survival(Fig3 ).
causesthe releaseof guaninelrom DNA so thatthepositionoccupied
b1,guaninecan then be lllled by anotherbase.Many other chemicals Fig 3. Changes in the frequencies of 'typical' and 'carbonaria'
arebaseanalogueswhich havesirniiarstructures to the normalbases peppered moths in industrial areas of England
andso can becomeincorporatedinto the DNA in placeof them during
rcplication.An exampleis 5-bromouracil. Othermutagenicchemicals
includedioxin, colchicine.cafteine.somepesticides andseveraltobacco +
products. I

: 100
Gene mutation and natural selection
Many genemutationsareharmful, suchasthe humanconditionsof sickle- - ;typ\ca,l
cell anaemia,haemophilia,musculardystrophy.albinoism.thalassaemia, .=
fibrocystic diseaseof the pancreasand Huntington's chorea. Without
medical treatmentand support, the individuals suffering trom these - \i
conditionsprobably would not survive.However.many gene mutations
can be of advanta_ee.

/t \t-
--J carbonaria
For example.themutantsickle-cellallelefor haemoglobin-S is codominant .J, O
1850 1900 1950
to the normal haemoglobin-A allele. Although an individual who is ra time/years
homozygousfbr allele S (genotypeSS)will havesicklingof all his or her + f
t l
red cells, causinga severe,usually f'atal.anaemia,an individual who is industrial clean
h e t e r o z y g o u s( - e e n o t y p eS A ) w i l l p r o d u c e 5 0 c / rs i c k l e c e l l s w i t h revolution air act
haemoglobin-S and507cnorrnalcellswith haemoglobin-A. This individual
can surviveand may reproduceto passon the sicklecell trait.
GeneMutations Bio Factsbeet

Othcr examplesin natureof gcnemutationswliich haveproducedbenetlcial 2. The drawingsbelou' shou'the appeffanceof normal human red cells
variationsto the mutatedorganismilre: andredcellsfiom iurindividualsufferinetiom sicklecell anaemia.The
. the development of antibioticresistauce
in certainstrainsof bacteria: conditionis causedbv a mutantco-dominantallele.In thehomozygous
o the development ol'w,artarin(ratpoison)resistancein rats: concliticlntheallelecausessicklecell anaemiawhich hasserious.otien
. the developmentof DDT resistancein mosquitocsanclman1,other fatal.eff'cctson suf'ferers.rvhilein theheterozygousconditionit causes
speciesof inscct: sicklc cell trait which is harmlessand sivesresistlnccagainstinl-ection
. thc developmentof camoullagingshell colours anclbanding on the bv malarialparasites.The abnormalgenealsochangesthepermeabilitl,'
shells o1'the snail. CrTa(a nentorolis.This reducespredationbrr o1reclcell membranesso thatthe recicellsloseDotassium ions.
. thc dcvelopmento1 resistanceto thc myxclmatosisvirus b1,manv

Remember :- otlter getrc mutatiotts u'liclt lou nru\. be asketl obout

ittcluclc lruemopliliu. recl-E'r,ett colout'ltlintlrrcss. cr.s/ic.fibt'osis and
alplru-lattitt't'ltsirt cleJiciartct'u,lticlt results irt arr irtlrct'ited for.m oJ normalred cells sicklecells
empltvsenta (lwtg cliseasc). You ntot' be girctt data intcrprctatit)n
q t t e s li o t ts u l x t t t t r t t l t ar n t t t t a li o t t . s . (at The mutatior-l
al-lectsthe aminoacid sequenceol the p-globin chainof
haemoglobin.The nomralaminoacidsequence. togetherwith themRNA
A t'en' conunon en'ot'is to cortlfusebase tleletiott of gerte nurtatiort u'itlr anclDNA baseswhich codetbr the sequenceare shou'nbelou,.
qa t rc claI at i t tttttJ'c lt rttnl()s()nr( n t ttI tt I i rt t t.
amino acid
sequence: r,alirre/histidine /leuciuc /threonine/proline /glutamic acid /slutarric acid

Exam Hint: - ln addition to questions abaut the nature of gene mR\A

mutations and their importance as sources of variation for natural codons: GI.IA CAI.I C TI C ' ACL] CCA GAA GAA
selection to act upon, examiners often set questions on the D\A
inheritancepatterns of gene mutationsin family trees. ln answering bases: C,{I CITA C;AC; TC;A C}C;T c-l-f cTI
these it is important that the genetic diagrams are laid out in the
correct, acceptable format. Some examples are shown in the
specimen questions and mark schemes below. Questions often
involve data interpretation. (i) If the basemarkedwith an lrrow was changedto A(adenine)
what would be the eflect on the amino aciclsequenceof the
-elobin'lExplain vour answer. 4
Most genemutationsin naturewill haveonly slight eftectsor unnoticable (ii) What will be the probableellect is this changein amino acid
eff-ectsand mav also conler survivalbenefits.Polygenicsystemswith sequenceon the structureof the haemo_elobin'? Explain vour
many dill-erent
allelesprobabli'ariseasa resultof manysuchgenemutations answer. 2
over long periodsof time. Thus.thoughan individualgenemutationgives (iii)Namethis type of genemutation. I
rise to discontinuous'minor mutationsto the samegene
over thousandsof yearsmav eive rise to the continuousvariation due to (b) The sicklecell hacmoglobinis knou'nashaemo-elobin S. This type
polygeneswhich can consistof hundredsof dilferentalleles. ol haemoglobinis lbund mainly'in peoplewho live in the malarial
beltsof the world. or in their descendents.Suggestan explanation
Practice Questions whv this is so. 4
l. Cysticfibrosis(CF) is the mostcommonrecessive geneticdisorderin
the UK Caucasianpopulationu,ith an overallbirth fiequencyof about -t. Alkaptonuria is a harmless.rare autosomal-eeneticdef-ect,due to a
I in 2-500. It is characterised bv severerespiratoryproblemsand humans.The family treebelou' showsthe pedigreeof
inadequatepancreatic lunction.causedbv accumulation of stickl,mucus. a tamill'af1'ected (lndividualsarenumberedi to l4)
There is no cure at presentbut improvedtreatmentscan increasethe
lif-eexpectancy to about30 years.deathusuallybeingdueto respiratory
lailure. Males u'ith CF are usualll,'sterile. Cystic llbrosis is due to a
mutation in the gene encodingthe cystic fibrosis transmembrane
conductance regulator(CFTR). This proteinregulatesthe transportof
chloride acrosscell membranes.The mutant allele is recessiveand
heterozygotes do not exhibit symptoms. The mutant allele occursin unaf'fected f'emale
about 4c/rof the populationanclusually arisesby deletion of three
adjacentnucleotides. afl-ectedlemale

unattected male
( a ) ( i ) S u g g e s th o w t h e d e l e t i o nc o u l d o c c u r a n d i n f l u e n c er h e
effectiveness of the CFTR gene. 5 allected male
(ii) Name two other tvpesof senemutation. 2
(a) (i) Is the conditiondominantor recessive?Explain vour answer
(b) (i) Bv meansof a the probability of two
(ii) Statethe numbersof all the incliviclualsthat are certainto be
carrierparentsproducin_e a CF child. -5
(ii) What would be the expectedpercenrageincidenceof cystic heterozy-eous for this gene 3
(iii) What is the probabilitythat individual l4 is heterozy-eous
fibrosisin the population'? Explain your answer. 5
(iii) Sincecystic flbrosis is a Iethalcondition,why does its aliele this gene? I
persistin the population'l I
(b) Alkaptonuriaoccursdue to point mutationof an allele of a -eene.
Statetwo other point mutation diseasesof humans. 2
GeneMutations Bio Factsheet

Anslr,ers (a) (i) recessive:

l. (a) (i) nucleotides could be omittedcluringreplicationof DNA (in b e c a u s eo b v i o u s h e t e r o z l , g o t e s / c a r r i edr so n ' t s h o w t h e
meiosis/gametetbmration): conditior/thealleles in 6/8/l3 ntusthavecomeliom theparents
thusrnRNA cloesnot includethc omittednucleoticles (clurins n'ho do not shou'the conclition: 1
t r a n s c r i p t i oru:
thusan aminoacidu,illbeomittedlrom thepolypeptide chain: ( i i )l + l : 3+4: l0+ll: ( k r s Ic mark lbr eachincorrect)
duringtranslation: 3
thusCFTR proteinwill not work/work properll,/beineftective: (iii)2/3: I
-5 (b) sicklccell anaemia:
haemophilia/colourbl indness/albinoi
orhervalid det'ec
t: 1
(ii) substitution:
inversiorr: max2

( b ) ( i ) ( u s es u i t a b l es y m b o l s e
. . s . C f o r n o r m a la l l e i e .c l o r c v s t i c

P C c Cc:
g a m e t e sC

F CC Cc Cc cc:
t \ , / t sutferer:
normal carriers
p r o b a b i l i t yI i n 4 :

(ii) CF malesaresterileso theirgenescanbe disregarded:

4% of the populationiue carriers:
thuschancesof carrierscrossing= .04x .04= .0016or 0.16%:
(allow other \,r'avsof showing1l-sures)
probabilitl,of carier crossproducinga CF child is I in 4:
thusexpectedincidencewill be 0.\6c/r=0.04c/r:

(if sa1,,lQQ= 0.O4c/(allow I mark onl1,.unlessexplained)

2-500 s

(iii)becausen e w m u t a t i o n s( o f t h e s a m et y p e ) a r e c o n s t a n t l y
happening: 1

2. (a) (i) DNA codonwould becomeCAT:

this would tbrm GUA by transcriprior.l ro tlie MRNA:
GUA codestbr valine:
thussixthamino acid in chain/penultimate
aminoacidis chan-ued
trom elutamicacid to valine:

( i i ) w i l l a f f e c t / a l t e rt h e c r o s s - b o n d i n gi n t h e g l o b i n c h a i n /
which u'ill alter the 3-D shape/confbrmation/tertiarl' structure
of themolecule:
(iii) substitution:

( h ) malarialparasitedevelopsinsidereclcellsof humans:
cannot surviveon haemoglobinS as substrate/cannot survive in
reducedpotassiunr ion environments:
thussicklecell sutl-erersareresisrantto malarialinf'ectionbut usuallv
die from sicklecell anaemiawhen young:
sicklecell trait heterozygotesa-reresistantto malarialinl-ectionand
do not die lrom sicklecell anaemia:
thus reproducenorrnally raising incidenceof mutant genein the
populationof the malarialzone:
(probably) have a greater reproductive capacity than malarial
suf'ferers(within the population): max 4

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