精准医学：基因组生物学研究的新境界

精准医学:

基因组生物学研究的新境界2024/1/41为什么启动大规模基因组计划?“Wehavetwooptions:eithertrytodiscoverthegenesimportantinmalignancybyapiecemealapproach,ortosequencethewholegenomeofselectedanimalspecies”.FromRenatoDulbecco:ATurningPointinCancerResearch:SequencingtheHumanGenome

“我们只有两个选择：要么零敲碎打地去发现一个个重要基因，要么就有选择地测定数个动物（包括人类）的全基因组序列。”

——杜贝克《癌症研究的转折点:测定人类基因组的序列》1964

Lasker1975

NobelDied2012atage98FromHGPtoNew

ParadigmTheHGPEra(1984-2003):“Onehumangenome”done,andweignoredthedifferencesamongindividualsThePostHGPEra:theHapMapProjectsandhundredsofgenomesdone,andwerealizedthatthedifferencesamongpeoplearevastinnumbersTheNewParadigm:tensofthousandsofgenomesdone,andwerealizedthatwecanmapallsequencevariationsandtailorthemtohumanhealthanddiseasestatus2024/1/4BIG-CAS3人类基因计划带动经济发展的因素“人类基因组计划”投入38亿美金，而截至2010年它的影响已经是带来7960亿美金的经济价值，以及31万个就业机会。Human人类基因组计划GenomeProject2024/1/44BIG-CASTheHumanGenomeProjectHasAchievedItsManyGoalsandPavedtheWayforaGenomicsFuture!2024/1/4BIG-CAS52003年发表人类基因组完成图2003年启动“单倍体型图计划”（5个群体共250人）2008年启动“1000

Genome

Project”2011年New

York基因组测序中心成立2011年提出精准医学报告:百万人基因组-精准医学研究;糖尿病基因组研究等“人类基因组计划”的完成与“续篇”2024/1/46BIG-CAS2024/1/4ImprovingHealthcareScienceofMedicineBiologyofDiseaseBiologyofGenomeStructureofGenome基因组学发展不同阶段需要强调不同研究对象和研究目标7BIG-CASChurch’s

PGP2024/1/48BIG-CASPersonalGenomewith

IdentityRevealed2024/1/4BIG-CAS9Photo:ReutersPhoto:ReutersLevy,S.etal.PLoSBiol.5,e254–e286(2007).Wheeler,D.A.etal.Nature452,872–876(2008).$100M$1M$50K$100KJapanese2024/1/410BIG-CASStephenQuakeCo-foudnerofHeliscos2024/1/4BIG-CASFortheFirsttime:Whole-GenomeSequencingDeliversNewTreatmentOptionsforTwinswithRareGeneticMovementDisorder11Yes,itishere—theeraofpersonalizedmedicine—whenphysiciansusewhole-genomesequencetoimprovemedicalcare

2024/1/4BIG-CASWhole-GenomeSequencingforOptimizedPatientManagement.

Bainbridge

etal.2011.SciTransl.Med3:87re3.1250-HourWholeGenomeSequencingProvidesRapidDiagnosisforChildrenWithGeneticDisordersSaudersetal.,SciTranslMed3October20124:154ra135.DOI:10.1126/scitranslmed.30040412024/1/413BIG-CASFifty-HourWholeGenomeSequencingProvidesRapidDiagnosisforChildrenWithGeneticDisorders2024/1/4BIG-CAS14C4RCDhasfourmajorcomponents—clinicalevaluationandgenomicdiagnosis;counselingandoptimizationofconventionaltherapy;noveltherapydevelopment;andcommunityoutreach.Eachchildbeingseenatthecenterwillreceiveaclinicalevaluation,includingwhole-genomesequencing.Differentfromclinicallyintegratedcentersandresearchlabs2024/1/415BIG-CASVision:

Toprovideinnovativegenomicmedicineforchildrenwithgeneticdiseases/Mission:Tobeagloballeaderandreferralcenterfordiagnosis,molecularunderstandingandtreatmentofinheritedchildhooddiseases.Wedothisthrough:TimelymoleculardiagnosisNoveldiseasediagnosisMultidisciplinaryteam-basedapproachestopatientmanagementTeammembers:experiencedingenomeanalysisBoard-certifiedClinicalMolecularGeneticistsBoard-certifiedClinicalGeneticistsandGeneticCounselorsPediatriciansrepresentingeverysub-specialtyinthehospitalBioinformaticsExpertsSoftwareDevelopers2024/1/416BIG-CASThe600ChildrenProject2024/1/417BIG-CASBaby’sDNAinmother’sblood2024/1/4BIG-CAS182024/1/4BIG-CAS192024/1/4BIG-CAS20基因检测的

分类与治疗基因检测的目的性分类着床前诊断（Pre-implantationdiagnosis）出生前诊断（Prenataldiagnosis）新生儿筛查（Newbornscreening）携带者检查（Carriertesting）诊断性检查（Diagnostic

testing）症状前检查（Pre-symptomatictesting）预见性检查（Predictivetesting）孕妇年龄染色体异常子宫内手术FetalSurgery2024/1/421BIG-CASDreamsandPromisesThroughput(lowcost),contiguity(readlength),andquality(fidelity)$1000pergenome$100pergenomeLessthan$100pergenomeHigh-throughputbutveryshortreads(2ndG)High-throughputandshortreads(2ndG

)Highquality,high-throughput,andlongreads(suchas>1000bp)(3ndG

)2024/1/4BIG-CAS222024/1/4BIG-CASCurrentDirectCost23NewParametersDaleYuzukiblog:/the-ion-torrent-proton-compared-to-the-illumina-hiseq-2500/2024/1/424BIG-CAS2024/1/4BIG-CAS25VenkatesanandBashir,2011,NatureNanotech6:615Whatcheapersequencingcando?Genome-centricgoals:genomesequencesandgenomicvariomesforpopulationgeneticsandevolutionCell-centricgoals:transcriptomesandproteomesforcellbiology,physiology,andpathologyEpigenome-centricgoals:methylomesandnucleosomemarks/fringerprintsforgeneregulationandphenomesRibogenome-centricgoals:RNA-mediatedmechanismsotherthanmRNAsforcellularmechanismsandcellularprocesses2024/1/4BIG-CAS262024/1/4BIG-CAS27NATIONALACADEMYPRESSWashington,D.C.19882024/1/4BIG-CAS282024/1/4BIG-CAS292024/1/4BIG-CAS30From“Omics”DatatoIntegratedInformation2024/1/431BIG-CAS数据整合需要云计算和超算技术2024/1/4BIG-CAS322024/1/4BIG-CAS332024/1/4BIG-CAS342024/1/4BIG-CAS35 Theexposomeisanewconceptthat"incorporatesalloftheexposuresencounteredbyhumans,"theysaidaddingthatitisequivalenttothehumangenomeand"includeslifetimeexposurestoenvironmentalpollutantsinfood,water,physicalactivity,medications,homes,anddaily