LEARNINGPROPORTIONSINASEMI-SUPERVISEDSETTING:ACASESTUDYIN

PRECISIONMEDICINE

PredragRadivojac

DEPARTMENTOFCOMPUTERSCIENCEANDINFORMATICSINDIANAUNIVERSITY,BLOOMINGTON

November28,2016

AtsomepredicLonthreshold[one]ThirdoftheAlternaLveSplicingIsoformspredictedtoproduceFuncLonalProteins….

WHATISTHEFRACTIONOFENZYMESINAGENOME?

WHATISTHEFRACTIONOFENZYMESINAGENOME?

CharlesDann,Chemistry YuzhenYe,ComputerScienceTuliMukhopadhyay,Biology

EXAMPLEFROMPSYCHOLOGY

GreeneMR.EsLmaLonsofobjectfrequencyarefrequentlyoveresLmated.Cogni&on(2016)149:6-10.

ANDSOWEGO…

HiPedja,Youpose interesLngquesLons. I'dexpectyeasttohavethehighestenzymefracLonas itdoesnotneedtohaveconservedgenesformulLcellulardevelopment,cogniLon,etc.(thoughmanyoftheseprocessesrequiressignalingpathwayswithenzymes).SoherearemyesLmatesforenzymefracLon,basedenLrelyonintuiLon.

Yeast~45%;E.coli~35%;Mouse~25%;Human~25%;Arabidopsis~40%(noideahere)

IimagineImayhitlowonallofthese...

CD3

SUPERVISEDLEARNINGPROBLEM

SUPERVISEDLEARNINGPROBLEM

SUPERVISEDLEARNINGPROBLEM

SUPERVISEDLEARNINGPROBLEM

SEMI-SUPERVISEDLEARNINGPROBLEM

UNSUPERVISEDLEARNINGPROBLEM

POSITIVE-UNLABELEDLEARNINGPROBLEM(PU)

IDENTIFIABILITY

ANTICIPATEDLIKELIHOODFUNCTION

ENZYMES:EXPERIMENTALPROTOCOL

>sp|P04637|P53_HUMAN Cellular tumor antigen p53 MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAK SVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHE RCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNS SCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELP PGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPG GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

DevelopanSVMpredictor

-  Linearkernel-  AUC≈75%-  Plam’scorrecLon

AAAA AAAC MEEP YYYY

0 0 1 0

VVVP

1 ... ...

RESULTS:ENZYMES

RESULTS:ENZYMES

DISEASEMUTATIONSINHUMANEXOME

PRECISIONMEDICINE

“Sotonight,I’mlaunchinganewPrecisionMedicineIniLaLvetobringusclosertocuringdiseaseslikecanceranddiabetes,andtogiveallofusaccesstothepersonalizedinformaLonweneedtokeepourselvesandourfamilieshealthier.Wecandothis.“–PresidentBarackObama.

01/20/2015

PrecisionMedicine

thescienceandpracLceofmatchingthebestdiagnosLc,therapeuLcand

prevenLonstrategiestopromotehealththataretailoredtoanindividual’sgeneLc,biological,behavioraland

psychosocialcharacterisLcs

PRECISIONMEDICINE

www.nih.gov/AllofUs-Research-Program

nih.gov

hmp://bgiamericas.com

GENOMESEQUENCING

TheAtlanLc

… AGCATACCGA …

HUMANGENOMEANDITSIMPACTONPHENOTYPEWHATISTHEMOLECULARBASISOFIT?

GENOMEPHENOME

… TTTACCGAGC …

… AGCATAGCGA …

Adaptedfrom:hmp://snp.ims.u-tokyo.ac.jp/samplesMethods.html#SNP

Gene

ExonDNA

>40millionknownuniquesitesofvaria5on!

Yueetal.JMolBiol,353:459(2005).

G38Din1tag

Anothergene…

regulatory non-synonymous intronicgenomicsynonymous

BASECHANGESRESULTINGINDIFFERENTPROTEINS

Whenappliedto43nsSNPsof18drugrelatedgenesfromtheThaiSNPresequencingprojecttherewerestrongcorrelaLons SlidefromSeanMooney’sgroup.

CURRENTTOOLSPREDICTEFFECTSOFVARIANTS

GROWTHOFDATA

HapMap Phase I

1000 Genomes project Phase I

TUMORBOARD

hmp://www.med.umich.edu/cancer/images/urologic-oncology-tumor-board.jpg

Person:68yearoldwomanCancertype:coloncancer,metastaLcMuta7ons:KRAS,C27FBRCA1,H57RTP53,T98*

Treatmentop7ons:-clinicaltrialatMDAnderson-conLnuewithchemotherapy-treatwithnewdrugforbreastcancer

MOLECULARCONSEQUENCESONP53

R175H: Metal-binding

V143A: Stability

K120R: Acetylation

R273H: DNA-binding

G245S: Protein-binding

p53–tumorsuppressorprotein

PDBstructures:2ybg,2j1w,1ycsand1tup

MUTPRED2.0

VikasPejaver,IndianaUniversity

Conservation Funct. Prop. Sequence Struct. Prop.

Neural networks

>sp|P04637|P53_HUMAN MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPRVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAK SVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHE RCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNS ...

...

Physicochemical Substitution matrices

Neural network ensemble:

•  Z-score normalized and PCA’d •  30 feed-forward networks •  bootstrap aggregating, balanced training •  trained using resilient propagation

Cataly7cresiduesofPCSK9(2qtw)

n  amemberoftheproteinaseKsub-familyofsubLlasesthatreducesthenumberofLDLreceptorsinliverthroughaposmranscripLonalmechanism.

n  D374Yleadstoa10-foldincreaseincatalyLcacLvitythatcauseshypercholesterolemia.

Lagaceetal.JClinInvest,116:2995(2006). Xinetal.Bioinforma&cs26:1975-1982(2010).

GAINOFCATALYTICACTIVITYCAUSESDISEASE