An open science integrated genotype-phenotype platform for

disease and model organism discovery

Melissa Haendel, PhD2015.10.10

ASHG 2015 “Opening Up Big Data”@monarchinit@ontowonka

monarchinitiative.org

Opening up big datalittle

monarchinitiative.org

There are 3,462 Mendelian or suspected Mendelian diseases

with no genetic basis identified in OMIM

There are 47,964 variants of unknown significance in

ClinVar

What can we do about that?

monarchinitiative.org

Phenotypic coverage of human coding genes

monarchinitiative.org

Model organisms supply ~50% phenotypic knowledge to human

genes

monarchinitiative.org

We have a common language for sequence data….

….not so much for phenotypes

monarchinitiative.org

Ulcerated paws

Palmoplantar hyperkeratos

is

Thick hand skin

monarchinitiative.org

Diversity of disease and phenotype vocabularies

monarchinitiative.org

Bridging the vocabularies

HPO is part of integrated ontology suite

Which phenotypic profile is most similar?

Model X

Patient

Disease Y

Model X

Patient

Disease Ywww.owlsim.org

OWLSim enables fuzzy phenotype matches

Combining genotype and phenotype data for variant

prioritizationWhole exome

Remove off-target and common variants

Variant score from allele freq and pathogenicity

Phenotype score from phenotypic similarity

PHIVE score to give final candidates

Mendelian filters

https://www.sanger.ac.uk/resources/software/exomiser/

monarchinitiative.org

PhenoGrid phenotype comparison widget

Patient phenotypes

Compare patients with: Other patients Known diseases Models

http://monarchinitiative.org/page/

phenogrid

monarchinitiative.org

Exomiser uses model phenotypes to reveal new

STIM1 disease

York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

monarchinitiative.orgImage credit: Viljoen and Beighton, J Med Genet. 1992

Schwartz-Jampel Syndrome, Type I

Hspg2 mutation, a proteoglycan

~100 phenotype annotations

How much phenotyping is a enough?

Phenotype annotation sufficiency metric

http://monarchinitiative.org/page/services

monarchinitiative.org

Monarch in Matchmaker Exchangewww.monarchinitiative.org www.patientarchive.org

Matchmake against known diseases and

models

Matchmake against patients

monarchinitiative.org

PubMed Browser

http://pubmed-browser.human-phenotype-ontology.org/

Search the literature for combinations of phenotype terms,using synonyms and HPO graph

http://pubmed-browser.human-

phenotype-ontology.org/

Monarch teamLawrence Berkeley

Chris MungallNicole WashingtonSuzanna LewisJeremy NguyenSeth CarbonHieko Dietze

CharitéPeter RobinsonSebastian KohlerMax SchubachTomasz Zemojtel

U of PittsburghHarry HochheiserMike DavisJoe Zhou

OHSUMelissa HaendelNicole VasileskyMatt BrushKent ShefchekJulie McMurryMark Engelstead

Sanger InstituteDamian SmedleyJules Jacobson

GarvanTudor GrozaCraig McNamaraEdwin Zhang

Funding:NIH Office of Director: 1R24OD011883NIH-UDP: HHSN268201300036C, HHSN268201400093P

http://monarchinitiative.org