第23期培訓(xùn)課件從基因組學(xué)到精準(zhǔn)醫(yī)學(xué)羽化之路

組學(xué)到精準(zhǔn)醫(yī)學(xué)的“羽 于軍

于軍BIG- NewandDistinctiveFunding

于軍BIG- 組 組科學(xué)項(xiàng)目技術(shù)突破

于軍BIG-

人類組學(xué) 結(jié)直腸癌分子分 FortheFirsttime:SequencingDeliversNewTreatmentOptionsforTwinswithRareGeneticMovementDisorder

于軍BIG- Yes,itishere—theeraof alizedmedicine—whenphysiciansusewhole-genomesequencetoimprovemedicalcare SequencingforBainbridgeetal.2011.SciTransl.Med3:87re3.

于軍BIG- 據(jù) 精準(zhǔn)醫(yī)學(xué)與大 據(jù) 科學(xué)項(xiàng)目：百（十）萬 計(jì) 態(tài)：精準(zhǔn)診斷、治療和健康據(jù) 精準(zhǔn)醫(yī)學(xué)與大 據(jù) 于軍BIG- 精準(zhǔn)醫(yī)學(xué)與大 據(jù)Life

LifeSpatiotemporal…CircadianCellSeasonal

于軍BIG- MicrobiomesMicrobiomesof第13

Falonyetal,Science,2016,Zhernakovaetal,Science,2016, – 于軍BIG- PhysicalScienceLifeS&TForMedicineandWell-beingPENCIL 于軍BIG- KeyGenomics?1975-SouthernDNAhybridizationtechnique?1977-Sanger’schain-terminationandMaxam/Gilbert’schemicalDNAsequencingmethods?1980-Automatedinsituoligonucleotidesynthesisinstrument?1985-Mullis’sdiscoveryofPCRatCetus?1992-Affymatrix(Fodor’sgroup)firstgene-chip?1995-ABI’sfirstautomatedDNAsequencer?2006-2ndgenerationDNAsequenceronmarket?2007andbeyond–singlemoleculesequencingtechniquesandnano-devices 于軍BIG- “吃遍天下”的DNA Messing&Llaca, 于軍BIG- SangerandSangerSequencingFrederickSanger(August13,1918–November19,1958hewasawardedtheNobelPrizeforhisworkinsequencingproteins.HissecondNobelPrize,awardedin1980wasdevelo thetechniquestillusedtoday-'dideoxy'or'Sanger'sequencing.

于軍BIG- ?MariaSklodowska-Curie,1903and1911,fordiscoveryofradioactivity(physics)andlaterforisolatingpureradium(chemistry)?JohnBardeen(1956and1972,forinventionofthetransistor(physics)andforcomingupwiththetheoryofsuperconductivity(physics)?LinusPauling(1954and1962,forresearchintothechemicalbondintermsofcomplexsubstances(chemistry)andforanti-nuclearactivism(peace)?FrederickSanger(1958and1980,fordiscoveringthestructureoftheinsulinmolecule(chemistry)andinventingamethodtodeterminebasesequencesinDNA(chemistry).

于軍BIG- 于軍BIG- DNA SangerCyclicarray√√√√√√√√√√PCR√√√√√√√√√√√√√√√√

于軍BIG-

于軍BIG-

于軍BIG- JimWatson改變了我的想法。認(rèn)識(shí)Jim是在我參加?類 容之后，我滿腹狐疑。Watson究竟想如何說服我相信所描述thesophisticatedpurechemisttolookatthismetabolicchartwithinitialskepticism（?位有經(jīng)驗(yàn)的專業(yè)化學(xué)家最初看到這

于軍BIG- questionariseswhetherthisfigure,byitssimplification,completemissesthepointofmetabolisminE.coli.（問題來了，這張簡(jiǎn)單的圖表能否完整概括?腸桿菌的代謝?絡(luò)TheSignificanceofaFiniteAmountofDNA（特定DNA數(shù)量的意義）”的部分他給我做出了的解答。通過對(duì)?腸桿菌組、?腸桿菌蛋白平均分?量以及典型代謝途徑步驟進(jìn)?簡(jiǎn)單的估算，Watson估算出了??估算到目前為?仍然是正確的。?此，我已經(jīng)目瞪?呆了，他用這樣?eevenacautiouschemist,whenproperlyinformed,neednotlokatabacterialcellasayx.Insteadheteasilyotanalmostjoosenthusiasm,foritisclearthath,unlikehisnineteenth-yequivalent,atlastpossessesthetoolstodescribecompleytheessentialfeaturesflife（”豁然開朗 組就是所有問題的關(guān)鍵，它是解釋?物復(fù)雜性的唯?約束?此，我就毫不猶豫地迷上 組學(xué)研究

于軍BIG- 哺乳動(dòng)物細(xì)胞中RNA是––––––調(diào)控表達(dá)和蛋白質(zhì)翻––RNA修飾組：ModomCarelletalAngewandteChemie,2012,51:RNARNAome＝（Transcriptome；代表?“由于目前各種RNA依賴特殊種類RNA擾檢測(cè)（細(xì)胞）所有RNADerks,2015,RNABiology,單細(xì)胞水平RNA直測(cè)技術(shù)決定新的人類RNA組 信息流

操作流

RNA毒

RNA是復(fù)

（Celson 物學(xué)的第一次思（TheFirstModernSynthesisofBiology）ReconcilingMendelwithDarwin(1860s

mutationand

randomdriftandofallelesofalleles

于軍BIG- FrancisCrick&FrancisCrick&JamesWatsonDNA雙螺旋模型的建立（2.28.1953）

于軍BIG- TheMolecularSynthesisofmolecularsinglegenesand

systemsCCC ctingmoleculesandtheirnetworks

variancein 于軍BIG-

于軍BIG- 表型表觀遺傳學(xué)表型表型 表型

于軍BIG- LifeIsSpatiotemporal…LifeSeasonal

Circadian

Cell

于軍BIG-

Stratification,Reconciliation&Prioritization:tesCellular-molecular

Genotypephenotypetes

Multi-trackSystemstes The5-TrackedSystemsBiology

TheInformationalTrack:GeneticsandGenomicsandComparativeGenomicsGenotype-phenotypeRelationship Lineage-specificGenomicsand

TheOperationalTheOperationalTrack-I:EpigenomicsTheOperationalTrack-II:RibogenomicsTheOperationalTrack-III:ProteomicsTheHomeostaticTrack

TheHomeostaticTrack-I:EnergyTheHomeostaticTrack-II:MatterTheHomeostaticTrack-III:Signaling

TheCompartmentalTheCompartmentalTrack-I：OriginofTheCompartmentalTrack-II:DevelopmentofdiverselifeTheCompartmentalTrack-III 分室流之四：細(xì)胞分化TheCompartmentalTrack-IV：DifferentiationandHeterogeneityof sticity sticityTrack-I:EnvironmentalInfluenceand

sticityTrack-II:The sticityofAffect,Behavior,andCognitionLietalMicrochiicaActa2016,183:941-（unnelingHaqueetalNanoToday.2013,8:56-

Carson&Wanunu,Nanotechnology.2015,26: 于軍BIG- Carson&Wanunu,Carson&Wanunu,

窗口要在1~6nt窗口要在1~6ntRNADNA:4nas4=ATGC;n=長(zhǎng)度；max7nasAAmTGCCmJRNA:4 as4=AUGC;max100步長(zhǎng)步長(zhǎng)：?jiǎn)螌邮┖穸龋?.35納米（～核苷酸長(zhǎng)度均值0.33納米）VenkatesanandBashir,2011,NatureNanotech 于軍BIG-

機(jī)通

ISFET序儀項(xiàng)目啟動(dòng) 系統(tǒng)集成技術(shù)（9項(xiàng)）波導(dǎo)和光學(xué)檢測(cè)技術(shù)（16項(xiàng)）納米 （25項(xiàng)

（13項(xiàng)

累計(jì)合作相關(guān)技 于軍BIG-

Illumina小于200bp（化學(xué)法保護(hù)PacBio低通量、低質(zhì)量（單分?的局限IonProton小于200bp低通量（信號(hào)弱、對(duì)雜質(zhì)

于軍BIG- ?

于軍BIG-

于軍BIG-

于軍BIG-

于軍BIG- Cellis3-D…

于軍BIG- WhyMultipleTracks:BalancingNature(Gene)andNurture(Environment)

于軍BIG- Navin,GenomeBiology

于軍BIG- ~6200SCA

于軍BIG-

于軍BIG- üABIü3130xL（停產(chǎn)）ü3730xL（停產(chǎn)）ü3500xLüRoche

üAG- üPstar- üGenomeSequencerFLXSystem（2015停產(chǎn)üGSJuniorSystem（2015停產(chǎn)

üBIGIS-1üBIGIS-üHiSeq1000/1500/2000（停產(chǎn)）üHiSeq2500üHiSeqXüNestSeqüThermoFisher ü5500SOLiD?System（停產(chǎn)ü5500xLSOLiD?System（停產(chǎn)

üHelicosüHelicos üPacificüRSSystem/RSüOxfordNanoporeüMinIONüIonTorrentPGM/IonProton/IonProtonüPolonatorG.007（停產(chǎn) 16letenoA

于軍BIG-

0 Ion 于軍BIG- 儀 于軍BIG- 于軍BIG- RocheGS（10臺(tái)以上量產(chǎn) 于軍元元u讀長(zhǎng)u質(zhì)量u成本u

5為什么強(qiáng)調(diào)讀長(zhǎng)：TheL-WSequencingdepthandcoverage:keyconsiderationsingenomic DavidSims,IanSudbery,NicholasE.Ilott,AndreasHeger&ChrisP.PontingNatureReviewsGenetics15,121–132(2014) 于軍

6KeyParametersforSequencing?Singlemoleculeaccuracy/precision?Allelediscriminationand ficationatsinglemoleculeresolution?Throughputpartition:96-to-384, 103-to-106,and106-?Averageaccuracy:longreadlength>1K,90%;MRL>400,99%;SRL<200,99.9%;?Timing:1–3?Cost:$100per109?Throughput:exomevs.whole