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UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout NAME____________________________ DATE______________________ INTRODUCTION Weoftentalkaboutskincolorasifithasjustthreevariations:peoplemayhaveblackskin,whiteskin,orbrown skin.Ifthisoversimplificationweretrue,itwouldsuggestthatskincoloristheresultofonegenewiththree alleles(variants)orevenonegenewithtwoallelesthatfollowanincompletedominancepattern.Butalook aroundtheworldshowsthatpeople’sskincomesinmanydifferentshadesfromthelightestpinktodarkest brown.Allofthisvariationcouldn’tbeexplainedbyasinglegene!Skincomesinsuchanarrayofcolorsbecause itisapolygenictrait.Polygenictraitsaredeterminedbyacombinedeffectofmorethanonegene,eachwith twoormorealleles,locatedatdifferentloci(locations)throughoutthegenome. PROCEDURE Answerthequestionsineachofthesectionsthatfollow. PARTI:Usingamodeltounderstandskincolorgenetics Scientistsoftenusemodelstoexplainorpredictphenomena.Inthissection,youwillexploreasimple mathematicalmodeltounderstandtherelationshipbetweenthenumberofgenesinvolvedinatraitandthe numberofphenotypesderivedfromthecombinationofalleles.Theassumptionsofthemodelarelistedbelow: • • • Eachgeneinvolvedinskincolorvariationhasexactlytwoalleles.Allele1resultsinpigment;Allele0 resultsinnopigment. Eachgeneaffectsskincolortothesamedegree. Eachgeneandalleleactsinanadditivefashion.Inotherwords,regardlessofthegene,thepresenceof anAllele1addsanequalamountofdarknesstotheskinphenotype. Usingthismodel,ifthereisonegeneaffectingskincolor(geneA)withtwoalleles(A1A0),there’dbefour possiblegenotypes:A1A1,A1A0,A0A1,andA0A0.Accordingtothemodel,A1A0andA0A1wouldresultinidentical phenotypes,sotherearethreepossiblephenotypes:twopigmentalleles(A1A1),onepigmentallele(A1A0and A0A1),andzeropigmentalleles(A0A0). Thetablebelowshowsallthegenotypespossiblewhenthereareone,two,orthreegenescontributingtoskin colorinourmodel.Completethetablebydeterminingthenumberofuniquephenotypesfortwogenes.Use coloredpensorpencilstocirclethegenotypesthatcorrespondtoeachuniquephenotype. www.BioInteractive.org PublishedAugust2016 Page1of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout Table1:Datafromthemodelinthreedifferentscenarios. Scenario 1:Onegene (A) 2:Twogenes (A,B) PossibleGenotypes NumberofUnique Phenotypes A1A1A1A0A0A1A0A0 3 A1A1B1B1A1A1B0B1A0A1B1B1A0A1B0B1 A1A1B1B0A1A1B0B0A0A1B1B0A0A1B0B0 A1A0B1B1A1A0B0B1A0A0B1B1A0A0B0B1 A0A0B1B0A1A0B0B0A0A0B1B0A0A0B0B0 A1A1B1B1C1C1A1A1B1B1C0C1A1A1B0B1C1C1A1A1B0B1C0C1 7 0 1 1 1 1 1 0 1 1 1 0 1 0 1 0 1 1 1 0 1 0 1 0 1 AABBCC AABBCC AABBCC AABBCC 1 1 1 1 1 0 1 1 1 1 0 0 1 1 0 1 1 0 1 1 0 1 0 0 AABBCC AABBCC AABBCC AABBCC A0A1B1B1C1C0A0A1B1B1C0C0A0A1B0B1C1C0A0A1B0B1C0C0 A1A1B1B0C1C1A1A1B1B0C0C1A1A1B0B0C1C1A1A1B0B0C0C1 A0A1B1B0C1C1A0A1B1B0C0C1A0A1B0B0C1C1A0A1B0B0C0C1 A1A1B1B0C1C0A1A1B1B0C0C0A1A1B0B0C1C0A1A1B0B0C0C0 0 1 1 0 1 0 0 1 1 0 0 0 0 1 0 0 1 0 0 1 0 0 0 0 3:Threegenes A A B B C C A A B B C C A A B B C C A A B B C C (A,B,C) A1A0B1B1C1C1A1A0B1B1C0C1A1A0B0B1C1C1A1A0B0B1C0C1 A0A0B1B1C1C1A0A0B1B1C0C1A0A0B0B1C1C1A0A0B0B1C0C1 A1A0B1B1C1C0A1A0B1B1C0C0A1A0B0B1C1C0A1A0B0B1C0C0 A0A0B1B1C1C0A0A0B1B1C0C0A0A0B0B1C1C0A0A0B0B1C0C0 A1A0B1B0C1C1A1A0B1B0C0C1A1A0B0B0C1C1A1A0B0B0C0C1 A0A0B1B0C1C1A0A0B1B0C0C1A0A0B0B0C1C1A0A0B0B0C0C1 A1A0B1B0C1C0A1A0B1B0C0C0A1A0B0B0C1C0A1A0B0B0C0C0 A0A0B1B0C1C0A0A0B1B0C0C0A0A0B0B0C1C0A0A0B0B0C0C0 1. Describetherelationshipbetweenthenumberofuniqueskincolorphenotypesgeneratedinthemodel andthenumberofgenesresponsible. www.BioInteractive.org PublishedAugust2016 Page2of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout 2. Thenumberofuniquephenotypesforthreegenesisseven.Basedonthispattern,predicthowmany distinctphenotypeswouldresultfromsixgenes,eachwithtwoalleles,accordingtothemodel. _______________________________ 3. Developamathematicalexpressiontosummarizethenumberofphenotypes(P)thatcanformfromN numberofgenes. 4. Studiesintothegeneticsofhumanskincolorhaveconcludedthatatleast34genes(SturmandDuffy 2012)haveadetectableinfluenceonskincolor,buttherearelikelymanymore.Basedonthe expressionyoudevelopedabove,andassumingthatthateachofthe34geneshavetwoalleles,how manyuniquephenotypeswouldbegenerated?Showyourwork. PARTII:Searchingforskincolorgenes Howdoweknowwhichgenesareinvolvedinskincolor?Scientistsinterestedinunderstandingskincancerand otherdiseasesassociatedwiththeskinusegenome-wideassociationstudiestolookfordifferencesamong individualsorevenpopulations.ThesestudiesinvolvecomparingDNAsequencesacrossthegenomesofalarge numberofindividualsinsearchofvariationsthatareconsistentlyassociatedwithparticularphenotypes.These variationsarecalledsingle-nucleotidepolymorphisms,orSNPs(pronounced“snips”).ASNPisavariationina singlenucleotideataparticularposition,orlocus,inthegenome.Notallsingle-nucleotidechangesareSNPs.To beclassifiedasaSNP,thechangemustbefoundinmorethan1%ofthepopulation.SNPsarealsocalled markers. OnceaSNPlocushasbeenidentified,scientistscanusethedifferencesinpopulationstodeterminethegeneor genesthatgeneratethephenotypestheysee.Usingthisapproach,manygeneshavebeenidentifiedashavinga roleindeterminingskinpigmentation.ThegenesidentifiedashavingthestrongesteffectonskincolorareTYR, TYRP1,OCA2,SLC45A2,SLC24A5,andMC1R.Amongthese,themelanocortin1receptorgene(MC1R)isthe majorcontributortonormalpigmentvariation.Todate,scientistshaveidentifiedmorethan50SNPswithinthe MC1Rgene.EachSNPrepresentsadifferentallele,sotherearemorethan50knownallelesfortheMC1Rgene. SNPscanalsobeusedtogaininsightintoanindividual’sancestry.ScientistshavecomparedSNPsamong populationsofindigenouspeople,orpeoplenativetoaparticularplace,andquantifiedhowoftenagivenallele (SNP)ofaspecificgeneispresentwithinthatpopulation.Thismeasureoftherelativefrequencyofagiven www.BioInteractive.org PublishedAugust2016 Page3of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout allele,whichiscalledallelefrequency,isoftenexpressedasapercentage.Forexample,theskincolorgene SLC24A5hasaSNPlocusknownasrs1426654.Therearetwoallelesatthislocus;anindividualcanhavean adenine(A)oraguanine(G).StudiesofindigenouspopulationshaverevealedthattheallelefrequencyoftheA alleleis100%amongEuropeans(makingthefrequencyoftheGallele0%)and2.5%amongAfricans(makingthe frequencyoftheGallele97.5%).Thus,anindividualwithtwoAalleleswouldlikelybeofEuropeanancestry, whileapersonwithanAandaGwouldlikelybeofbothEuropeanandAsianancestry.Bylookingatthe frequenciesofSNPsthroughouttheirgenome,aresearchercanmakeaninformedhypothesisaboutthe ancestryofanindividualbasedontheirDNA,asyouwillseeinPartIII. 5. Tosearchforgenesinvolvedindeterminingskincolor,scientistslookforSNPsassociatedwithdifferent skincolorphenotypes.SNPsarevariationsatasinglenucleotidewithinthegenome.Howcanachange inasinglenucleotideberesponsiblefordifferencesinskincolororthefunctionofageneingeneral? Mostphenotypictraitsvaryamongtheindividualsinapopulation.Formanytraits,anindividual’sphenotypeis determinedbyenvironmentalinfluencesaswellastheirgeneticmakeup.Ameasureofthedegreetowhich differencesinatraitaretheresultofgeneticsiscalledheritability.Heritabilityvaluesrangefrom0to1. • Aheritabilityvalueof1.0meansthat100%ofthedifferencesinatraitfoundamongindividualsina populationarecausedbygeneticdifferences. • Aheritabilityvalueof0.0meansthat100%ofthedifferencesinatraitfoundamongindividualsina populationarecausedbyenvironmentaldifferences. Foranygiventrait,heritabilityusuallyfallssomewherebetweenthesetwoextremes.Aslongasatraithas heritabilitygreaterthan0,itcanbeactedonbynaturalselection. Notethatameasureofheritabilityisonlyusefulforagivenpopulationatagiventime.Itisnotanabsoluteand unchangingnumber. Biologistsestimateheritabilityofageneinapopulationbycomparingatraitamongcloserelatives,forexample, amongparentsandchildrenorbetweentwins.Themoresimilartheexpressionofatraitisbetweenclose relatives,themorelikelyitistohaveahighheritability. 6. Whyareidenticaltwinsagoodsourceofdataforstudiesintotheheritabilityofagene? www.BioInteractive.org PublishedAugust2016 Page4of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout Inoneparticularstudy(Clarketal.1981),scientistsmeasuredskincolorusingareflectometer(adevicethat measuresreflectanceofasurface)in134pairsoftwins.Someofthetwinswereidentical,otherswerefraternal. Studyparticipantslivedinthesamegeographicareaandhadsimilarsunexposure.Thestudyconcludedthat skincolorhasaheritabilityof0.83. 7. Supportthisclaimusingevidencefromtheinformationprovided:Differencesinhumanskincolorare causedprimarilybydifferencesingenetics. 8. Weknowthatmultiplegenes(somewithmanydifferentalleles)contributetoskincolor,butgenes alonedonotaccountforthediversityofpigmentationweseeamonghumans;environmentalfactors playarole.Proposeanexplanationforhowoneofthesefactorscouldaltertheexpressionofskincolor genes. PARTIII:Puttingitalltogether Haveyoueverwonderedhowcompaniesareabletotraceyourancestrybyanalyzingasalivasample?By understandinggenetics,mathematicalmodeling,andhavingtheabilitytosequenceDNA,scientistscanuse computerstocompareanindividual’sDNAagainstadatabaseofknownallelefrequencies.First,DNAis extractedfromthesalivasampleandanalyzedusingaSNPchip,asmallpieceofsiliconglasswithshortpiecesof DNAattachedtoit.ThesepiecesofDNAarecomplementarytocertainSNPs.Whenanindividual’sDNAis exposedtotheSNPchip,onlytheDNAmoleculewhosenucleotideiscomplementary“sticks”orannealstothe chip.ThisidentifiesthenucleotideatadesignatedSNPlocus.AsingleSNPchipcanlookatseveralhundred thousandSNPsinasample.Anindividual’sSNPsarethencomparedtothedatabanktomakeapredictionabout theirancestry.Thisprocessisaccomplishedusingamathematicalmodel. Tosimplifythings,wewilllookatprofileswithonly13SNPsrelatedtoskinpigmentation,buttracingancestry requireslookingatmanySNPsthroughouttheentiregenomeandisnotspecifictojustskinpigment. Table2providestheallelefrequenciesforvariousSNPsoffivedifferentgenesinvolvedinhumanskin pigmentation.Frequencydataisprovidedforfourdifferentindigenouspopulations:European,Chinese, Japanese,andAfrican. www.BioInteractive.org PublishedAugust2016 Page5of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout Table2:Frequenciesofvariousskinpigmentationallelesindifferentnativepopulations.(DatafromStrumR.A. 2009andThe1000GenomesProjectConsortium.) Gene AlleleFrequencyinIndigenousPopulation European Chinese Japanese African 0.583 1.0 1.0 1.0 0.417 0.0 0.0 0.0 0.604 1.0 1.0 0.935 0.396 0.0 0.0 0.065 0.783 1.0 1.0 1.0 0.217 0.0 0.0 0.0 0.30 0.989 0.978 0.775 0.70 0.011 0.022 0.225 0.367 0.989 0.977 0.933 0.633 0.011 0.023 0.067 0.935 1.0 1.0 0.979 0.065 0.0 0.0 0.021 0.933 1.0 1.0 1.0 0.067 0.0 0.0 0.0 1.0 0.367 0.477 1.0 0.0 0.633 0.523 0.0 0.208 1.0 1.0 1.0 0.792 0.0 0.0 0.0 1.0 0.611 0.591 0.95 0.0 0.389 0.409 0.05 0.017 0.989 1.0 1.0 0.983 0.011 0.0 0.0 0.0 0.989 0.989 0.975 1.0 0.011 0.011 0.025 0.136 0.267 0.114 0.922 0.864 0.733 0.886 0.0778 SNPLocus Allele C rs1042602 A G rs1800422 A G rs1126809 A C rs1408799 T C rs2733832 T C rs1800401 T G rs1800407 A A rs1800414 G T rs12913832 C G rs26722 A G rs16891982 C G rs1426654 A A rs642742 G TYR TYRP1 OCA2 SLC45A2 SLC24A5 KITLG Profile1(onthenextpage)showstheallelespresentinthosefivegenesinanindividual.Usetheinformationin Table2todeterminethemostlikelypredominantancestryofthatindividual;inotherwords,isthisindividualof mostlyEuropean,Chinese,Japanese,orAfricanancestry? Toanswerthisquestion,lookateachallelepresentinthisindividualandrecorditsassociatedfrequencyineach ofthefourpopulationsfromTable2.Forexample,thisindividualhasalleleCfortheTYRSNPrs1042602. AccordingtoTable1,thefrequencyofthisalleleis0.583,whichmeansthat58.3%ofEuropeanindividualshave thisallele.Ontheotherhand,thisallele’sfrequencyis100%amongpeopleofChinese,Japanese,andAfrican ancestry. www.BioInteractive.org PublishedAugust2016 Page6of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout Afteryoufillinthefrequencies,circlethehighestone(s)foreachalleletohelpyouconcludethemostlikely predominantancestryfortheindividualprofiled.Row1hasbeencompletedforyou. Profile1 Gene AlleleFrequencyinIndigenousPopulation SNPLocus Allele European Chinese Japanese African rs1042602 C 0.583 1.0 1.0 1.0 rs1800422 G rs1126809 G rs1408799 C rs2733832 C rs1800401 C rs1800407 G rs1800414 A rs12913832 T rs26722 G rs16891982 C SLC24A5 rs1426654 G KITLG rs642742 A TYR TYRP1 OCA2 SLC45A2 9. Basedonyouranalysis,isthisindividualofmostlyEuropean,Chinese,Japanese,orAfricanancestry? Explainyouranswer. www.BioInteractive.org PublishedAugust2016 Page7of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout Repeattheprocessforthisindividual. Profile2 Gene AlleleFrequencyinIndigenousPopulation SNPLocus Allele European Chinese Japanese African rs1042602 C rs1800422 G rs1126809 G rs1408799 T rs2733832 C rs1800401 C rs1800407 G rs1800414 G rs12913832 T rs26722 A rs16891982 G SLC24A5 rs1426654 G KITLG rs642742 G TYR TYRP1 OCA2 SLC45A2 10. Whatcanyouconcludeaboutthepredominantancestryofthisindividualbasedonthedata?Explain youranswer. 11. Whentryingtodistinguishancestry,someSNPallelesaremorehelpfulthanothers.Whichismore usefulindetermininglikelyancestry:aCalleleatrs1042602oraCalleleatrs12913832?Explainyour answer. www.BioInteractive.org PublishedAugust2016 Page8of9 UNDERSTANDINGVARIATIONINHUMANSKINCOLOR StudentHandout 12. HowcouldadditionalSNPlocihelptodrawconclusionsabouttheancestryoftheindividualwithProfile 2? 13. IfyouweretodevelopaSNPchipusingfiveofthelocifromTable2,whichfivewouldyouchoose,and why? 14. Whenapersongetstheirancestryinformationbackfromthecompany,itisoftennotconclusive. Insteadofstating“youareJapanese,”onemightbetoldthattheywere23%European,65%Japanese, 6%Chinese,and6%African.Howmightanindividualcometohavesuchavariedancestry? References: ClarkP.,StarkA.E.,WalshR.J.,JardineR.,MartinN.G.“Atwinstudyofskinreflectance,”AnnalsofHuman Biology8(1981):529–541. SturmR.A.,DuffyD.L.“Humanpigmentationgenesunderenvironmentalselection,”GenomeBiology13(2012): 248.doi:10.1186/gb-2012-13-9-248. SturmR.A.“Moleculargeneticsofhumanpigmentationdiversity,”HumanMolecularGenetics18(2009):R9– R17.doi:10.1093/hmg/ddp003 The1000GenomesProjectConsortium.“Aglobalreferenceforhumangeneticvariation,”Nature526(2015): 68–74.doi:10.1038/nature15393 www.BioInteractive.org PublishedAugust2016 Page9of9
