1. SO-Monarch Workshop
Toward the Integration of Genetic Variation Modeling
Sept 16-18, 2013
Oregon Health and Science University
Portland, OR
Funded by the Phenotype RCN
MONARCH INITIATIVE
Matthew Brush
Melissa Haendel
Chris Mungall
Mike Bada
Karen Eilbeck
Bret Heale
A rough transcript of audio from this presentation can be found here:
https://docs.google.com/document/d/13oifUZeWxK5hXPlMW6pl3BXoxr6xTossUT4_Fl2cgg/edit

2. The Sequence Ontology

An OBO Library ontology developed to standardize the vocabulary
and semantics of biological sequence annotation
 Use has expanded from genome annotation into new applications
- variation description, text mining, experimental data annotation
 Undergoing significant refactoring to meet new needs:
- align with BFO
- enhance variation representation
- develop parallel representation of physical sequence entities
- SO vs MSO (molecular sequence ontology)
- improve explicit representations across central dogma

3. Monarch Initiative
The Monarch Initiative
The Monarch Initiative aims to bring G2P and related data together under a
common semantic framework and develop tools and services for user-guided
exploration and analysis
Data integration and application functionality driven by a suite of ontologies
that include many community resources as well as new ontologies (GENO)

4. GENO: A Genotype Ontology
 The core use case of GENO for Monarch is to support aggregation and
semantic integration of genotype data and its link to phenotypes across
these diverse sources.
 GENO is an ontology of 'genotype' sequence information that describes
types and scales of genetic variations associated with phenotypes, and
places these variations in a broader biological context.
 Genotype information in GENO is viewed broadly to include any variation in
gene expression that is tied to an observed phenotypic effect. We
distinguish two types of variation:
environment
SEQUENCE-VARIATION
AGACTACTACGTAGGTCCTCC
Arg-Leu-Leu-Arg-Stop
PHENOTYPE
‘short fin’

5. GENO: A Genotype Ontology
 The core use case of GENO for Monarch is to support aggregation and
semantic integration of genotype data and its link to phenotypes across
these diverse sources.
 GENO is an ontology of 'genotype' sequence information that describes
types and scales of genetic variations associated with phenotypes, and
places these variations in a broader biological context.
 Genotype information in GENO is viewed broadly to include any variation in
gene expression that is tied to an observed phenotypic effect. We
distinguish two types of variation:
morpholinos
EXPRESSION-VARIATION
PHENOTYPE
environment
AGACTACTACGTACGTCCTCC
X
Arg-Leu-Leu-Arg-Thr-Ser-Ser
‘short fin’

6. GENO: A Genotype Ontology
 The core use case of GENO for Monarch is to support aggregation and
semantic integration of genotype data and its link to phenotypes across
these diverse sources.
 GENO is an ontology of 'genotype' sequence information that describes
types and scales of genetic variations associated with phenotypes, and
places these variations in a broader biological context.
 Genotype information in GENO is viewed broadly to include any variation in
gene expression that is tied to an observed phenotypic effect. We
distinguish two types of variation:
SEQUENCE-VARIATION
EXPRESSION-VARIATION
‘Intrinsic’ Genotype
‘Extrinsic’ Genotype
apchu745/+; fgf8ti282/ti282(AB)
shhbMO1-shhb(2ng); ihhbMO2-ihhb(1ng)
Together these artifacts can capture the complement of all genetic variation in an
organism in terms of the loci that are altered in their sequence or their expression level

7. Decomposition of an ‘Intrinsic’ Genotype
Intrinsic Genotype – specifies a sequence variation across an entire genome in
terms of its differences from some reference genome
AACGTAGCGACGCTCGCTACGGGCGTATC
AACGTAGCGACGCTCGCTACGGGCGTATC
X
=
AACGTACCGACGCTCGCTACGGGCGTATC
X
GCGAAGTGCCAACTTCTACACACACAAAG
CGTAGC
AACGTACCGACGCTCGCTACGGGCGTATC
CGTACC
GCGAAGTGCCAACTTCTACACACACAAAG
X
GCGAAGTGCCAACTTCTACACACACAAAG
+
X
X
ACAC
X
ACAC
GCGAAGTGCCAACTTCTACACACACAAAG
genotype
genomic background
genomic variation
complement
apchu745/+; fgf8ti282/ti282(AB)
(AB)
apchu745/+; fgf8ati282/ti282
X
X
X
X
genomic variation
complement
has_part
variant single locus
complement
has_part
X
variant locus
(aka allele)
has_part
X
sequence alteration
apchu745/+; fgf8ati282/ti282
has_part
apchu745/+
has_part
apchu745
has_part
hu745

8. Decomposition of an ‘Extrinsic’ Genotype
‘Extrinsic genotypes’ describe
sequences subject to transient
variation in expression at the
time of an experiment
Morpholino-mediated
gene knockdown
An extrinsic genotype is
comprised of the collection of all
genes in the organism that are
variant in their expression as a
result of some experimental
intervention

9. ‘Effective’ Genotypes

10. Workshop Motivation
 Both GENO and SO are developed to cover different
perspectives on the domain of abstract biological sequence
information.
 GENO is new and developing. SO is mature but undergoing
major refactoring.
 Primary workshop goal was to ensure models are
interoperable to allow integration of data described using SO
and GENO.
 Our work fell into three categories:
o Ontology
o Community
o Logistics/Planning

11. Workshop Goals and Outcomes
Ontology
1. Ontological Debate: to align high-level ontological modeling
of sequence features and intrinsic and extrinsic variation
2. Core terminological standardization: Establish clear
definitions and usage of core domain terms (gene, allele,
variant, etc) . . .in progress
3. SO vs MSO: Developed strategy for parallel SO and MSO
development and maintenance . . in progress
4. Conceptual Integration of SO and GENO: Intrinsic genotype
modeling in scope of SO, but extrinsic modeling is not and will
live exclusively in GENO

12. Workshop Goals and Outcomes
Community
1. Gene representation: strategy to provide an ontological
representation and identifiers for genes and their variants as a
community resource for diverse applications
2. Modeling the central dogma: build from gene representation
to describe relations to sequences at RNA and protein levels,
and properties that emerge here
3. Phenotype annotation practices: develop a standard for use
of phenotype ontologies for GVF file annotation
• http://www.sequenceontology.org/so_wiki/index.php/Using_Phenotype_Ontologies_in_GVF
4. GENO as a community ontology: plan for separating monarch
specific features from a more generally useful community
model

13. Workshop Goals and Outcomes
Planning and Logistics
Technical Integration Plan: decide how GENO and SO will interact
at technical level (namespaces, imports, mappings, etc)
Collaborative Development Plan: establish framework of tools
and practices for parallel development of SO and Monarch
ontologies
Data and Use Case Plan: to collect use cases and build test data
sets from the community to inform and test our modeling
Continued Working Group : weekly Tuesday afternoon calls, open
to community

14. Thank You
Thanks to the Phenotype RCN for their support!
Details about workshop outcomes can be found here:
https://docs.google.com/document/d/1AUEVX0Sx_iy9mTI6F59Yo7ZCXu4zv5uSk28AHid5zhc/edit#
Questions?