genome and proteome annotation using automatically recognized concepts and functional networks

7/28/2019 Genome and Proteome Annotation Using Automatically Recognized Concepts and Functional Networks

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Genomeandproteomeannotationusingautomaticallyrecognizedconceptsand

functionalnetworks

AdrianBivol,TobiasWittkop,DarcyDavis,andSeanMooney

Mooneylaboratory,BuckInstituteforResearchonAging,Novato,CA

NationalCenterforBiomedicalOntology,StanfordUniversity,Stanford,CA


2/21

Genefunction/diseaseprediction

Typically uses Gene Ontology (GO) or disease annotation (e.g. OMIM)

Many tools utilize similar set of features/networks, e.g. PPI networks,

co-expression networks, sequence similarity,...

Input: Set of genes with known function/disease

Output: ranked list of remaining genes (closest at the top)

Can these tools be used for other annotations then GO or disease?


3/21

Systematicevaluationofautomated

annotations

1.Annotate all (human) genesto terms from ontologiesoutside GO and OMIM, e.g. Phenotype Ontology,CHEBI, or Pathway Ontology.

2.For each term (gene set) evaluate predictability,i.e. how well can we predict the genes that areannotated to it using existing gene function predictionmethods.


4/21

GeneannotationsoutsideofGO

NCBO currently includes over 250 ontologies

Ontologies are structured controlled vocabularies

Gene/protein summary in Entrez Gene and UniProt often moreup-to-date than manually curated GO

NCBO provides annotator service1 that matches text to terms

1C.Jonquetetal.AMIASummitonTranslationalBioinformatics(2009)


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1.Collect genes/proteins fromEntrez Gene andUniProt

2.Collect descriptivetext for each gene/protein from EntrezGene/UniProt

3.Annotate text toover 200 ontologiesvia NCBOAnnotator

Automaticgeneannotationpipeline

1"

Genome/Proteome*

Q147X3**human*****The*status,*quality,*and*expansion*of*the*NIH*fullBlength*cDNAproject:*

the*Mammalian*Gene*CollecKon*(MGC).*;*inaseBselecKve*enrichment*

enables*quanKtaKve*phosphoproteomics*oShe*kinome*across*the*cell*

cycle.*;*A*quanKtaKve*atlas*of*mitoKc*phosphorylaKon.*;*A*synopsis*of*

eukaryoKc*NalphaBterminal*acetyltransferases:nomenclature,*subunits*

a nd * s u bs t ra t es . * ; * n oc kd ow n* o f* h um a n* N * a l ph aB t er m in al *

acetyltransferase*complex*C*leadsto*p53Bdependent** ** ** ** *apoptosis*

and* aberrant* human*Arl8b*localizaKon.*;* Lysine* acetylaKon*targets*

protein* complexes* and* coBregulates* majorcellular* funcKons.* ;B!B*

FUNCTION:* CatalyKc* subunit* of* the* NBterminal* acetyltransferase*

C(NatC)* c omplex.* Catalyzes* ac etylaKon * of* th e* NBtermin al*

methionineresidues*of*pepKdes*beginning*with*MetBLeuBAla*and*MetB

LeuBGly.Necessary* for* the* lysosomal* localizaKon* and* funcKon* of*

ARL8.B!B* CATALYTIC* ACTIVITY:* AcetylBCoA* +* pepKde* =* N(alpha)B

acetylpepKde+* CoA.B!B* UUNIT:* Component* of* the* NBterminal*

acetyltransferase* C* (NatC)complex,* which* is* composed* of* NAA35,*LMD1* and* NAA30.B!B* UCELLULAR* LOCATION:* Cytoplasm.B!B*

ALTERNATIVE* PRODUCT:Even t=Altern aKve* sp licin g;* Named*

i s o f o r m s = 2 ; N a m e = 1 ; I s o I d = Q 1 4 7 X 3 B 1 ; *

e q u e n c e = D i s p l a y e d ; N a m e = 2 ; I s o I d = Q 1 4 7 X 3 B 2 ;*

eq u enc e=VP_031581;Note=No* exp erimen tal* c on firmaKon*

available;B!B*IMILARITY:*elongs*to*the** ** * ** ** ** ** acetyltransferase*

family.*MA3subfamily.B!B*IMILARITY:*Contains*1*NBacetyltransferase*

domain.*B.**

Gene"Ontology"

iological*process*

Apoptosis" signaling*

Molecular*funcKon*

Cellular*

funcKon*

2"

3"

Cell"cycle"ontology"

iological*process*

DNA*replicaKon*iniKaKon*

*

CytokineKc*process*

iological*conKnuant*

Acetyltransferase"

Over*200*

biomedical*

ontologies*

acetyltransferase*

apoptosis*

2"


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Gene/proteinspecifictextas

annotationsource

Gene text from Entrez Gene

Protein text from UniProt

Gene/Protein summary

Publication titles

GO annotations

Pathway annotations

GeneRIFs

Protein complexes, domains, interactions

We filter for author names, db names, numbers

Q147X3''human'''''The' status,' quality,' and' expansion' of' the' NIH' full>length' cDNAproject:' the'

Mammalian' Gene' Collecon' (MGC).' ;' Kinase>selecve' enrichment' enables'

quantave'phosphoproteomics'ohe'kinome'across'the'cell'cycle.';'A'quantave'atlas' of' mitoc' phosphorylaon.' ;' A' synopsis' of' eukaryoc' Nalpha>terminal'

acetyltransferases:nomenclature,'subunits'and'substrates.';'Knockdown'of'human'N'

a lpha>terminal ' acety l t ransferase' complex' C ' leadsto' p53>dependent'

apoptosis' and' aberrant' human' Arl8b' localizaon.' ;' Lysine' acetylaon'targets'protein'complexes'and'co>regulates'majorcellular'funcons.';>!>'FUNCTION:'

Catalyc' subunit' of' the' N>terminal' acetyltransferase' C(NatC)' complex.' Catalyzes'

acetylaon'of' the'N> terminal'methionineresidues'of' pepdes'beginning' with'Met>

Leu>Ala'and'Met>Leu>Gly.Necessary'for' the'lysosomal' localizaon'and'funcon'of'

ARL8B.>!>' CATALYTIC' ACTIVITY:' Acetyl>CoA' +' pepde' =' N(alpha)>acetylpepde+'

CoA.>!>'SUBUNIT:'Component' of'the' N>terminal'acetyltransferase'C' (NatC)complex,'

which' is' composed' of' NAA35,' LSMD1' and' NAA30.>!>' SUBCELLULAR' LOCATION:'

Cytoplasm.>!>' ALTERNATIVE' PRODUCTS:Event=Alternave' splicing;' Named'

isoforms=2;Name=1;IsoId=Q147X3>1;'Sequence=Displayed;Name=2;IsoId=Q147X3>2;'Sequence=VSP_031581;Note=No' experimental' confirmaon' available;>!>'

S IMILAR ITY:' Belongs' to' the' acetyltransferase' family.'MAK3subfamily.>!>'SIMILARITY:'Contains'1'N>acetyltransferase'domain.'>.KEGG;'hsa:

122830;'>.UCSC;' uc001xcx.2;'human.CTD;'122830;'>.GeneCards;' GC14P038022;'>.H>

InvDB;' HIX0011696;' >.HGNC;' HGNC:19844;' NAA30.neXtProt;' NX_Q147X3;'

> . Pha rmGKB ;' PA134931315; ' > . eggNOG ; ' p rNOG15463 ;' > .GeneTree ;'

ENSGT00390000005665;' >.HOGENOM;' HBG282398;' >.HOVERGEN;' HBG082671;'

>.InParanoid;' Q147X3;' >.OMA;' AGVHSGE;' >.OrthoDB;' EOG4KKZ4S;' >.PhylomeDB;'

Q147X3;' >.NextBio;' 81013;' >.ArrayExpress;' Q147X3;' >.Bgee;' Q147X3;' >.CleanEx;'

HS_NAT12; ' >.Genevesgator;' Q147X3;' >.GO;' GO:0005737; ' C:cytoplasm;'

IEA:UniProtKB>SubCell.GO;' GO:0004596;' F:pepde' alpha>N>acetyltransferase'

acvity;' IEA:EC.InterPro;' IPR000182;' AcTrfase_GCN5>related_dom.InterPro;'

IPR016181;' Acyl_CoA_acyl transferase.Gene3D; ' G3DSA:3 .40.630.30;'

Acyl_CoA_acyltransferase;'1.Pfam;' PF00583;'Acetyltransf_1;' 1.SUPFAM;'SSF55729;'

Acyl_CoA_acyltransferase;'1.PROSITE;'PS51186;'GNAT;'1.'

'


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TheNCBOannotator1

Simple string matching usingmgrep

Synonyms are annotated

Annotations are propagatedto the root

No NLP

Very fast

Gene$Ontology$

Biological$process$

Apoptosis$ signaling$

Molecular$func6on$

Cellular$func6on$

3"Cell$cycle$ontology$

Biological$process$

DNA$replica6on$

ini6a6on$$

Cytokine6c$process$

Biological$con6nuant$

Acetyltransferase$

1C.Jonquetetal.AMIASummitonTranslationalBioinformatics(2009)


8/21

683,753,623 annotations of 426,392 genes and proteins to

529,544 terms from 267 ontologies for 7 organism (human,mouse, rat, fly, worm, yeast, E. coli)

For human:

94,844,772 annotations of 43,823 genes to436,576 terms

146,221,448 annotations of 68,079 proteins to 373,222 terms

Availability:

RESTful webservice at: rest.mooneygroup.org

Term enrichment tool STOP1: mooneygroup.org/stop

Annotationresults

1Wittkopetal.BMCBioinformatics(2013)


9/21


annotations

1.Annotate all (human) genesto terms from ontologiesoutside GO and OMIM, e.g. Phenotype Ontology,CHEBI, or Pathway Ontology.

2.For each term (gene set) evaluate predictability,i.e. how well can we predict the genes that areannotated to it using existing gene function predictionmethods.


10/21


annotations

Use GeneMANIA1 for gene prioritization:

Combine biological networks with more weight tonetworks that connect input genes

Find closest genes in genome

Fast, accurate and can be executed locally

1Mostafavietal.GenomeBiol.(2008)


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annotations

3-fold cross-validation of all terms (between 5 and1000 genes) using the gene prioritization toolGeneMANIA

3-fold cross-validation of random control using twodistributions (uniform and gene-annotation-frequencybased)

3-fold cross-validation of GO annotations from GOA1

(including/excluding IEA annotations) and from DAVID2

Use AUROC as quality measure to comparepredictability

1E.Camonetal.NAR(2004),2D.Huangetal.GenomeBiol.(2007)


12/21

Automatedannotationsaremore

predictablethanrandom...

For human genes: 127.000 out of 200.000 analyzed termsare statistically significant above random

Control uniform Control annotation-frequency-based Automated annotations


13/21

...andperformcomparabletoexisting

annotations

GOA (EXP) GOA (IEA) DAVID (GO db) Automated annotations

Note that GOA annotations are more sparse and have onaverage smaller gene sets


14/21

Differencesbetweenontologiesdemand

furtheranalysis

PRotein Ontology (PRO)Molecule role (INOH Protein name/family name ontology)

Cell Cycle Ontology

Online Mendelian Inheritance in Man

Gene Ontology Extension

Gene Ontology

Neural-Immune Gene Ontology

Medical Subject Headings

NIFSTDNational Drug File

NCI Thesaurus

CRISP Thesaurus 2006

Logical Observation Identifier Names and Codes

MedDRA

Chemical entities of biological interest

SNOMED Clinical Terms

Experimental Factor OntologySuggested Ontology for Pharmacogenomics

Read Codes Clinical Terms Version 3 (CTV3)

Bone Dysplasia Ontology

RadLex

Galen

Human developmental anatomy timed version

0.78 0.803 0.825 0.848 0.87

Ontologies with more then 1000 terms ordered by average AUROC


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ribonuclease P protein subunit p40 Protein Ontology AUC = 1

Examples


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GO:0032041 (NAD-dependent histone deacetylase activity)

Gene Ontology AUC = 1

Examples


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GO:0072599 (establishment of protein localization in endoplasmic

reticulum) Gene Ontology AUC = 0.99

Examples


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Pancytopenia OMIM AUC = 0.96

Examples


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Severe combined immunodeficiency OMIM AUC = 0.97

Examples


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Existing Gene function prediction methods might beapplied to other gene annotations

Automated annotations have prediction power

Differences in prediction performance betweenontologies/terms exist

Future directions: What are the important features forindividual ontologies or subgroups of terms ?

Conclusions


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Thank you for your attention

Special Thanks to ...

Buck Institute for Research on AgingAdrian Bivol, Darcy Davis, Emily TerAvest, Uday Evani, Ari Berman,Tal Oron Ronnen, Mathew Fleisch, Corey

Powell

! ! ! ! ! ! ! FundingNCBO! ! ! ! ! ! NIH R01 LM009722 (PI:Mooney),Nigam Shah and Trish Wetzel Stanford University National Center for Biomedical Ontology U54 HG004028,

and the Buck Trust.! ! !

genome and proteome annotation using automatically recognized concepts and functional networks

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