RamMD Winter Issue 2022: Genetics

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TableofContents

Pedigrees

SarahKalimi‘25

TaySachsDisease

AlexandraPaul‘23

DownSyndromeandCysticfibrosis

KerenTeichner‘25

JewishGeneticDiseases

RomiChaovat‘24

MaleGeneticDisorders

AvitalSarao‘24

Telomeres:Alzheimer’sDisease

GabbyBesharim‘23

KlinefelterSyndrome

RebeccaPaikin‘23

DogBreedingandGenetics

SarahSilverman‘24

Pedigrees

Aperson’spedigreeistheirgeneticancestryandisusuallyportrayedbyachart.Pedigree chartsarefamilytreesthathelponeunderstandwhattraitswerepasseddowntothem.Itportrays womenascircles,menassquares,andeverynewgenerationbyanotherrow.Eachtraithasa possibledominantandrecessiveallele.Recessiveallelesaremuchlesslikelytoberepresented thandominantallelesbecausetheyneedtwotobeshown. Ifsomeonehastworecessivealleles, thentheircircleorsquarewouldbefilledinbecausetheyhavethetrait.Iftheyhavethe recessiveallele,butitishiddenbythedominantallele,thentheyarecalledcarriers.Eventhough carriersdon’tdisplaytherecessiveallele,dependingonwhotheymatewith,theycanpassthe specificcharacteristicontotheirchildren.Onthechart,carriersarerepresentedbyhalf-filled shapes.

Humanshave23pairsofchromosomeswhichareresponsibleforholdingallofour DNA.Thetwotypesofalleles,dominantandrecessive,caneithercorrespondtoonepairofthe 22autosomalchromosomesortothepairofsexchromosomesweallhave.AfemalehastwoX chromosomesandamalehasanXandaYchromosome.Whenatraitislocatedonasex chromosome,itiscalledasex-linkedtrait.TheYchromosomeofamaleincludeslesstraits.In turn,manyofthesex-linkedtraitsformenonlyneedtohaveonealleleontheXchromosome. Thismakesitmucheasiertohavearecessivetraitbecauseitdoesn'thavetocompetewitha dominanttraittoseewhichonewillbeexpressed.

Sources:

PrinciplesofEvolution,EcologyandBehavior,BasicTransmissionGenetics.

https://oyc.yale.edu/ecology-and-evolutionary-biology/eeb-122/lecture-2

IKnowledge,PatternsofGeneticTransmission.Scott,Daryl.Lee,Brendan

https://clinicalgate.com/patterns-of-genetic-transmission/

WhatArePedigreeCharts?Drollinger,Mark.November28,2011

https://www.youtube.com/watch?v=Wuk0W10EveU

SexLinked.

https://www.genome.gov/genetics-glossary/Sex-Linked#:~:text=Sex%20linked%20is%20a%20tr ait,than%20the%20smaller%20Y%20chromosome.

TaySachsDisease

AlexandraPaul‘23

AcommonconcernwhentwoAshkenaziJewsgetengagedisiftheyhavebeentestedfor TaySachs.Why’sthat?TaySachsisarare,genetically inheriteddiseasethatpreventsthebody’s nervesfromworkingproperlyandinmostcasesleadstodeath.ThecauseofTaySachsisthe absenceofanenzymecalledhexosaminidase-A(Hex-A), whichaidsinbreakingdownfatty substances.Asthediseasedevelops,theimpactedpatient(usuallyaninfant)oftenlosesmuscle control,vision,andexperiencesparalysis.TaySachsalmostalwaysleadstodevastatingfatality. Approximately1in27JewsintheUnitedStatesisaTaySachsgenecarrier.Before genetictestingwasavailable,itwasrelativelyunknownwhetheraperson(oftenanAshkenazi Jew)wasacarrierornot.Adangerousguessinggamewasbeingplayed,especiallyina communitywhereintermarriageisconsideredunreligious.Thankfully,genetictestingisnowa usefulamenitythatcanrevealtopeopletheirstatusaspossibleTaySachsgenecarriers.A simplebloodtestcanmeasuretheamountofHex-Ainaperson’sblood,quicklyalertingthem whetherornottheypossessthegene.

AmajorquestionthatfollowseverypositivetestresultfortheTaySachsgene:what next?Amazinglyenough,thereareoptionsavailablefortwoTaySachscarriersorcarrierswith anyharmfulinheritedgene,thatcanallowthemtohaveaviableinfant:assistedreproductive therapyandgenetherapy Thisnewtherapyisusedinconcurrencewithin-vitrofertilizationand makesitpossibleforthesefutureparentstogivebirthtohealthybabies.Thewaythetherapy worksisthatembryoscreatedin-vitro(outsideofthebody)aretestedforgeneticmutations beforebeingchosentobeimplantedintothemother.Thisresultsinonlyviableembryosbeing selected,andeventually,healthierchildren.

Sources:

https://www.mayoclinic.org/diseases-conditions/tay-sachs-disease/symptoms-causes/syc-203781

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DownSyndromeandCysticfibrosis

Today,thereisanabundanceofpeoplelivingwithgeneticdisorders,yetmanyofusdon’t know what a genetic disorder is. The National Human Genome Research institute defines a genetic disorder as“AdiseasecausedinwholeorinpartbyachangeintheDNAsequenceaway from the normal sequence.” What this means is that genetic disorders are caused either bygene mutations and or by an issue with the chromosomes. While there are many more genetic disorders, this article will focus on two of the most common geneticdisorders:Downsyndrome andCysticfibrosis.

Downsyndromeoccursinoneoutofevery700babies.Whilesymptomsandseverity vary,itgenerallycausesphysicaldifferencessuchasaflattenedface,almondshapedeyesand smallhandsandfeet.Inaddition,itoftencausesintellectualdifferences.Forexample,people withDownsyndromeareoftenslowertospeakandtypicallyhavealowerIQ.

Currently,thereare30,000peoplelivingwithCysticFibrosisintheUnitedStates. In Cysticfibrosispatients,mucus,whichisgenerallythinandslippery,isthickanddoesnotmove throughthebodyproperly Thiscancauseinfections,breathingdifficultiesandintestinal blockage.Cysticfibrosisresultsinseveredamagetothelungs,digestivesystemandother organs.

Inonlyasmallpercentageofcases,Downsyndromeisinheritedfromaparent.Inmost instances,Downsyndromeresultsfromabnormalcelldivisions;thereisacomplicationduring celldivisionthatcausesachildtobebornwithanextrachromosome.Incontrast,Cysticfibrosis iscausedbyageneticmutation.Achildmustreceiveonecopyofthegenefromeachparentto inheritCysticfibrosis.

Symptomsofbothdisordersbecomeapparentatdifferentstages. AchildwithDown syndromewouldbediagnosedatbirthwiththegeneticdisorder.Ontheotherhand,anindividual cangomanyyearsbeforeofficiallybeingdiagnosedwithCysticfibrosis.Thisispartlybecause peoplewithCysticfibrosisdonothaveapparentphysicalorintellectualdifferenceslikethose withDownsyndrome.Inrareinstances,peoplehavebeendiagnosedwithCysticfibrosisaslate asage70.LatediagnosisofCysticfibrosisisbecomingrarerasitisnowpartofanewborn screenroutine.

Oneinterestingobservationisthatabnormalperspirationisacommoncharacteristicof bothdisorders.PeoplewithDownsyndromeoftensweatmuchlessthantheaverageperson. ThosewithCysticfibrosissweatmoreoftenandtheirsweathasamuchhighersaltcontent. WhileDownsyndromeandCysticfibrosisarebothgeneticdisorders,theyarevery differentfromeachother Thedisorders'causes,diagnoses,andsymptomsareallvastlydifferent. Justlikenotwovirusesarethesame,notwogeneticdisordersarethesame.Suchvast differencesbetweenthesegeneticdisordersshowjusthowcomplexwereallyare.

Sources:

The 7 most common genetic disorders - sonas home health care.Sonas.(2021,January25). RetrievedNovember12,2021,from https://www.sonashomehealth.com/most-common-genetic-disorders/.

About cystic fibrosis.AboutCysticFibrosis|Cystic FibrosisFoundation.(n.d.).Retrieved November12,2021,fromhttps://www.cff.org/intro-cf/about-cystic-fibrosis.

AliceMelão,M.S.(2018,February2). Sweat test is reliable for CF diagnosis in down syndrome patients... CysticFibrosisNewsToday.Retrieved November12,2021,from

https://cysticfibrosisnewstoday.com/2018/02/02/cystic-fibrosis-sweat-test-is-reliable-downsyndrome-patients/#:~:text=After%20evaluating%20the%20sweat%20secretion,in%20the %20Down%20syndrome%20group.

CentersforDiseaseControlandPrevention.(2021,April6). Facts about down syndrome. CentersforDiseaseControlandPrevention.RetrievedNovember12,2021,from https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html.

Cystic fibrosis.NORD(NationalOrganizationforRareDisorders).(2020,December9). RetrievedNovember12,2021,fromhttps://rarediseases.org/rare-diseases/cystic-fibrosis/. Genetic disorders.Genome.gov.(2018,May18).RetrievedNovember12,2021,from https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders.

Hamburg,S.,Lowe,B.,Startin,C.M.,Padilla,C.,Coppus,A.,Silverman,W.,Fortea,J., Zaman,S.,Head,E.,Handen,B.L.,Lott,I.,Song,W.,&Strydom,A.(2019,August30).

Assessing general cognitive and adaptive abilities in adults with Down Syndrome: A systematic review.JournalofNeurodevelopmentalDisorders.RetrievedNovember12, 2021,from

https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-019-9279-8.

MayoFoundationforMedicalEducationandResearch.(2020,March14). Cystic fibrosis. MayoClinic.RetrievedNovember12,2021,from

https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-2035 3700#:~:text=Cystic%20fibrosis%20(CF)%20is%20an,are%20normally%20thin%20and% 20slippery.

JewishGeneticDiseases

EveryfamilyhascertaingenetictraitsthatarepresentintheirDNA.Whensomeonegoes tothedoctor,theyusuallyaskifyourfamilyhasanyhistoryofanumberofgeneticdiseases,one commononeaskedaboutisdiabetes.Thesamecouldbesaidaboutethnicgroupssuchas AshkenaziJews.Althoughitisrareforsomeonetodevelopadisease,itisestimatedthatevery1 in5JewscarryatleastoneofthemainrecessiveJewishgeneticdisorders.Thismeansthatiftwo peoplewithintheJewishcommunityhaveababyandiftheybothhavearecessivegenefora geneticdisorderoroneofthemhasthediseasethemselves,itishighlylikelytheiroffspring coulddevelopthedisease.

ThemostcommonAshkenazigeneticdiseaseisGaucherdisease.Oneineveryten AshkenaziJewsinheritedthedisease-causingmutatedgeneforit.Havingthisdiseasemeans yourbodydoesn'tproduceenoughGCase,anenzymethatbreaksdownfattychemicalsinthe body.Lucky,althoughmanyJewscarrythemutatedgeneandhencearemorelikelyto geneticallypassdownGaucher,AshkenaziJewsaremostlikelytohavethetreatabletype,type 1.Thistypeincludesboneandorganproblems,butexcludesbraindevelopmentproblemsdueto mutationN370S.Thismutationprotectsagainstneurologicalproblemswithintype1.

AlthoughGaucherdiseaseisthemostapparentinthegeneticsofAshkenaziJews,there arestillothersthatareimpactfulsuchasCysticFibrosis,withoneinevery24Jewsbeinga carrier,andTaySachsdiseasewithoneinevery27.Noonecanknowforcertainwhythese geneticdiseasesareinJewishDNAbutitisnotuncommonforethnicgroupstohavegenetic diseases.ItisthoughttobeanissuewithintheAshkenaziJewishcommunityformultiple reasons.OnebeingthatsinceJewishcommunitieswereusuallyisolatedtothesamegroupand innercircle,therewasalotofintermarrage.Thisledtoaspreadingeneticmutationsthatstayed apparenteventothisdaywithintheJewishcommunity.

Sources:

https://www.gaucherdisease.org/blog/5-common-ashkenazi-genetic-diseases/ https://www.jnetics.org/jewish_genetic_disorders/

MaleGeneticDisorders

AvitalSarao‘24

Geneticdisordersrangefromsicklecellanemia,cysticfibrosis,todownsyndrome. Amongthose,therearealsoseveralgeneticdisordersthatonlythemalesexcandevelopandor inherit.TheseincludeKlinefeltersyndromeandJacob’ssyndrome.Bothofwhichcanonlybe diagnosedinmales.

Klinefeltersyndromeincludessymptomssuchaslonglegs,delayedorincomplete puberty,weakbones,andlowenergylevels.Thisdiseaseisneverpresentinfemalesbecause KlinefeltersyndromeoccurswhenapersonhastwoXchromosomesandaYchromosomeanda personwithaYchromosomeisalwaysmale.InsteadoftheusualXYchromosomesthatare foundinthemaleDNA,individualswithKlinefeltersyndromehavetwoXchromosomesanda Ychromosome.TheextracopyoftheXchromosomecausesextracopiesofgenesthatinterfere withthedevelopmentofthetesticles,leadingtoadecreaseintestosteroneproduction.A decreasedtestosteroneproductionisthesourceofallthesymptomsthatappearwithKlinefelter syndrome.Althoughthisdiseasecancauseseveraldevelopmentalissues,somecaseshavemild symptomsthatmayevengounnoticed.

AlongwithKlinefeltersyndrome,Jacob’ssyndromeisalsoageneticdisorderthatisonly foundinmales.Jacob’ssyndrome,alsoknownasXYYsyndrome,iscausedbythepresenceof anextraYchromosome.ThecreationoftheextraYchromosometakesplaceduringanerrorin thecelldivisionofthespermbeforeconception.Inaddition,itisalsopossibleforamaletohave a“mosaic”formofXYYsyndrome.ThisconsistsofsomecellshavinganextraYchromosome, butnotall.Symptomsmayincludetallerthanaverageheight,widelyspacedeyesalsoreferredto ashypertelorism,lowmuscletone,andmuscleweakness.BecauseofthepresenceofanextraY chromosome,XYYsyndromeisneverpresentinfemales.Asofrightnow,thereisnocureor treatmentforthediseaseitself.However,therearetreatmentsthatcanmakethesymptomseasier tomanage,suchascounselingandregulardoctorvisits.

Sources:

https://medlineplus.gov/genetics/condition/klinefelter-syndrome/

https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-203

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Klinefeltersyndrome-NHShttps://www.nhs.uk›conditions›klinefelters-syndrome

https://rarediseases.org/rare-diseases/xyy-syndrome/

https://kidshealth.org/en/parents/xyy-syndrome.html

Telomeres:Alzheimer’sDisease

Telomeresarechromatinstructureslocatedattheendsofchromosomesthatprotectthem duringcelldivision.Theyforma“cap”topreventchromosomesfromstickingtoeachother. Theyalsohelporganizeourchromosomesinthenucleusofourcells.Telomeresaremadeof repetitivesequencesofnon-codingDNAthatbecomeshortereachtimeacelldivides(theycan shortenfromarangeof25-200bases).Eventually,telomeresbecomesoshortthatcellscanno longerdivide.Withouttelomeres,everytimeacelldivides,criticalDNAwouldbelost,which wouldleadeventuallytothelossofgenes.

Telomerelengthispreservedduetoanenzyme,knownastelomerase,thatisfoundin verylowconcentrationsinoursomaticcells.Inmostcells,telomerelengthdecreaseswithage andisanindicationofcelldeterioration,orsenescence(inactivity).However,ingermlinecells (eggandsperm)andstemcells,telomeresmaintaintheirlengthafterDNAreplication,allowing thesecellstoavoidsignsofaging.Thisisalsotrueincancercells.Telomerase,whichisfoundin highconcentrationincancercells,allowsthesecellstoreproduceindefinitely

Iftelomerasecouldbeinactivatedincancercells,theendlessreplicationofcancercells couldbestopped.Studiesintodrugsthatcouldinhibittelomeraseactivityareongoingand inconclusive.

ArecentprospectivestudyinCopenhagen(MadridAS;RasmussenKL;RodeLetal, 2020)foundthatshorttelomerelengthwasassociatedwithariskofAlzheimer’sdisease.Further studyisneededtodeterminewhethershortenedtelomeresareabiomarkerthatcanbeusedto diagnoseAlzheimer’sdisease,orarebetterunderstoodasanelementinthediseaseprogression, appearingalongwithAlzheimer’sdiseaseduetoageandanadverselifestyle.Aprospective studyonshorttelomeresandAlzheimer’sdisease,whichstudied67,000individualsforupto21 years,suggestedthat“telomerebiologymighthaveacausalroleinthedevelopmentof Alzheimer’sdisease.”Danishresearcherssuggestedthatimmunesystemcellsinthecentral nervoussystemandinthebloodcouldbeaffectedbychangesintelomerebiology,coupledwith areducedcapacityfortissuerepair.TheRotterdamstudyfoundthatbothshortandlongtelomere lengthwasassociatedwithanincreasedriskofAlzheimer’sdisease.

Sources:

MadridAS,RasussenKL,RodeL,Frikke-SchmidtR,NordestgaardBG,BojesenSE. ObservationalandgeneticstudiesofshorttelomeresandAlzheimer’sdiseasein67,000and 152,000individuals:aMendelianrandomizationstudy European Journal of Epidemiology 2020:35(2)147

ForeroDA,González-GiraldoY,López-QuinteroC,Castro-VegaLJ,BarretoGE,PerryG. Meta-analysisofTelomereLengthinAlzheimer'sDisease. J Gerontol A Biol Sci Med Sci 2016;71(8):1069-1073.doi:10.1093/gerona/glw053

FaniL,HilalS,SedaghatS,etal.TelomereLengthandtheRiskofAlzheimer'sDisease:The RotterdamStudy J Alzheimers Dis.2020;73(2):707-714.doi:10.3233/JAD-19075

KlinefelterSyndrome

Klinefeltersyndromeisageneticconditionthatoccursinmalesbornwithanadditional copyoftheXchromosome.Majorityofcasesoftengoundiagnoseduntiladulthood.Thereasons forthisarechildrenandteenspresentmildsigns,ifany,andsymptomsandsignsmayvary. Whilethesyndromeisgenetic,itisnotaconditionthatcanbeinherited.Itonlyoccursas aresultofrandomerroratbirth.MenaregeneralybornwithbothanXandaYsettodetermine theirsex(XY). MenwithKlinefelterSyndromeareusuallybornwithanadditionalX chromosome(XXY).Sometimestheerroroccursinfewercellsresultinginlessersymptoms.In rarecasestheremaybemorethanoneadditionalcopyoftheXchromosomewhichresultsina severeformofthesyndrome.

GeneralsignsofKlinefelterSyndromemaystunttesticulargrowth,andinturncan possiblyleadtolowertestosteroneproduction.Thesyndromemaycauseenlargedbreasttissue, reducedfacialandbodyhairaswellasreducedmusclemass.Menaffectedwiththesyndrome oftenproducelittletonospermandareunlikelytofatherchildrenwithoutthehelpof reproductiveprocedures.

Whilechildrenandteenagersrarelyreceiveadiagnosis,therearecaseswherethe symptomsareclear.Babiesmayhaveweakmuscles,speechdelay,andslowermotor development.Whileteenagersmaydisplayacademicissuesinmath,reading,writingorspelling, aswellasatendencytobeshy,theycanalsoexperiencedifficultiesinexpressingemotionsand thoughts.Teensmayalsostandtallerthantheaverageboy,aswellaspossessinglongerlegs, withwidehipsandshortertorsos.Attheadultage,thesymtomsmanymatureintolowsex drives,weakerbones,andpossiblyanincreaseinbellyfat.

Likeanycondition,KlinefelterSyndromemayhavecomplications.Itcancreaseriskof anxiety,depression,socialissues,heartandbloodvesseldisease,breastcancer,lungdisease, autoimmunedisorders,autism,oralcomplicationsandmetabolicsyndrome.Alargeamountof complicationscausedbythesyndromearecorrelatedtolowlevelsoftestosterone.Toreducethe riskofcertainhealthproblems,testosteronereplacementtherapycanbeimplemented.Itismost successfulwhenbegunatthebeginningofpuberty.

Sources:

https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-203

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DogBreedingandGenetics

Poodles,Chihuahuas,andJackRusselTerriersaretheworld’smostpopulardogbreeds. Whenadogmisbehaves,wealwayssayit’sbecausetheydescendedfromwolves.Theirnatureis toberoughandwild,andtheyarerevertingtotheirways.Butwhatdoesthatevenmean?And whyaretheresomanyvariationsofdogsinthefirstplace?

Allanimalsalivetodayaredescendantsofothercreatures.Thestoryofevolutionisa largeandcomplextreewithalternatebranchesdependentonlineage.3.5billionyearsago,our firstancientancestorwasborn.ScientistssuspecttheyweresimpleProkaryotesthatfedon carboncompoundsthatwereaccumulatinginEarth’searlyoceans.Overbillionsofyearsand persistingenvironmentalfactors,thesecreaturesbecamedistinct.Inscience,therearedifferent levelsofclassificationbasedonancestors.Graywolvesanddogsareinthesamegenus,Canis, andspeciesC.lupus.Adogisjustadomesticatedgraywolfwhoovertime,adaptedtraits becauseofhumaninterference.Dogswerethefirstanimalsdomesticatedandmanyscholars believethatthishappenedbecauseofhungrywolvesroamingandpickingoffscrapsarounda humansettlement.Overtime,ourancientancestorsbuiltarelationshipwiththesewolves. The differenceincolorandsizeofthesewolvesweremostlybecauseofgeneticandenvironmental factors.Whenananimalistamed,differentgenetictraitsareexpressed.Thephenotypeofawolf differsvastlyfromthatofadog,anddifferentiallyexpressedgenetictraitsareneededforeach. Howdiddomesticationleadtothestrangenessofabulldog?Thesedogshaveaseverely compromisedrespiratorysystemandoftensufferfromnarrownostrilsandwindpipes.The leadingcauseofdeathforthemisrespiratoryissues.Withoutveterinaryintervention,theywould diebeforetheageoffive.NaturedidnotcreatetheBulldog,humansdid.Intheearlydaysof domestication,humanswouldbreeddogsforspecific/functionalpurposes.Iftheyneededa huntingdog,mixaNewfoundlandandwetdogtomakeaLabradorRetriever.IntheVictorian era,theBritishelitedecideditwouldbe“fun”tobreeddogsandseewhatcrazyconcoctionsthey couldmake.Theydevelopedcompetitivedogshowsandproducedthedogsthatweknowtoday. Manydogshowsarestilloperatingtoday,themostpopularbeingTheWestminsterKennelClub DogShow.Whattheseearlybreedersdidnotsee,orrathercaretosee,washowthis interbreedingaffectedtheanimal’shealthandwell-being.Manywereinbredandwhensimilar geneticsarecrossed,healthissuesmayarise.Thisisthesamewaysiblingsshouldnothave childrentogether.Ifageneticdiseaseisprevalentasarecessivegene,ifbothhavethatgiven gene,healthissuesaremorecommon.Manyveterinarianssaythatmixeddogsarehealthierand abetteroptionforownersbecausetheyhavealargergeneticpool.

Formanypeople,dogsareforonepurposeandonepurposeonly,tolookadorableandbe playthings.Butthehealthissuesthatmayarisearedrasticandlife-damaging.Treatinga bulldog’srespiratoryissuescancosttensofthousandsofdollars.Itisnecessarytodiversifythe genepoolsothatdogsdon’tcontinuegettingsickerandsickerandhavetobeputdownat youngerages.Beautyandprestigeareimportant,butnotwhenitdamagesananimal’slife.

Sources:

Marshall,Michael.“HumansMayHaveDomesticatedDogsbyAccidentbySharingExcessMeat.” New Scientist,7Jan.2021,

https://wwwnewscientistcom/article/2264329-humans-may-have-domesticated-dogs-by-accident-b y-sharing-excess-meat/.

Watson,Joey “TheCuriousOriginsofModernDogBreeds” ABC News,ABCNews,18Apr 2019,

https://www.abc.net.au/news/2019-04-18/history-of-modern-dog-breeds-invented-in-victorian-era/1 1019320

“WhatAretheEffectsofInbreeding?” BBC Earth, https://www.bbcearth.com/news/what-are-the-effects-of-inbreeding.

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