1. Relations in GO for 2009

2. Intro We have many relations ready to GO live in the scratch directory – within GO ontologies – across GO ontologies – between GO and external ontologies – Both cross product (N+S conditions) and regular links Requires a fundamental change in how we and our users think about GO and annotations – Tools that make use of these will better serve users

3. Relations in GO In the beginning there was is_a and part_of – Benefits: simplicity We could effectively ignore relations Most tools and users effectively do this – Speculation: recent introduction of regulates had no effect on majority of users – Drawbacks: lack of expressivity We need more relations – Regulation – Spatial relations – has_part for Process-Function – annotations

4. Example of a relation rule in GO Rule: – A is_a B, B is_a C  A is_a C Example: We can generalize this by having a rule for transitive relations – transitive r, A r B, B r C  A r C We can also write this as a composition rule: – is_a. is_a  is_a – Open question: does this notation help or hinder??

5. Transitivity We currently have two transitive relations in GO: – is_a. is_a  is_a – part_of. part_of  part_of Example: – mitotic prophase part_of mitosis – In GO, part_of is an all-some relation regulates is not defined to be transitive in GO (but the majority of tools still treat it as if it were!) Example:

6. Composition with is_a Any relation that follows the all-some pattern composes with is_a to itself Example: – (all) nucleus part_of (some) cell Composition: – is_a. R  R – R. is_a  R Example: – (all) mitotic prophase part_of (some) mitosis – mitosis is_a cell cycle phase  – (all) mitotic prophase part_of (some) cell cycle phase

7. is_apart_of is_a part_of Read row first, the column (so far the table is symmetric) Composition Table

8. is_apart_of is_a part_of Composition Table mitotic prophase part_of mitosis is_a cell cycle phase  (all) mitotic prophase part_of (some) cell cycle phase

9. is_apart_of is_a part_of Chained compositions A part_f B is_a C is_a D part_of E  A part_of B is_a D part_of E  A part_of D part_of E  A part_of E order of reduction does not matter

10. regulates transitive_over part_of regulates. part_of  regulates inferred link inferred link

11. regulates transitive_over part_of regulates. part_of  regulates inferred link inferred link (all) RoSPoMCC regulates (some) MCC

12. regulates transitive_over part_of regulates. part_of  regulates inferred link inferred link (all) RoSPoMCC regulates (some) MCC

13. is_apart_ofregulates is_a part_ofregulates part_of - regulates - Composition Table: Regulates

14. is_apart_ofregulates is_a part_ofregulates part_of - regulates - Composition Table: Regulates regulates. part_of  regulates

15. is_apart_ofregulates is_a part_ofregulates part_of N/A regulates - Composition Table: Regulates part_of. regulates  N/A

16. is_apart_ofregulates is_a part_ofregulates part_of - regulates indirectly regulates We have the option of defining additional relations These may be entirely implicit (i.e. we would never assert indirectly regulates in GO) regulates. regulates  indirectly regulates

17. is_apart_ofregulatesindirectly regulates is_a part_ofregulatesindirectly regulates part_of -- regulates indirectly regulates Regulates is not transitive Indirectly regulates is transitive

18. is_apart_ofregulatesindirectly regulates is_aIPR~R part_ofPP-- regulatesRR~R indirectly regulates ~R USE SYMBOLS? OR IS THIS GETTING TOO ABSTRACT?

19. Sub-relations regulates – negatively_regulates – positively_regulates

20. is_apart_ofregulates+ regulates - regulates is_aIPR+R-R part_ofPP regulatesRR + regulates +R - regulates -R

21. is_apart_ofregulates+ regulates - regulates indirectly regulates is_aIPR+R-R~R part_ofPP---- regulatesRR~R + regulates +R ~+R~-R~R - regulates -R ~-R~+R~R indirectly regulates ~R

22. Sub-relations + indirect R R R+ R- ~R ~R+ ~R- normal regulates relations asserted in GO indirect regulates relations never asserted, only implied

23. Regulation relation lattice RDRD RDRD RD+RD+ RD+RD+ RD-RD- RD-RD- ~R ~R+ ~R- renamed to DIRECTLY regulates?indirect regulates relations never asserted, only implied ~R G ~R G + ~R G - super-relation of indirect and direct regulation (call this one “regulates”?)

24. has_part NOT the inverse of part_of at the ontology level Example: – nucleus part_of cell: YES every nucleus is part_of some cell – by definition; e.g. extruded nuclei are ex-nuclei – cell has_part nucleus: NO not every cell has_part nucleus – mammalian erythrocytes, bacteria Example: –

25. Annotations and relations not just an ontology issue – this is of relevance to annotations too… The current simple methodology of propagating annotations up the graph only works for a small subset of relations – To understand how annotations and new relations interact we must think in terms of gene product relations

26. Gene product relations What is the relation between a gene product and – A molecular function? – A biological process? – A cellular component? Why care? What’s wrong with “annotated_to”? – We need to define these relations: to do justice to the biology to be able to deal with new relations within the GO itself

27. Why we should care How should annotation queries, analysis tools (slimmers, enrichment tools) etc treat the (pseudo-)new regulates relation? How should we recommend the process- function links be vizualized? How should these links be treated in queries?

28. Proposed relations for gene products For MF and BP: – has_potential – has_function_during For CC: – localized_to – This is more specific than has_location A gene product may travel through different locations – Formally: GP localized_to CC : GP executes some function in CC Names TBD MFs are ontologically like BPs (bfo processes)….

29. How to read a GAF gene product may not be explicitly in GAF – that’s OK – gene as proxy The relation does NOT apply to the gene however genes are only localized_to chromosomes, and only participate in gene expression. It’s the products that do the work is implicit, depending on F, C or P Examples:

30. Annotation relation composition is_a – always propagate over is_a localized_to. is_a  localized_to has_function_in. is_a  has_function_in part_of localized_to. part_of  localized_to has_function_in. part_of  has_function_in This is effectively what we do with gene product annotations now post-hoc logical justification for why it’s OK to propagate

31. Annotation relation composition: regulates regulates – localized_to. regulates  NEVER POSSIBLE localized_to never has a process as target regulates always has process as subject – has_function_in. regulates  regulator_of This introduces an addition implicit relation that can be used to sum gene product results – Fake AmiGO screenshot here

33. Annotation relation composition: inter- ontology links We have 183 CC->MF/BP links in scratch regulates – localized_to. has_function_in  ??may_contribute_to?? Example: RPS25A localized_to ribosome ribosome has_function_in protein biosynthesis –  RPS25A ??has_function_in?? protein biosynthesis No need for curator to make explicit IC claims Q: we never want “may” in relation names? Can we make a stronger claim? How does a curator know when to make an IC claim here? Potential confusion with contributes_to qualifier

34. Annotation relations and has_part Need some graphical illustrations See – http://wiki.geneontology.org/index.php/Has_part http://wiki.geneontology.org/index.php/Has_part – for now

35. Qualifiers Annotation qualifiers (contributes_to) have the effect of modifying the relation – NOT is not a qualifier – it is a logical operator We can add new relations to the qualifier column – geneProductA acted_on_during protein secretion by the type II secretion system

36. Secondary taxon IDs

37. Cell component relations We have 674 xp defs within CC in scratch – adjacent_to – surrounds/surrounded_by – spans – overlaps Use case: reactome Can we say anything about gene products here? – we can perform spatial gene product queries

38. Spatial reasoning – spans. adjacent_to  overlaps (??TBD!!) – SUN-KASH complex spans nuclear inner membrance – nuclear inner membrane adjacent_to nuclear lumen –  – SUN-KASH complex overlaps nuclear lumen

39. Links from BP to external ontologies Process-continuant links – A has_function_in cysteine biosynthesis  A ??has_participant?? cysteine this is true but can we make stronger claims – A has_function_in heart development  A has_participant heart c.f. heart process, TAZ gene How can we use this? – Browse GO annotations via other ontologies – Enrichment using anatomy terms… – AmiGO screenshots

40. what next?

41. Won’t this confuse users? We will provide a pre-made inferred relation table for all of GO – we could do this for gps too but it would be over a billion entries.. We can always distribute a dumbGO – just is_a and part_of, not even regulates Need more guidance on how this can be used

42. Discussion

43. What’s next? Move relations into GO editors file – post OE2 – CC-self spatial relations – BP->MF has_part regulates – BP->BP has_part (??) – External onts Dual releases? dumbGO and fullGO? Fix GOC tools (AmiGO, slimmer, enrichment, graphviz, refG) to deal appropriately – OE2 should already be fine Educate non-GOC folks