GO slimming tips
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This document discusses the use and development of Gene Ontology (GO) slims. GO slims provide a summary of an organism's biology using a reduced set of GO terms with less redundancy. The document outlines best practices for creating useful GO slims, including: 1) balancing coverage of annotated genes with biological relevance of terms; 2) minimizing overlaps between terms; and 3) splitting or lumping related terms as needed to improve biological interpretation. An iterative process is proposed to continually evaluate and improve existing GO slims.
GO slimming tips
- 1. Gene Ontology Slimming tips Val Wood GO consortium meeting Cambridge Oct 2017
- 2. Whole genome slims ● Provide a summary of an organim’s biology ● As a resource to plan curation (unannotated genes, intersections); to identify “unknown/uncharacterised genes” ■ Need to be biologically relevant, reduced redundancy is better ■ Need as complete coverage as possible Single gene overview (Allied Genome Resources ribbon) ○ Informs database user to branches of GO applicable to a single gene product (filter) ■ Usually higher level general grouping terms (redundancy is less critical) ● To interpret analysis (slimming prior to enrichment helps to interpret results, orientation) ● Summarize/display experimental results- smallest possible number of terms, but specific enough to convey results ● Taxon specific slim Slimming results sets (subsets of genes) ● There is no “one size fits all”, different slims for different use cases. ● With a ‘generic slim’ we should to provide instructions how to refine Common Uses of GO Slims
- 3. Coverage 1: Only slim one aspect at a time! All 3 aspects “unknown” = Biological Process unknown = (103+195+23+429) 103 750
- 4. Pombe using Pombase slim Unslimmed Unknown Coverage 2: Distinguish unannotated/unknown/unslimmed = IDs not recognised by the slim tool (i.e not in GO database) http://go.princeton.edu/cgi-bin/GOTermMapper will provide all 3 numbers (and can use your own slim) Unannotated
- 5. These 365 identifiers were not annotated in the slim, but they had non-root annotations that were not in the slim: These 734 identifiers had no non-root annotations: Total 1099 un-slimmed Pombe using AGR slim This number should be small in a slim with good coverage Coverage 3: Minimise “unslimmed” Pombe using PomBase slim It is difficult to define a slim to cover all annotated gene products without including terms with: ■ very small numbers of annotations, ■ or high level or biologically uninformative terms
- 6. PomBase AGR slim summary in matrix http://amigo.geneontology.org/matrix (Terms are on both axis, totals on diagonal) Some terms are not biologically informative for a generic slim because they can apply to *any* biological process Indicated by intersections with every process Information content low Non-specific Exact subset OK Relevance 1: A balance between coverage and content
- 7. Relevance 1: Avoid going “to high” Broad groupings Good for ribbon diagrams (display) Not good for summarizing biology. “Response to stimulus” is not very informative about biology (but covers >8000 (33%) mouse gene products ) Regulation of biological process 50% Mouse AGR slim in matrix http://amigo.geneontology.org/matrix (Terms are on both axis, totals on diagonal)
- 8. Mouse using AGR slim and GO term slim mapper Your input list contains 22928 genes. These 2037 identifiers were found to be unannotated: These 420 identifiers were not annotated in the slim, but they had non-root annotations that were not in the slim: These 4037 identifiers had no non-root annotations: Deleting “cell differentiation” loses 0 (descendant of development). Deleting “cell proliferation” loses only 5, most covered by development and cell cycle. Deleting “regulation of biological process” only loses 51 even though over half 11658 proteins annotated. These 476 identifiers were not annotated in the slim, but they had non-root annotations that were not in the slim: Relevance 2: Minimising overlaps (redundancy) Because many gene products are annotated to multiple terms, it not possible to create a slim with no overlaps. If term removal doesn’t change number slimmed is might not be so be useful for a slim. Complete subset terms should be avoided
- 9. Relevance 3: Lumping vs. splitting with common parent Very little intersection Between/within modules Largely unconnected but have common parent in the GO: nuclear and mitochondrial gene expression transmembrane and vesicle-mediated and nucleocytoplasmic transport
- 10. Relevance 3: Value of splitting, example with real data Geneexpression From Hayles et al A genome-wide resource of cell cycle and cell shape genes of fission yeast.
- 11. Current PomBase slim in matrix, overlaps low, information content high Zero overlaps between vesicle-mediated transport Nucleocytoplasmic transport and transmembrane transport, not biologically connected. Relevance 3: Lumping vs. splitting with common parent
- 12. Relevance 4: Avoid single step processes ● GO:0016570 histone modification ● GO:0006468 protein phosphorylation ● GO:0006470 protein dephosphorylation ● GO:0043543 protein acylation ● GO:0016310 phosphorylation ● GO:0016311 dephosphorylation ● GO:0055114 oxidation-reduction process ● GO:0006464 cellular protein modification process ● GO:0043086 negative regulation of catalytic activity All are examples of molecular function grouping terms in the BP ontology. Not informative about physiological role, only biochemical role For this reason “protein metabolism” the ancestor of protein modifications should also be avoided in the generic slim.
- 13. Proposed Iterative procedure Evaluate individual species coverage of existing generic slim (BP) What is missing? Add terms to cover Evaluate species coverage Which terms could be removed without affecting coverage? Remove Test (evaluate species coverage changes) What is missing? Add terms to cover Evaluate species coverage Which terms should be split to improve biological relevence? Split Check coverage was not affected (or recommend improved annotation specificity)
- 14. Spares
- 15. Possible changes to evaluate Remove cell proliferation cell differentiation cellular component organization and biogenesis RNA processing (see Gene expression) regulation of biological process Add cytoskeleton organization chromatin organization ribosome biogenesis (>1000 annot) tRNA metabolic process (1157 annot) gene expression (includes translation) Not covered currently detoxification amino acid metabolic process (or vitamin metabolic process small cofactor metabolic process molecule?)