Genetic variation

Genetic Variation

1. GeneticVariationanditsRole in
Health/Pharmacology
BP 104 T –CMPUnit -IV 10-05-2021
Department of Pharmacology

3. Geneticvariation
•Inaverysimplelanguage,geneticvariationisameasureofthe
variationthatexistsinthegeneticmakeupofindividualswithin
population.
•Variationinallelesofgenesthatoccursbothwithinandamong
populations
GeneticDiversity
•Thelevelofbiodiversity,referstothetotalnumberofgenetic
characteristicsinthegeneticmakeupofaspecies
CrossingOver
•Theexchangeofgeneticmaterialbetweenhomologous
chromosomesthatresultsinrecombinantchromosomes

4. PhenotypicVariation
•Variation(duetounderlyingheritablegeneticvariation);a
fundamentalprerequisiteforevolutionbynaturalselection
Alleles
•Eachoftwoormorealternativeformsofagenethatariseby
mutationandarefoundatthesameplaceonachromosome.
NaturalSelection
•Theprocesswherebyorganismsbetteradaptedtotheir
environmenttendtosurviveandproducemoreoffspring.
•ThetheoryofitsactionwasfirstfullyexpoundedbyCharles
Darwin,anditisnowregardedasbethemainprocessthatbrings
aboutevolution.

5. Whatisgeneticvariation?
Polymorphisms
•Variationbetweenindividualsinapopulation(withinspecies)
Substitutions
•Fixedvariationbetweenindividualsofspecies(betweenspecies)
SpeciesA SpeciesBSpeciesC

6. Geneticvariationgenerallyreferstothedifferencesingenesbetween
individualmembersofapopulation,orthefrequencyinwhichthe
variousgenetypesareexpressed.
Geneticvariationisincrediblyimportantforthesurvivalandadaptation
ofaspecies,asithelpsintermsofnaturalselectionandevolution.
Individualsofaspecieshavesimilarcharacteristicsbuttheyarerarely
identical,thedifferencebetweenthemiscalledvariation.
Ingeneticvariation,thegenesoforganismswithinapopulation
change.
Geneallelesdeterminedistincttraitsthatcanbepassedonfromparents
tooffspring.
Genevariationisimportanttotheprocessofnaturalselection.
Thegeneticvariationsthatariseinapopulationhappenbychance,but
theprocessofnaturalselectiondoesnot.

7. Gene allelesdeterminesthedistinct traitsofan
individual
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8. SourcesofGeneticVariation
•Geneduplication,mutation,orotherprocessescanproducenewgenesand
allelesandincreasegeneticvariation.
•Newgeneticvariationcanbecreatedwithingenerationsinapopulation,so
apopulationwithrapidreproductionrateswillprobablyhavehighgenetic
variation.
•However,existinggenescanbearrangedinnewwaysfromchromosomal
crossingoverandrecombinationinsexualreproduction.
•Overall,themainsourcesofgeneticvariationaretheformationofnew
alleles,thealteringofgenenumberorposition,rapidreproduction,and
sexualreproduction.

11. DNAMutation
•Mutationsarechangestoanorganism’sDNAandareanimportant
driverofdiversityinpopulations.
•Speciesevolvebecauseoftheaccumulationofmutationsthatoccurover
time.
•Theappearanceofnewmutationsisthemostcommonwaytointroduce
novelgenotypicandphenotypicvariance.
•Somemutationsareunfavorableorharmfulandarequicklyeliminated
fromthepopulationbynaturalselection.
•Othersarebeneficialandwillspreadthroughthepopulation.
•Whetherornotamutationisbeneficialorharmfulisdeterminedby
whetherithelpsanorganismsurvivetosexualmaturityandreproduce.
•Somemutationshavenoeffectonanorganismandcanlinger,
unaffectedbynaturalselection,inthegenomewhileotherscanhavea
dramaticeffectonageneandtheresultingphenotype.

12. Mutationinagardenrose:Amutationhascausedthisgardenmossrosetoproduce
flowersofdifferentcolors.Thismutationhasintroduceanewalleleintothepopulation
thatincreasesgeneticvariationandmaybepassedonthenextgenera
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tion.

13. GeneFlow
Animportantevolutionaryforceisgeneflow:theflowofallelesin
andoutofapopulationduetothemigrationofindividualsor
gametes.
Whilesomepopulationsarefairlystable,othersexperiencemore
movementandfluctuation.
Manyplants,forexample,sendtheirpollenbywind,insects,orbirds
topollinateotherpopulationsofthesamespeciessomedistance
away.
Evenapopulationthatmayinitiallyappeartobestable,suchasa
prideoflions,canreceivenewgeneticvariationasdevelopingmales
leavetheirmotherstoformnewprideswithgenetically-unrelated
females.

14. Thisvariableflowofindividualsinandoutofthegroupnotonly
changesthegenestructureofthepopulation,butcanalsointroduce
newgeneticvariationtopopulationsindifferentgeologicallocations
andhabitats.
Maintainedgeneflowbetweentwopopulationscanalsoleadtoa
combinationofthetwogenepools,reducingthegeneticvariation
betweenthetwogroups.
Geneflowstronglyactsagainstspeciation,byrecombiningthegene
poolsofthegroups,andthus,repairingthedevelopingdifferences
ingeneticvariationthatwouldhaveledtofullspeciationand
creationofdaughterspecies.

15. Forexample,ifaspeciesofgrassgrowsonbothsidesofahighway,
pollenislikelytobetransportedfromonesidetotheotherandvice
versa.
Ifthispollenisabletofertilizetheplantwhereitendsupand
produceviableoffspring,thentheallelesinthepollenhave
effectivelylinkedthepopulationononesideofthehighwaywiththe
other.

16. Geneflow:Geneflowcanoccurwhenanindividualtravelsfromone
geographiclocationtoanother.

17. Crossingoverandsexualreproduction
•Chromosomalcrossover(orcrossingover)istheexchangeof
geneticmaterialbetween2homologouschromosomesnon-sister
chromatidsthatresultsinrecombinantchromosomesduringsexual
reproduction.
•Crossingoveraccountsforgeneticvariation,becauseduetothe
swappingofgeneticmaterialduringcrossingover,thechromatids
heldtogetherbythecentromerearenolongeridentical.
•Sexualreproductionpromotesgeneticvariationbyproducing
differentgenecombinations.
•Meiosisistheprocessbywhichsexcellsorgametesarecreated.
•Geneticvariationoccursasallelesingametesareseparatedand
randomlyuniteduponfertilization.

18. Crossingoverandrecombinationduringmeiosis
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19. NonrandomMatingandEnvironmental Variance
Populationstructurecanbealteredbynonrandommating(thepreference
ofcertainindividualsformates)aswellastheenvironment.
Nonrandommatingcanoccurwhenindividualsprefermateswith
particularsuperiorphysicalcharacteristicsorbythepreferenceof
individualstomatewithindividualssimilartothemselves.
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Assortativematinginthe
AmericanRobin
•TheAmericanRobinmaypractice
assortativematingonplumage
color,amelaninbasedtrait,and
matewithotherrobinswhohave
themostsimilarshadeofcolor.
•However,theremayalsobesome
sexualselectionformorevibrant
plumagewhichindicateshealth
andreproductiveperformance.

20. EnvironmentalVariance
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•Genesarenot theonlyplayersinvolvedindetermining population
variation.
•Phenotypes arealsoinfluencedbyother factors,such asthe
environment.
Temperature-dependent sex
determination:
•ThesexoftheAmerican
alligator(mississippiensis)is
determinedbythetemperature
atwhich theeggsare
incubated.
•Eggsincubatedat30degrees
Cproducefemales,andeggs
incubatedat33degreesC
producemales.

21. Genetic variation in the shells of Donax variabilis: An enormous amountof
phenotypicvariation existsintheshells ofDonax varabilis

22. Humangeneticvariation
•Humangeneticvariationisthegeneticdifferencesinandamong
populations.
•Theremaybemultiplevariantsofanygivengeneinthehuman
population(alleles),asituationcalledpolymorphism.
•Notwohumansaregeneticallyidentical.
•Evenmonozygotictwins(whodevelopfromonezygote)haveinfrequent
geneticdifferencesduetomutationsoccurringduringdevelopment.
•Thestudyofhumangeneticvariationhasevolutionarysignificanceand
medicalapplications.
•Itcanhelpscientistsunderstandancienthumanpopulationmigrations
aswellashowhumangroupsarebiologicallyrelatedtooneanother.

23. •Formedicine,studyofhumangeneticvariationmaybeimportant
becausesomedisease-causingallelesoccurmoreofteninpeoplefrom
specificgeographicregions.
•Newfindingsshowthateachhumanhasonaverage60newmutations
comparedtotheirparents.

24. HIVAttachment

25. Role of geneticvariationinhealth andpharmacology
•Differencesinallelefrequenciescontributetogroupdifferencesinthe
incidenceofsomemonogenicdiseasesandtheymaycontributeto
differencesintheincidenceofsomecommondiseases.
•Forthemonogenicdiseases,thefrequencyofcausativeallelesusually
correlatesbestwithancestry,whetherfamilial(forhemoglobinopathies
amongpeoplewithancestorswholivedinmalarialregions).
•Totheextentthatancestrycorrespondswithracialorethnicgroupsor
subgroups,theincidenceofmonogenicdiseasescandifferbetween
groupscategorizedbyraceorethnicity,andhealth-careprofessionals
typicallytakethesepatternsintoaccountinmakingdiagnoses.

26. •Someothervariationsontheotherhandarebeneficialtohuman,asthey
preventcertaindiseasesandincreasethechancetoadapttothe
environment.
•Forexample,mutationinCCR5genethatprotectsagainstAIDS.
•CCR5geneisabsentonthesurfaceofcellduetomutation.
•WithoutCCR5geneonthesurface,thereisnothingforHIVvirusesto
grabonandbindinto.
•ThereforethemutationonCCR5genedecreasesthechanceofan
individual’sriskwithAIDS.
•ThemutationinCCR5isalsoquitepopularincertainareas,withmore
than14%ofthepopulationcarrythemutationinEuropeandabout6-
10%inAsiaandNorthAfrica.

27. •Apartfrommutations,manygenesthatmayhaveaidedhumansin
ancienttimesplaguehumanstoday.
•Forexample,itissuspectedthatgenesthatallowhumanstomore
efficientlyprocessfoodarethosethatmakepeoplesusceptibleto
obesityanddiabetestoday.
•Asfaraspharmacologicalroleofgeneticvariationisconcerned,
Variabilityindrugefficacyandadverseeffectsareobservedinclinical
practice
•Drug-relatedgenesshowhighextentofgeneticvariabilityacrossmillions
ofindividuals

28. Cancerdrugtargetgeneshavemanygermlinefunctional-variants
•Especiallyincancertherapy,geneticvariationindrugtargetshasbeen
recognizedtoplayacrucialrolefortreatmentsuccess.
•Whilesomecancerdrugsdonotactinthetumortissue,thecancer
drug’sprimarysiteofactionusuallyisinthetumor,whosegenome
containstumorspecificsomaticvariantsaswellasasubsetofpatient-
specificgermlinevariants30.
•Informationonsomaticvariantsfromtumorsamplesisthus
increasinglyusedtoenableresearchondrugdesignandtoimplement
stratifiedorpersonalizedcancertherapy.
•SouthAsianandEuropeanancestrycomparedtothecohortofAfrican
ancestry(DRP
SAS/NFE=85%vsDRP
AFR=45%)duetofunctional
variantsinthefourtaxanetargets,TUBB1,MAP2,MAP4,andMAPT.

30. •DopamineD2(encodedbytheDRD2gene)receptorsareprimarily
expressedintheterminalregionsofdopaminergicneurons.
•StudiesinDRD2-nullmicesuggestthattheD2receptorfunctionsasan
autoreceptorondopamineneurons.
•Themostwell-establishedpolymorphismintheDRD2geneisTaq1A,a
C>Tsubstitutionlocated10kb(kilobases)3’oftheDRD2gene.
•ThisTaq1Apolymorphismisassociatedwithanincreasedriskfor
multipletypesofsubstanceabuse,includingheroinuse,cocaine
dependency,psychostimulantpolysubstanceabuseandsmoking.
•Inadditiontothedopaminergicsystem,nicotinicacetylcholinereceptors
havebeenimplicatedinnicotinerewardanddependency.
•Twonon synonymousSNPsonexon5(rs1044396/1629G>T
andrs1044397/1659G>A)ofthegeneencodingfortheα4subunitofthe
nicotinicacetylcholinereceptor(CHRNA4)wereassociated

31. IsGeneticDiversityGoodorBad?
Geneticdiversityis,ingeneral,agoodthingforapopulation,fora
simplereason:adaptationvianaturalselectiondependsonthe
existenceofvariation
Otherthingsbeingequal,apopulationpossessingagreateramountof
geneticdiversityhasagreaterprobabilityofalreadypossessing
adaptiveallelesthatmightbenecessarytomeetnewenvironmental
challenges(e.g.,pathogens).
Eventheboundariesbetweentheuseful/neutral/deleterious
categoriesareblurred.
Deleteriousanaemia-causingmutationsareknowntohavebenefitsof
malaria-resistance.

32. Neutralvariantsmaybe“useful”onesinwaiting:forexample,lactase
persistentmutantsmayhaveexistedinthehumanspeciesfor
hundredsofthousandsofyears,appearingandre-appearingby
mutation,butitiswhentheyencounteredcow’smilkandtheneedto
drinkitthattheyshiftedfrom“neutral”to“useful”.
And,evenusefulallelescanceasetobeso,e.g.,theeradicationof
swampsandmalariainGreecehasremovedthebenefitofmalaria-
resistence,andleftonlytheharmofanaemia.