Annotating downstream processes

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  TO BE REVIEWED BASED ON NEW RELATIONS (acts upstream of...) 

Downstream Process guidelines

  • Where there is limited knowledge regarding the processes that a gene product is directly involved in, curators may often have annotated to terms that describe the processes that are downstream of the direct activity of the gene product. Where more knowledge regarding a gene product's functional activity exists, curators need to make a judgement as to how to represent its direct activities and whether to continue to include downstream processes in the annotation set. Curators are encouraged to request more specific terms to describe how the gene product is involved in a downstream process and also evaluate the annotation set as more functional information becomes available. More detailed curator guidance is provided below.

Requesting more specific terms for downstream processes

  • Where a specific, descriptive GO term does not exist (for instance to describe the involvement of a process in another process), curators are encouraged to request these terms to provide more specificity to their annotation. For example, to describing the "intent" of growth factor BMP2 to change the "state" of the cell is instrumental in cardiac cell differentiation. Therefore requesting the new GO term BMP signaling involved in cardiac cell differentiation would make it possible to qualify how the gene product is involved in the downstream process of cardiac cell differentiation than annotating to separate terms BMP signaling and cardiac cell differentiation.

Annotating downstream processes for gene products involved in core or specific processes

  • Curators should annotate to the experimental evidence in the paper. However, curator judgement should be used, taking into account what the curator knows about:
  • The background of the gene product; is it widely known to have a central role causing it to affect multiple processes, or does it have few specific targets?
  • 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. Yeast RNA polymerase II subunit RPB2 RNA polymerase II subunit RPB2 has a core function of RNA polymerase activity, which has downstream effects on a large number of processes. However, curators should only annotate to the gene product's transcription activity, rather than the multiple downstream processes altered as a consequence of its activity. Yeast spliceosome In S. cerevisiae, the mutation of several genes that are components of the spliceosome result in translation defects. However, later work supplied evidence for the genes' involvement in mRNA splicing, not translation. Downstream effects on translation are to be expected as many ribosomal transcripts are spliced in yeast. The curation decision was to remove annotations to the term translation for spliceosome component genes once data was available to describe the direct activity the genes contributed towards. Example 2. Gene product involved in core and specific process(es). S. pombe gene Sre1 The S. pombe gene Sre1 is a transcriptional regulator of genes that are involved in heme and phosphoplipid biosynthesis. From reading PMID:16537923 the curator decided this information should be captured in the annotation. Therefore annotations were made to:
       RNA polymerase II core promoter proximal region sequence-specific DNA binding
       regulation of transcription, DNA-dependent or regulation of transcription from RNA polymerase II promoter
       positive regulation of heme biosynthesis
       positive regulation of phospholipid biosynthesis

In addition, in accordance with these guidelines for annotating downstream processes, we would recommend that new terms are requested for:

       regulation of transcription involved in heme biosynthesis
       regulation of transcription involved in phospholipid biosynthesis

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

  • Curators should anotate ligand-receptor signaling pathways as shown in the following diagrams. For a signaling pathway, the ligand is considered part of the pathway. Therefore a factor which limits or increases the availability of a ligand to a receptor should be annotated as regulating the ligand/receptor pathway. N.b. Ongoing work to clarify of the start/end of a signaling pathway in the definition of GO terms will allow us to refine these guidelines.


Updating annotations to downstream processes in light of new findings

  • If a gene product has limited experimental literature, such as a newly characterised protein, it is understandable that curators need to annotate to more general 'downstream' process terms that may, in fact, represent a phenotype. However, as more functional information is published about a gene product, curators may decide to revise these annotations to downstream processes. However currently different actions are taken by different curation groups, based on considerations of user requirements and curation capacity:
  • Annotations may be removed to indirect/downstream processes, or updated to 'regulation' terms. This 'deleted' information is usually stored in the annotating group's phenotype database.
  • Annotations not removed to indirect/downstream processes because downstream annotations are supported by good evidence, or the group wants to keep as history of annotation or give a complete overview of knowledge about the gene product.
  • the curation group does not have resources to revise annotation sets or do not have alternative place to store data
  • Curation groups need to be aware that keep annotations to downstream processes will be a source of such data to other groups who may have a different annotation philosophy.