Gene Ontology GO

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Gene Ontology (GO)

• An Introduction
• Dev H. W. Oliver

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References

• GO For Newbies
• Introduction to the Gene Ontology Suparna
  Mundodi PAG 2006
• http//www.geneontology.org/GO.teaching.resources
  .shtmlpresent
• GO the Gene Ontology Introduction to GO, its
  purpose, structure, annotation and applications,
  plus other biomedical ontologies
• Pascale Gaudet Presentation to bioinformatics
  graduate students
• http//www.geneontology.org/GO.teaching.resources
  .shtmlpresent
• Building Biomedical Ontologies Jennifer Clark
  EBI internal seminar
• http//www.geneontology.org/GO.teaching.resources
  .shtmlpresent

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Outline

• Introduction and Motivation
• Building an Ontology
• GO Annotations
• Editing The Gene Ontology
• Applications of Gene Ontology (GO)

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Introduction and Motivation

• Gene annotation system
• Controlled vocabulary that can be applied to all
  organisms
• Used to describe gene products

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What is in a name?

• Example What is a cell?
• Mundodi, et al

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The Importance of a Name

• A cell is

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The Importance of a Name

• A cell is

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The Importance of a Name

• A cell is

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The Importance of a Name

• A cell is

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The Importance of a Name

• A cell is

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The Importance of a Name

• Different names can be used to describe the same
  concepts
• Different concepts can be described by the same
  name
• Example Glucose synthesis, Glucose biosynthesis,
  Glucose formation, Glucose anabolism,
  Gluconeogenesis all refer to the process of
  making glucose from simpler components

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What is the Gene Ontology?

• A controlled vocabulary that can be applied to
  all organisms
• Used to describe gene products - proteins and RNA
  - in any organism
• Gaudet, et al

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Ontology

• Study of being or existence
• Seeks to describe the basic categories and
  relationships of being or existence
• Defines entities and types of entities within its
  framework
• Studies the conceptions of reality
• Wikipedia

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Ontology

• Includes
• A vocabulary of terms (names for
• concepts)
• Definitions
• Defined logical relationships to each other

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Ontology Structure

• Ontologies can be represented as graphs, where
  the nodes are connected by edges
• Nodes concepts in the ontology
• Edges relationships between the concepts

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Ontology Structure

• The Gene Ontology is structured as a hierarchical
  directed acyclic graph (DAG)
• Terms can have more than one parent and zero, one
  or more children
• Terms are linked by two relationships
• is-a
• part-of

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Simple hierarchies (Trees)
Directed Acyclic Graphs
Single parent
One or more parents
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Directed Acyclic Graphs (DAG)
protein complex
organelle
other organelles
mitochondrion
other protein complexes
fatty acid beta-oxidation multienzyme complex
is-a part-of
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Parent-Child Relationships
The cell component term Nucleus has 5 children
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True Path Rule

• The path from a child term all the way up to its
  top-level parent(s) must always be true
• cell
• cytoplasm
• chromosome
• nuclear chromosome
• nucleus
• nuclear chromosome

is-a ? part-of ?
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How does GO work?

• What information might we want to capture about a
  gene product? i.e. The biochemical material,
  either rna or protein, resulting from expression
  of a gene. The amount of gene product is used to
  measure how active a gene is
• What does the gene product do?
• Why does it perform these activities?
• Where does it act?

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The Three Gene Ontologies
Molecular Function
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ExampleGene Product hammer

• Function (what) Process (why)
• Drive nail (into wood) Carpentry
• Drive stake (into soil) Gardening
• Smash roach Pest Control
• Clowns juggling object Entertainment

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Molecular Function

• A single reaction or activity, not a gene product
• A gene product may have several functions
• Sets of functions make up a biological process

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Biological Process
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Cellular Component

• Where a gene product acts

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Mitochondrial membrane
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What is in a GO Term?

• term gluconeogenesis
• id GO0006094
• definition The formation of glucose from
  noncarbohydrate precursors, such as pyruvate,
  amino acids and glycerol.

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Areas Not Covered By GO

• No pathological processes
• No experimental conditions
• NO evolutionary relationships
• NO gene products
• NOT a system of nomenclature

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Content Of GO

• Current term counts as of September 17, 2006 at
  200 Pacific time
• 20623 terms, 95.7 with definitions
• 11360 biological_process
• 1806 cellular_component
• 7457 molecular_function
• There are 1007 obsolete terms not included in the
  above statistics
• http//www.geneontology.org/GO.
  downloads.shtmlont

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Outline

• Introduction and Motivation
• Building an Ontology
• GO Annotations
• Editing The Gene Ontology
• Applications of Gene Ontology (GO)

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Clark et al., 2005
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Clark et al., 2005
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Synonyms

• classes GO terms, types, kinds, universals
• instances annotated gene product attributes,
  tokens, individuals, particulars

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A Deeper Look at Relationships

• Recall
• is_a
• part_of

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part_of

• Represents how objects combine together to form
  complex objects
• E.g. Steering wheel is a part of Ford Explorer.

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How to define A is_a B

• A and B are names of universals (natural kinds,
  types) in reality
• All instances of A are as a matter of biological
  science also instances of B

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Easy term request

• Please add
• leucophore differentiation
• erythrophore differentiation
• cyanophore differentiation
• neuron differentiation

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part_of
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Examples Of Cell Differentiation
is_a
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Circular Definitions BAD!

• What is X-Cell Differentiation?
• Differentiation of an x cell.

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Non Circular Definitions Good

• What is X-Cell Differentiation?
• The process whereby a relatively unspecialized
  cell acquires specialized features of an x cell.
• Here we list the characteristics of the x cell

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This is a term in the GO
Term id GO0030182 name neuron
differentiation namespace biological_process def
"The process whereby a relatively unspecialized
cell acquires specialized features of a neuron."
GOmah is_a GO0030154 ! cell
differentiation relationship part_of GO0048699
! neurogenesis
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This is the related term in the cell type
ontology
Term id CL0000540 name neuron def "The
basic cellular unit of nervous tissue. Each
neuron consists of a body\, an axon\, and
dendrites. Their purpose is to receive\,
conduct\, and transmit impulses in the nervous
system." MESHA.08.663 xref_analog
FBbt00005106 xref_analog FBbt00005146 is_a
CL0000393 ! electrically responsive cell is_a
CL0000404 ! electrically signaling
cell relationship develops_from CL0000031 !
neuroblast
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Once we put the info together then the term in GO
is much better and has far fewer circular
definitions
Term id GO0030182 name neuron
differentiation namespace biological_process def
"The process whereby a relatively unspecialized
cell acquires specialized features of a neuron.
The basic cellular unit of nervous tissue. Each
neuron consists of a body\, an axon\, and
dendrites. Their purpose is to receive\,
conduct\, and transmit impulses in the nervous
system." MESHA.08.663, GOmah is_a
GO0030154 ! cell differentiation relationship
part_of GO0048699 ! neurogenesis intersection_o
f is_a GO0030154 ! cell differentiation inte
rsection_of has_participant CL0000540 !
neuron
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Basis in Reality

• When building or maintaining an ontology, always
  think carefully about how classes relate to
  instances in reality

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Ontology
cartoon character super power ontology
super senses super physical powers x-ray
cat super
super vision senses
leaping strength
is_a
Every genus (parent class) has an instantiated
species (differentia genus) Every genus (parent
class) has at least two children
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No instance should be annotated to two leaf terms
or two terms on the same level, but they are
here, so what is wrong?
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Cartoon Character Super Power Ontology

• Actually it is the superpowers that are
  annotated, not the superheros. Once we fix that,
  the rule is obeyed and the ontology is being
  correctly used so is more powerful for reasoning

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Ontology
cartoon character super power ontology
super senses super physical powers x-ray
cat super
super vision senses
leaping strength
is_a
Supermans X-ray vision
Catwomans cat senses
Catwomans super strength
Supermans super leaping
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Ontology
cartoon character super power ontology
super senses super physical powers
is_a
Supermans X-ray vision
Catwomans cat senses
Catwomans super strength
Supermans super leaping
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Outline

• Introduction and Motivation
• Building an Ontology
• GO Annotations
• Editing The Gene Ontology
• Applications of Gene Ontology (GO)

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substrate O2 CO2 H20 product
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Types of GO Annotations

• Electronic Annotation
• Manual Annotation
• All annotations must
• be attributed to a source
• indicate what evidence was found to support the
  GO term-gene/protein association

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Manual Annotations

• Highquality, specific gene/gene product
  associations made, using
• Peer-reviewed papers
• Evidence codes to grade evidence
• Very time consuming and requires trained
  biologists

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Manual Annotations Methods

• Extract information from published literature
• Curators performs manual sequence similarity
  analyses to transfer annotations between highly
  similar gene products (BLAST, protein domain
  analysis)

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Electronic Annotations

• Provides large-coverage
• High-quality
• Annotations tend to use high-level GO terms and
  provide little detail

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Electronic Annotations Methods

• Database entries
• Manual mapping of GO terms to concepts external
  to GO (translation tables)
• Proteins then electronically annotated with the
  relevant GO term(s)
• Automatic sequence similarity analyses to
  transfer annotations between highly similar gene
  products

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Additionally

• A gene product can have several functions,
  cellular locations and be involved in many
  processes
• Annotation of a gene product to one ontology is
  independent from its annotation to other
  ontologies
• Annotations are only to terms reflecting a normal
  activity or location
• Usage of unknown GO terms

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Unknown v.s. Unannotated

• Unknown is used when the curator has determined
  that there is no existing literature to support
  an annotation
• Biological process unknown GO0000004
• Molecular function unknown GO0005554
• Cellular component unknown GO0008372
• NOT the same as having no annotation at all
• No annotation means that no one has looked yet

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Outline

• Introduction and Motivation
• Building an Ontology
• GO Annotations
• Editing The Gene Ontology
• Applications of Gene Ontology (GO)

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How is GO maintained?

• Several full-time editors
• Requests from community
• database curators, researchers, software
  developers
• SourceForge tracker
• GO Consortium meetings for large changes
• Mailing lists

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Ensuring Stability in a Dynamic Ontology

• Terms become obsolete when they are removed or
  redefined
• GO IDs are never deleted
• For each term, a comment is added to explains why
  the term is now obsolete

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Why modify the GO?

• GO reflects current knowledge of biology
• New organisms being added makes existing terms
  arrangements incorrect
• Not everything perfect from the outset

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Example - parasites

• Original GO

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Example - parasites

• Annotation of P. falciparum
• protozoan cellular parasite
• intracellular infection (erythrocytes)
• Parasite proteins located in host nucleus
• What cellular component term to annotate to?
• nucleus refers to parasite nucleus when
  annotating parasite

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Example - parasites

• Added new term host

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Example - parasites
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Requesting changes to GO - curator requests
tracker

• Common changes suggested
• new term requests
• reporting errors (typos, etc)
• obsoletion/merge requests
• add synonym
• queries
• term move (change parents)

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Outline

• Introduction and Motivation
• Building an Ontology
• GO Annotations
• Editing The Gene Ontology
• Applications of Gene Ontology (GO)

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What can scientists do with GO?

• Access gene product functional information
• Find how much of a proteome is involved in a
  process/ function/ component in the cell
• Map GO terms and incorporate manual annotations
  into own databases
• Provide a link between biological knowledge and
  
• gene expression profiles
• proteomics data

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What can scientists do with GO?

• Microarray analysis / gene expression
• See http//www.geneontology.org/GO.tools for
  current Microarray analysis tools

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End of Talk

• Thanks