Annotation Conf. Call 2015-08-25

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We continued our discussion on the col-16 relations from the last call-,_August_11,_2015

7. examples for in_presence_of

in_presence_of: "Identifies a chemical, gene product or complex in the presence of which an ontology term is observed to apply to the annotated gene product

in_presence_of example Q550R2 ctxB

annotation: positive regulation of gene expression has_regulation_target carA, acaA, rasG,rasC, in_presence_of cAMP
FIGURE 6: Inhibition of cAMP-activation of Ras in ctxA−/B− cells. (A) cAMP activation of RasC and G.
FIGURE 5: Cortexillin-null cells have delayed and diminished expression of cAR1 and ACA. Suspensions of WT and cortexillin-null cells in starvation buffer were pulsed with cAMP…. ctxA− and ctxB− cells had delayed and reduced expression of ACA and cAR1, and ctxA−/B− cells had almost no expression of either ACA or cAR1.
COMMENT: Even though in Fig. 6 authors mention ‘cAMP activation, I like in_presence_of’ as it implies the correct thing; dependent_on implies that the regulation of the gene expression is dependent of cAMP, but it’s really dependent on the mutated gene(s) shown in this study. The addition of cAMP is mimicking natural starvation induced behaviour and in the assay they used cAMP. A more interpretive annotation would be:
positive regulation of gene expression has_regulation_target carA, acaA, rasG,rasC, happens_during response to starvation. Here the user must know what happens during starvation and it is more my interpretation than annotating what actually happens where users can interpret.

[Response from Rachael] If the authors are studying starvation but using cAMP to mimic this you should really add the starvation term to the extension, as this is the physiological process. In this case I would annotate to positive regulation of gene expression has_regulation_target x,y,z (,) part_of cellular response to starvation. This is saying (I think!) that as a result of starvation, ctxB regulates the expression of x,y,z. I'm not sure if there is an easy way to determine when to use part_of and when happens_during, but I would expect some regulation of gene expression to occur as a result of starvation, therefore I would say reg. of gene expression is part of starvation, rather than it occurs at the same time as starvation (in which case it would be happens_during).

Ruth: I would consider the role of the genes being regulated. Did the authors look at these genes because of their known/expected role in the cell's response to starvation? If these genes play a role in what the cell does in starved conditions then use 'part_of', if the genes are not known to have any role in starvation conditions, then use 'happens_during'.

Discussion 08-25-15 - need to look at more carefully. cAMP is well-studied, should we be capturing its role as a primary GO term here? Could use part_of cellular response to cAMP in the extension as well as the starvation term]

in_presence_of example Q54BD4 dstC

annotation: response to cation stress happens_during sorocarp development in_presence_of potassium chloride
PMID: 22944283
There are four such annotations made for all 4 tested stress factors that resulted in developmental defects.
p.793: we investigated the development under stress of the dstC− (STATc) mutant. The dstC− mutant showed severe defects with fewer and/or smaller fruiting bodies under all of the stressing conditions (KCl, NaCl, MgCl2, LiCl) FIGURE 6. TacA is involved in the stress response during development.
COMMENT: Here it feels not appropriate to replace in_presence_of with ‘dependent_on’ and I would have lots of gripes against using ‘has_input’. Not clear what ‘has_agent’ means, never used that and wouldn’t like it either in this context.
Petra Fey, dictyBase

[Response from Rachael] Here it sounds like you would want a new term 'response to potassium cation stress', in which case I think you should use has_input so that the OWL interpretation of a new term would be correct - but an editor should confirm this.

Discussion 08-25-15 - best way forward is to request a new GO term.
David OS: there might be some value in keeping this relation. Restricted definition for this relation is still acceptable.
Pascale: Are we trying to decompose too much? cAMP signaling is well studied pathway. We might be able to capture this with a GO term itself.

9&10. examples on the wiki how to use the in_presence_of relationship.

These examples were created to guide curators, if the relationship is being obsoleted it is important to give guidance on how this information can be captured, or state that it is out of the scope of GO.

9. Catabolism of hyaluronic acid (HA) by Hyal-1 only when CD44 antigen is present

Statement from paper:

In this study, CD44, a receptor for HA, and hyaluronidase-1, -2, and -3 (Hyal-1, -2 and -3) were stably expressed in HEK 293 cells and the mechanism of HA catabolism was systematically investigated using fluorescein-labeled HA. Without CD44 expression, none of Hyal-1, Hyal-2, and Hyal-3 affected catabolism of fl-HA. Most of the fl-HA in the medium remained intact and was eluted in the void volume of the Sepharose CL-2B column (Fig. 2, A)

previous recommendation Hyal-1: hyaluronan catabolic process: PMID:17170110: in_presence_of(UniProtKB:P16070 CD44)

Ruth: could this be captured using IGI and including CD44 in the with column, and also creating the forwards annotation?:
Hyal-1: hyaluronan catabolic process: PMID:17170110: IGI: CD44 CD44: hyaluronic acid binding: PMID:17170110: IDA: causually_upstream of hyaluronan catabolic process

Discussion Update 08-25-15 - did not discuss again, Ruth's example and she was not present]

10. Activation of caspases by ACER2 in presence of 4-hydroxyphenyl retinamide

Statement from paper:

We found that ACER2 knockdown significantly inhibited both the 4-HPR-induced cleavage of PARP (Fig. 5E) and activation of caspase-3 (Fig. 5F), supporting that ACER2 knockdown inhibits the 4-HPR-induced cell death in tumor cells... ACER2 overexpression markedly augmented both 4-HPR-induced cleavage of PARP (Fig. 6D) and activation of caspase-3 (Fig. 6E), supporting the view that ACER2 overexpression sensitizes tumor cells to 4-HPR-induced cell death.
previous recommendation ACER2: activation of cysteine-type endopeptidase activity involved in apoptotic process: PMID:20628055: IMP : in_presence_of(CHEBI:42588 4-hydroxyphenyl retinamide)

Ruth: looking again at the abstract: Increased generation of dihydrosphingosine (DHS), a bioactive sphingolipid, has been implicated in the cytotoxicity of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in tumor cells. However, how 4-HPR increases DHS remains unclear. Here we demonstrate that 4-HPR increases the expression of ACER2, which catalyzes the hydrolysis of dihydroceramides to generate DHS, and that ACER2 up-regulation plays a key role in mediating the 4-HPR-induced generation of DHS as well as the cytotoxicity of 4-HPR in tumor cells. ACER2 converts of DHC into DHS.

The abstract suggests that important process is the generation of DHS, and the other side is that I think currently discussing whether or not to include drugs in column 16, or whether this drugs should just be added to the WITH field, currently this would not be possible as this is not a binding expt and WITH cannot be included with IDA. Plus I think this annotation should be removed as I am not convinced that ACER2 directly activates caspases. (but it might be good to have the discussion assuming that it is possible to make the annotation).

Do we need a term to capture role of proteins which produce DHS which then induces apoptosis?

Discussion Update 08-25-15 - did not discuss again, Ruth's example and she was not present]

Logistics of maintaining relations

  • How do we inform curators/groups if they have used an obsolete relation?
    • Rama: one option is to post a message on the go-consortium list about the relations that are going obsolete, how many annotations are affected, possible remedy etc
  • How do groups rehouse annotations? In some cases there are several 1000 annotations. When a relation goes obsolete should we suggest an alternate relation that may be weaker and offer automatic substitution?
  • Until the groups have fixed their annotations we can suppress just the flagged col-16 data from going to production (not the entire annotation, just the col-16 data)
  • It would be very useful to have a place where curators can search for relations, see the definitions and example annotations