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  • 7/27/2019 Tom Blumenthal: Down Syndrome: How Does the Extra Chromosome 21 Cause the Condition?

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    Downsyndrome:Howdoestheextra

    chromosome21causethecondi7on?

    !

    TomBlumenthalExecu0veDirectorLindaCrnicIns0tuteforDownSyndromeUniversityofColorado,[email protected]

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    Whyisthistheright7metostudy

    Downsyndrome?

    4,peoplewithDSintheU.S.alone.New

    knowledgecouldprovepowerful

    DStouchessomanydifferentissuesandcondi0ons

    Newtools

    !

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    WhatistheLindaCrnicIns7tuteDoing?

    PartnerswithGlobalDownSyndromeFounda0oninfundraising,researchini0a0vesandprograms

    !

    $1.3millioningrantsthisyear Cogni0on Synapsefunc0on Leukemia Alzheimers Sleepapnea Reac0ontoanesthesia Celldeath Howdoestheextrachromosomeaffectgeneexpression?

    Supergroup In-houseresearch

    Alzheimers Molecularbiologyonstemcells Cogni0oninDSmice

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    2013Grantrecipients

    !

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    OurBiomarkersproject

    SearchingforproteinsinindividualswithDSorthatpredictseverityofsymptoms

    Aretherecorrela0onsbetweenphenotypesandpresenceofproteins?

    Yes,thesewouldbemarkers,buttheymightalsobepoten0aldrugtargets.

    !

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    Theress7llalottofigureout,but

    Therearemorescien0stsinterestedinfiguringthisout.Theyrecognizethatthiscouldbeakeytounderstandingtheinterplayofgene0cs,theenvironment,andchance.

    Theyhavenewtoolscapableofunlockingtheanswers.

    TherearealotofpeoplewithDSwhoselivescanpoten0allybeimprovedwithadeeperunderstandingofthecondi0on.

    !

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    Promises,promises:basicscience

    canbefrustra7ng Mustdiscoverwhatisresponsibleforthevarious

    aspectsofDS

    Needtofindthepathfromheretothere Cantformulateideasforhowtosolvetheproblemun0lyouunderstandtheproblem Clearpath=0meline Whenisit0metomovetotheclinic? Ifitstoosoon,whatyoutrydoesntwork.

    !

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    Rigorousscienceisslow

    Butworththe0me!

    !

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    Downsyndrome:whatisresponsible?

    Allthegenesarenormal Thesuspects:oneextracopyofonly3-5geneson

    chromosome21(outofmorethan2,genesinthegenome)

    Mystery#1:whatcausesallofthemanyDS-associatedcondi0ons? Mystery#2:whyisDSsodifferentforsomepeoplethanthesame

    condi0onisforothers?

    !

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    Thetools:deepDNAsequencing

    CannowdeterminetheDNAsequenceofsomeonesen0regenomeforunder$5,

    Aretheregene0cdifferencesamongthosewithDSthatcanpredictsomeoneslikelihoodofgengapar0cularcondi0on,

    suchasseverecogni0veissuesorAlzheimers?

    Canwelearnhowdifferencesingeneexpressionresultinthemanycondi0onswhichindividualswithDShave?

    !

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    IPSCs,forshort Cellsorigina0ngfromhumanskin,induced

    tobecomestemcells

    Stemcellscandividealmostindefinitely Stemcellscanbemadetodifferen0atetobecomevirtually

    anytypeofcell

    AllowsustostudyhowcellsfromindividualswithDSdifferfromcellsfromtypicalpeople

    !

    Thetools:inducedpluripotent

    stemcells

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    Thetools:sensi7venewkindsofimaging

    Canlookatthebraininnewways Canlookatindividualcellsinnewways Candetectandiden0fyplaqueburdenduringlife etc.Newtechnologyisverypowerful

    !

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    Istheextrachromosomeresponsible?

    ThefewhundredgenesonChromosome21areinthreecopiesinsteadoftheusualtwo. Itcouldbetheextrachromosomeitself,butsome

    observa0onsargueagainstthatexplana0on:

    Duplica0onofChromosome21ontoadifferentchromosome:noextrachromosome,buts0llresultsinDS

    TrisomyoftheXchromosomedoesnotcauseseriousproblems

    !

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    Areextracopiesofafewgenes

    responsible? Eachgenemakesaproteinwithauniquefunc0on Some,especiallyproteinsthatcontrolotherproteins,maybe

    veryimportanttocertainprocessesalteredinDS

    !

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    APPAlzheimersPrecursorProtein

    OnChromosome21 ExtraexpressionofAPPisaclearcauseofproduc0onof

    A-betaplaqueataveryyoungage,andthenofearlyonset

    Alzheimers,inadultswithDownsyndrome

    ButitisntnecessarilytheonlythingthatcontributestoADinDS

    Aclearinstanceofasinglegenebeingtheculprit

    !

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    Isover-expressionofproteinsingeneral

    responsible? IstheextraproteinfromoverexpressedChromosome21

    overwhelmingthecellsregulatorynetworks? Produc0onoftoomuchproteincanbedealtwithunder

    normalcircumstances,butchronicinduc0onmaycause

    trouble.

    !

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    Isitreallyspecifictotrisomy21?

    Inhumans,mostaneuploidyislethal.(Eventrisomy21ojenis).

    Canmakehumancellscarryingoneextracopyofanyhumanchromosome

    Theyallhavesimilarcellularphenotypes ToomuchDNA?Toomuchprotein?

    !

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    Whatswrongwiththesecells?

    Induc0onofthestressresponse Slowercellprolifera0on Programmedcelldeath

    !

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    Mystery#2:whyarethecharacteris0csofpeoplewithDSsoincrediblyvariable?

    Ajerall,theyallhavetheverysameextra

    chromosome

    Gene0cdifferences

    Chance

    Environmentalinfluences

    !

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    Couldgene7cdifferencesberesponsible

    forthevariability?

    EveryonewithDShasthesameextrachromosome:21 Buttherearethousandsofgene0cdifferencesbetween

    anytwoindividuals(exceptiden0caltwins).Someareon

    Chromosome21.

    CanwesequencethecompletegenomesofhundredsofindividualswithDSandfindgene0cchangesthatcorrelatewithphenotypes?

    !

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    Regulatorychaos

    CausedbyimbalancebetweenproteinsonChromosome21andtheirpartnersfromotherchromosomes

    Manygenesonotherchromosomesareknowntobeexpressedattoohighortoolow

    levelsintrisomy21

    Transcrip0onfactorsareproteinsthatcontrolothergenes,some0mesquitealotofother

    genes

    !


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