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# Introduction to GO annotations

<!-- GO annotations: the model of biology. Annotations are statements describing the functions of specific genes, using concepts in the Gene Ontology. The simplest and most common annotation links one gene to one function, e.g. FZD4 + Wnt signaling pathway. Each statement is based on a specified piece of evidence. -->
GO annotations come in two flavors: **standard GO annotations** and **GO-CAM Models**.

## Standard GO annotations
+ A standard GO annotation is a statement that links a gene product and a GO term via a relation from the [Relations Ontology (RO)](http://www.obofoundry.org/ontology/ro.html){:target="blank"} . In standard GO annotations, each statement is independent; this is a key difference between standard annotations and [GO-CAMs](#go-causal-activity-models).
+ A standard GO annotation minimally contains:
+ a gene product; may be a protein, an miRNA, a tRNA, etc.
+ a [GO term](/docs/ontology-documentation/)
+ a reference, usually a PMID, but DOIs and [GO Reference (GO_REF)](/gorefs.html) are also used.
+ an evidence code, using [a GO Evidence Code](/docs/guide-go-evidence-codes/), which describes the type of evidence: experimental evidence, sequence similarity or phylogenetic relation, as well as whether the evidence was reviewed by an expert biocurator. If not manually reviewed, the annotation is described as 'automated'.
+ Any number of annotations can be made to a gene, in order to fully describe its function and the location(s) in which it acts.
+ **Annotation extensions** are used to provide additional biological context to a GO term, using a relation from the [Relations Ontology (RO)](http://www.obofoundry.org/ontology/ro.html){:target="blank"} and a term from GO or an external ontology, e.g. [UBERON](http://uberon.github.io/){:target="blank"}. Further description of annotation extensions can be found in tha paper of [Huntley & Lovering 2017](https://www.ncbi.nlm.nih.gov/pubmed/27812947){:target="blank"} and [Huntley *et al.* 2014](https://www.ncbi.nlm.nih.gov/pubmed/24885854){:target="blank"}.

### Semantics of a standard GO annotation
+ Associations of gene products to GO terms are statements that describe:
+ **Molecular Function**: the *normal* molecular activity of a gene product; mutants and roles in disease are outside the scope for GO
+ **Cellular Component**: where the gene product is located when the activity occurs
+ **Biological Process**: the pathways and larger processes to which the gene product's activity contributes
+ By the transitivity principle, an annotation to a GO term implies annotation to all its parents.
+ GO annotations are meant to reflect the most up-to-date understanding of a gene product's role. As biological knowledge advances, annotations for a particular gene product may be updated to align with new insights or adjustments in the ontology.
+ GO adopts an open-world model, meaning that the absence of an annotation for a specific class does not imply that the gene product lacks that function, is not localized to that cellular component, or is uninvolved in that biological process. Moreover, if a gene product is unannotated, it does not mean that its role is unknown. Genes for which no role has been demonstrated are annotated to the root term (*molecular_function, biological_process, cellular_component*) with the evidence code ND (No Data available).

A GO annotation is a statement about the function of a particular gene. GO annotations are created by associating a gene or gene product with a GO term. Together, these statements comprise a “snapshot” of current biological knowledge. Hence, GO annotations capture statements about how a gene functions at the molecular level, where in the cell it functions, and what biological processes (pathways, programs) it helps to carry out.

There are four pieces of information that uniquely identify a GO annotation. Although there are additional components a curator can use to indicate more information, including [relations](/docs/go-annotations/#annotation_relations) and [annotation extensions](/docs/go-annotations/#annotation-extensions), at the very minimum an annotation consists of:
+ Gene product (may be a protein, RNA, etc.)
+ GO term
+ Reference
+ [Evidence](/docs/guide-go-evidence-codes/)

Different pieces of knowledge regarding gene function may be established to different degrees, which is why each GO annotation always refers to the evidence upon which it is based. All GO annotations are ultimately supported by the scientific literature, either directly or indirectly. The Reference almost always a PMID or [GO Reference (GO_REF)](/gorefs.html). In GO, the supporting evidence is presented in the form of a [GO Evidence Codes](/docs/guide-go-evidence-codes/) and either a published reference or description of the methodology used to create the annotation. The GO evidence codes describe the type of evidence and reflect how far removed the annotated assertion is from direct experimental evidence, and whether this evidence was reviewed by an expert biocurator.


<!-- if ok to keep, delete from wiki: http://wiki.geneontology.org/index.php/Introduction_to_Annotation-->

## Semantics of a GO annotation
Associations of gene products to GO terms are statements that describe
+ Molecular Function: the molecular activities of individual gene products
+ Cellular Component: where the gene products are active
+ Biological Process: the pathways and larger processes to which that gene product's activity contributes

## General principles of GO annotations
+ Annotations represent the normal functions of gene products.
+ A gene product can be annotated to zero or more terms from each ontology.
+ Each annotation is supported by an [GO Evidence Codes](/docs/guide-go-evidence-codes/) from the [Evidence and Conclusions Ontology](http://www.evidenceontology.org/) and a reference.
+ Gene products are annotated to the most granular term in the ontology that is supported by the available evidence.
+ By the transitivity principle, an annotation to a GO term implies annotation to all its parents (except for *NOT* annotations, which propagate down the ontology).
+ GO annotations are meant to reflect the most up-to-date view of a gene product's role in biology.
+ Because biological knowledge changes, annotations for a given gene product may change to reflect changes in knowledge and/or changes in the ontology.
+ There is an open-world assumption, that is, if a gene product is unannotated then its role is still unknown.

## Annotation relations

A specific set of terms from the Relations Ontology (RO), sometimes referred to as 'gp2term' (gene product to term) relations, are used to link gene products to GO terms in standard annotations. The modifer *NOT*, as well as qualifiers like *enables*, *acts upstream of or within , and *enables* are used in the [GAF format](/docs/go-annotation-file-gaf-format-2.2/). For the full list of permitted gp2term relations, see the [GO wiki](https://wiki.geneontology.org/Annotation_Relations#Standard_Annotation_Relations){:target="blank"}. Some of the most common relations are:
## GO-Causal Activity Models
+ GO-Causal Activity Models (GO-CAMs) provide a system to extend GO annotations with **biological context** as well as **causal connections** between activities.
+ The network representation of GO-CAMs enables pathway visualization and analysis.
+ The biological context captured for each GO aspects corresponds to:
+ MF: substrates ("input"), products ("output"), activators, inhibitors
+ BP: the broader process that the molecular function helps accomplish: cell cycle transition, transcription, signaling pathways, etc. Processes can be nested, i. e., a biological process can be part of another biological process. For example, a signaling pathway can be part of a developmental process, like the [Wnt signaling pathway](https://amigo.geneontology.org/amigo/term/GO:0016055){:target="blank"} is part of [dorsal/ventral pattern formation](https://amigo.geneontology.org/amigo/term/GO:0009953){:target="blank"}.
+ CC: the cellular component, cell, and/or tissue the function/process take place.
+ See the ([GO-CAM example](http://model.geneontology.org/5323da1800000002){:target="blank"} for an illustration. **REALLY ??????**

### The *NOT* modifier
The primary unit of biological modeling in GO-CAM is a molecular activity, e.g. protein kinase activity, of a specific gene product or complex. A molecular activity is an activity carried out at the molecular level by a gene product; this is specified by a term from the GO MF ontology. GO-CAM models are thus connections of GO MF annotations enriched by providing the appropriate context in which that function occurs. All connections in a GO-CAM model, e.g. between a gene product and activity, two activities, or an activity and additional contextual information, are made using clearly defined semantic relations from the [Relations Ontology](https://obofoundry.org/ontology/ro.html){:target="blank"}.

*NOT* is used when a GO term is expected to apply to a gene product, but an experiment, sequence analysis, etc. proves otherwise. *NOT* makes an explicit statement that a gene product has been experimentally demonstrated not to be able to carry out a particular activity or it has been shown to have lost that function (e.g. sequence analysis showing a loss of an active site or rapid divergence after a duplication event) over the course of evolution.
The *NOT* modifier is not to be used for negative or inconclusive experimental results.
GO-CAMs can be browsed and visualized at [http://geneontology.org/go-cam](https://geneontology.org/go-cam){:target="blank"} **REALLY ??????**

Contrary to positive annotations, *NOT* statements propagate down the ontology, such that the annotation `gene product` `NOT|enables` `protein kinase activity` means that the gene product does not enable protein serine/threonine kinase activity or protein tyrosine kinase activity either. Full guidelines for *NOT* are [on the GO wiki](https://wiki.geneontology.org/Elements_of_an_annotation){:target="blank"}.
## Gene product to term relations relations
+ Gene product to term relations ('gp2term') relations link gene products to GO terms in standard annotations.
+ Any of the relations can be associated with the modifer *NOT*. For the full list of permitted gp2term relations, see the [GO wiki](https://wiki.geneontology.org/Annotation_Relations#Standard_Annotation_Relations){:target="blank"}. The most common relations are:

### The *enables* relation
### *enables*

*enables* links a gene product to a Molecular Function it executes.

### The *contributes to* relation
### *contributes to*

*contributes to* links a gene product to a Molecular Function executed by a macromolecular complex, in which the Molecular Function cannot be ascribed to an individual subunit of that complex. Only the complex subunits required for the Molecular Function are annotated to the Molecular Function term with 'contributes to'.

### The *involved in* relation
### *involved in*

*involved in* links a gene product and a Biological Process in which the gene product's Molecular Function plays an integral role.

### The *acts upstream of or within* relation
### *acts upstream of or within*

*acts upstream of or within* links a gene product and a Biological Process when the mechanism relating the gene product's activity to the Biological Process is not known.

### The *located in* relation
### *located in*

*located in* links a gene product and the Cellular Component, specifically a cellular anatomical anatomy or virion component, in which a gene product has been detected.

### The *part of* relation
### *part of*

*part of* links a gene product and a protein-containing complex.

### The *colocalizes_with* relation
### *colocalizes_with*
*colocalizes_with* indicates a peripheral association of the protein with an organelle or complex. For example, human microtubule depolymerase KIF2A is dynamically localized to spindle poles, regulating the degradation of microtubule during mitotic progression.

<!-- ????-->
## Annotation extensions
Annotation extensions provide additional information about a GO annotation that cannot be captured in a single GO term. Please see publications describing annotation extensions: [Huntley & Lovering 2017](https://www.ncbi.nlm.nih.gov/pubmed/27812947){:target="blank"} and [Huntley *et al.* 2014](https://www.ncbi.nlm.nih.gov/pubmed/24885854){:target="blank"}. Annotation extensions are available in both the [GAF File Format](/docs/go-annotation-file-gaf-format-2.2/#annotation-extension-column-16) and the [GPAD File Format](/docs/gene-product-association-data-gpad-format/#annotation-extension).
## The *NOT* modifier

<!-- ????-->
## Annotation quality control
The GO Consortium implements a number of automated queries to check the quality of the annotations submitted to the GO database.
The *NOT* statement indicates that the gene product *does NOT* enable a Molecular Function, is *not part of* a Biological Process or is *not located in* or *active in* a specific Cellular Component. NOT statements are only used when a user might expect that the gene product would have a specific biological property (MF, BP or CC). *NOT* makes an explicit statement that a gene product has been experimentally demonstrated not to be able to carry out a particular activity or sequence analysis shows loss of an essential active site or rapid divergence after a duplication event over the course of evolution. The *NOT* modifier is not used for negative or inconclusive experimental results.

## GO-Causal Activity Models
GO-Causal Activity Models (GO-CAMs) use a defined “grammar” for linking multiple standard GO annotations into larger models of biological function (such as “pathways”) in a semantically structured manner. Minimally, a GO-CAM model must connect at least two standard GO annotations ([GO-CAM example](http://model.geneontology.org/5323da1800000002){:target="blank"}).
Both positive and NOT statements can be used between a single gene product and a GO term when there is unresolved conflicting experimental findings in the literature. If an isoform has a different function from the main isoform represented by the gene-centric entity, a NOT annotation can be captured together with the isoform identifier.

The primary unit of biological modeling in GO-CAM is a molecular activity, e.g. protein kinase activity, of a specific gene product or complex. A molecular activity is an activity carried out at the molecular level by a gene product; this is specified by a term from the GO MF ontology. GO-CAM models are thus connections of GO MF annotations enriched by providing the appropriate context in which that function occurs. All connections in a GO-CAM model, e.g. between a gene product and activity, two activities, or an activity and additional contextual information, are made using clearly defined semantic relations from the [Relations Ontology](https://obofoundry.org/ontology/ro.html){:target="blank"}.

GO-CAMs can be browsed and visualized at [http://geneontology.org/go-cam](https://geneontology.org/go-cam){:target="blank"}
Contrary to positive annotations, *NOT* statements propagate *down* the ontology to more specific terms, such that the annotation `gene product` `NOT|enables` `protein kinase activity` means that the gene product does not enable `protein kinase activity`, and neither does it enable and more specific functions, such as protein serine/threonine kinase activity and protein tyrosine kinase activity.

## Types of GO annotation files
## GO annotation files
* [Gene association file (GAF) 2.2](/docs/go-annotation-file-gaf-format-2.2/)
* [Gene Product Association Data (GPAD) 2.0 files](/docs/gene-product-association-data-gpad-format-2.0/) + [Gene Product Information (GPI) 2.0 files](/docs/gene-product-information-gpi-format-2.0/): companion files

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* Download [GO annotations by species](/docs/download-go-annotations/)
* Download [GO-CAM models](https://geneontology.org/go-cam){:target="blank"}

## GO as a dynamic source of biological annotations
GO aims to represent the current state of knowledge in biology, hence it is constantly revised and expanded as biological knowledge accumulates.

With the ever-increasing number of published articles, experiments and methods, covering all biology with the latest annotations is always challenging. We therefore invite researchers and computational scientists to [submit requests for missing, erroneous or out-of-date annotations to improve the GO database](/docs/contributing-to-go/).
## GO as a dynamic source of biological knowledge
GO aims to represent the current state of knowledge in biology, hence it is constantly revised and expanded as biological knowledge accumulates. With the ever-increasing number of published articles, experiments and methods, covering all biology with the latest annotations is always challenging. We therefore invite researchers and computational scientists to [submit requests for missing, erroneous or out-of-date annotations to improve the GO database](/docs/contributing-to-go/).

## Statistics
[GO statistics](/stats.html) are available both for the current release and over time.
Overall [GO statistics](https://geneontology.org/stats.html) and [detailed statistics](https://current.geneontology.org/release_stats/index.html) are available. The statistics are also [achived](https://release.geneontology.org/).

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