Column 16 discussion 12-12-09

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For reference page on column 16 Annotation_Cross-Products, see: http://wiki.geneontology.org/index.php/Annotation_Cross_Products

On the call

  • Emily Dimmer
  • Chris Mungall
  • Harold
  • Rama
  • Kimberly
  • Mary

Use of Cell Type as an Annotation_Cross_Product in column 16.

CL identifiers would be included in column 16 for a GO annotation whenever that information is present in a particular paper. No judgment is made as to whether a gene product is involved in a particular process in just a particular cell type or in all cell types. In other words, curators simply annotate all available data in a paper.

Therefore it is incorrect to assume that a gene product used in a GO annotation that has a CL identifier in column 16 is involved in the curated process only in that annotated cell type. Similarly, it would be a mistake to conclude that lack of a CL co-annotation indicates that a given gene product is involved in a process in all cell types where it is found. The only correct interpretation of a GO annotation with a CL co-annotation is that in one particular experiment a given gene product was found to be involved in a particular process in a particular cell line.

Annotation Format of column 16 for Cell Type:

• If CL is used to refine a CC annotation, then the relation (for now) must be part_of

• If CL is used to refine a BP or MF, then the relation (for now) must be occurs_in

Simple annotation for Column 16

Gene (col 2/3) Term (col 5) Ref (col 6) Ext (col 16)
TLR4 cell surface (GO:0005887) PMID:nnn part_of(CL:0000576)
CREB gluconeogenesis (GO:0006094) PMID:nnnn occurs_in(CL:0000182)

Where a protein has multiple cellular locations, CL identifiers should be separated by a pipe (|):

e.g. part_of(CL:0000127) | part_of(CL:0000236)


N.B. no meaning is attached to the order of that the CL identifiers are listed in column 16.

Questions

from the GOA team:

pre-meeting notes from Chris in green

1. Is there any timeline for inclusion of additional cross-references to other OBO ontologies/details on annotation targets?

Individual groups should not be restricted by I suggest for simplicity we focus efforts on a smaller set of well-understood ontologies.

  • Cell
  • CHEBI
  • Certain anatomical ontologies (although there are myriad issues here we should discuss)

And of course gene products, for which we should use UniProtKB for proteins and I'm not sure what for RNA products. Individual MOD IDs?

By focusing on Cell we make things simpler as we can say a lot with just two relation: occurs_in, for refining a biological process term to the cell where that process takes place, and part_of, for refining a subcellular localization with the cell. But if this group wants to focus on other areas where they feel additional expressivity is required, we can discuss that.

The original col16 documentation is too ontology-centric and does not pay enough attention to the gene product use cases. Apologies for this, we can discuss this more during the call.

2. In the proposed format for column 16, I can't see how I could indicate the biological processes which are dependent on a certain protein-protein interaction? Perhaps we need a new relationship such as 'required_for', to be used in conjunction with BP terms, which could be added into column 16 for the annotation to the 'protein binding' term? Example: The biological processes GO:0008284, GO:0050870, GO:0022409, occur when Q9P1W8 interacts with Q08722 (PMID:15383453).

The relationship would be "requires" rather than "required_for", because it is the relationship between the process/function in col5 and the entity referenced in col 16.

I would be interested in discussing this particular example and possibly some others as I think the gene product issue is an important one. What does "requires" mean here? Do the two gene products have to come together to form a complex or join a larger complex? Does one participate in signaling?

  • Q9P1W8 = SIRP beta2
  • Q08722 = CD47
  • GO:0008284 ! positive regulation of cell proliferation
  • GO:0050870 ! positive regulation of T cell activation
  • GO:0022409 ! positive regulation of cell-cell adhesion

Signal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPalpha binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPbeta1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPbeta2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

If the exact mechanism is not known then it is safe to simply use has_participant. E.g.

 col2 = Q9P1W8
 col5 = GO:0022409
 col16 = has_participant(Q08722)

(see next question)

3. We were confused on how to use 'has_input' and 'has_output'. There is not much information on these two relationships on this wiki page. In particular could we have examples describing the use of the 'has_output' relationship?

The idea here is that a process or function must have one or more participants - these are physical objects such as ions, molecules, proteins, RNAs, cell components, organs, etc. Participants can play different roles in a process, such as input, output or catalyst. The relation hierarchy is:

all participants must be present at some point during the process. If a participant is present at the beginning of the process, and it is changed in some way then it is an input. If it is present at the end, and has been changed in some way by the process, then it is an output.

This is very similar to [Reactome]

The meanings become more specific when paired with a biological process.

  • biosynthesis - the output is what is made from simpler parts during the process
  • catabolism - the input is what is broken down during the process

However, this is not always clear cut. Consider the case of binding to a protein such as importin. Is this input or output? In the Reactome model, the input would be an importin in the 'unbound' state and the output would be importin in the 'bound' state. But this is harder to state within the confines of the GO model. What we need to do here is work out the core types of function and process we wish to use in compositions and come up with clear guidelines. For the binding case I suggest usage of has_input

Note that in the majority of cases it is not wrong to state has_participant, any more than it is wrong to annotate higher up the GO DAG, this just doesn't communicate as much


4. What relationship should be used if we would like to indicate the target of a certain molecular function or biological process? For instance:

The target of protein Q9BRA2's protein-disulfide reductase activity is P63167

Q9BRA2 TXNDC17 GO:0047134 protein-disulfide reductase activity PMID:18579519 IDA F Thioredoxin domain-containing protein 17 TXNDC17|TXNL5|IPI00646689|TXD17_HUMAN protein taxon:9606 20080627 UniProtKB

The definition of GO:0047134 ! protein-disulfide reductase activity is Catalysis of the reaction: protein-dithiol + NAD(P)+ = protein-disulfide + NAD(P)H + H+.

Here we have two inputs and two outputs. Again here I think has_input is appropriate.

5. Should there be annotation guidelines requiring that when a column 16 is used to link a GO MF to a CC term, it needs to be complemented by an annotation using the same PMID for the corresponding CC term?

yes. we can discuss automatically filling these in as part of the GAF publishing pipeline, but I have a feeling people will be more comfortable with guidelines for what to do at annotation time, in which case, yes, it should be required to make the semi-redundant annotation.

6. Is it correct to assume that when a protein is the target of some transcription activity, we should indicate the target in column 16 in both the annotation to the process terms (e.g. positive regulation of transcription) and molecular function terms (e.g. transcription factor activity)?

If we ignore col16 for a moment I feel that in these cases groups should just make the F annotation, as we have the inter-ontology part_of links. See [GAF Inference].

If we are making just the F annotation, what is the relation that should be used for TF activity? I see now that the original documentation is too weak on the subject of gene products, and this is clearly an important use case.

Let's leave time to discuss this one during the call


Another question I feel will come up:

7. When do we use col 16 and when do we request a new term?