Guidelines from Annotation Camp

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Downstream Process guidelines

Guideline 1: Requesting more specific terms for downstream processes

Quite often it is the case that the most relevant GO term will not exist. It is desirable to request terms which describe the involvement of a process in another process, if that will give more specificity to the annotation. For example, to describe a gene product's "intent" to change the "state" of the cell; • Growth factor BMP2 is instrumental in cardiac cell differentiation • Following stimulation with BMP2, large numbers of genes are up/down regulated Requesting the new GO term 'BMP signaling involved in cardiac cell differentiation' may be preferable to annotating to the separate terms 'BMP signaling' and 'cardiac cell differentiation' as it will be clear how the gene product is involved in cardiac cell differentiation. i.e. qualify how the gene product is involved in the downstream process in preference to annotating to the downstream process term.

To assist in the creation of these new terms, the AmiGO 'Cross-product Term Request' tool will be useful, when it has been put into production.

Guideline 2: Annotating downstream processes for gene products involved in core or specific processes

For small scale experiments, curators should annotate to the experimental evidence in the paper.

However, curator judgement should be used, taking into account what the curator knows about:

a) the gene product; does it have a central role causing it to affect multiple processes, or does it have few specific targets?

b) the quality of the experimental assays performed in the paper; are they fully explained and the evidence supplied convincing? (See separate guidelines for annotation of high-throughput experiments.)

Example 1. Gene product involved in core process.

a) Yeast RNA polymerase II subunit RPB2

• has core function of RNA polymerase activity

• likely to affect large number of processes unrelated to its function

• most curators agree should annotate only to 'transcription'

b) Yeast spliceosome

• in S. cerevisiae several genes are components of spliceosome

• when mutated the strains have defects in translation

• later evidence confirmed the genes' involvement in mRNA splicing, NOT translation

• since most splicing in yeast is to ribosome genes the effect on translation was seen

• so annotations to 'translation' were removed from the spliceosome components Example 2. Gene product involved in core and specific process(es).

S. pombe gene Sre1

• direct transcriptional regulator of genes which have a role in heme and lipid biosynthesis (PMID:16537923)

• the curator judged this to be important information for this gene product

• annotations were made to:

    • specific RNA polymerase II transcription factor activity
    • regulation of transcription
    • positive regulation of heme biosynthesis
    • positive regulation of lipid biosynthesis

• In accordance with Guideline 1 for Downstream Processes, we would recommend that new terms are requested for;

    • Regulation of transcription involved in heme biosynthesis
    • Regulation of transcription involved in lipid biosynthesis

Guideline 3: Annotating downstream processes to poorly characterised gene products

If a gene product has limited experimental literature, such as a newly characterised protein, it is acceptable to annotate to more general 'downstream' process terms that may represent a phenotype.

As more functional information is published about a gene product, these annotations to potential downstream processes may be removed if they are deemed by the annotating group as indirect, or they may be kept depending on each MOD's strategy.

Always remove annotations that are incorrect or are from substandard evidence (NAS/TAS/IC) when replaced with better evidence to the same or more-granular term.

Guideline 4: Annotating downstream processes to gene products in a ligand-receptor signaling pathway

Annotate ligand-receptor signaling pathways as shown in following diagrams

General consideration; For a signaling pathway the ligand is considered part of the pathway, e.g. the insulin signaling pathway. In this case, a factor which limits/increases the availability of a ligand to a receptor should be annotated as regulating the ligand/receptor pathway.

N.B. Clarification of the start/end of a signaling pathway by the signaling group will allow us to refine these guidelines

File:Pathway annotation diagram.pdf

General note on revision of annotation sets

Relevant to gene products with little annotatable evidence

When further information about a gene product is obtained, there are two options for the annotation set:

1. Remove annotations to indirect/downstream processes (or update them to ‘regulation’ terms). This ‘deleted’ information is usually stored in the annotating group’s phenotype database.

2. Do not remove annotations to indirect/downstream processes because;

a) downstream annotations are supported by good evidence / want to keep as history of annotation / want to give a complete overview of knowledge about the gene product.

b) do not have resources to revise annotation sets / do not have alternative place to store data

It is important to note that MODs that keep these annotations will be a source of downstream process terms to MODs which do not keep these terms, via ISS from orthologs (e.g. PAINT).

Quality control checks

1. Check for co-annotation of a less-granular term with a more-granular term in the same path. Any action from this check is optional for each group as it may still be appropriate to keep both annotations, for example, it is acceptable to retain the less-granular annotation if;

• It has a 'better' evidence code

• The curator feels it adds weight to the more-granular annotation

• Both annotations add value, e.g. 'histone methylation' and 'protein amino acid methylation'