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BI class 2010 Gene Ontology Overview and Perspective

BI class 2010 Gene Ontology Overview and Perspective. What is Ontology?. Dictionary: A branch of metaphysics concerned with the nature and relations of being. 1606. 1700s. What is the Gene Ontology?.

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BI class 2010 Gene Ontology Overview and Perspective

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  1. BI class 2010Gene OntologyOverview and Perspective

  2. What is Ontology? • Dictionary: A branch of metaphysics concerned with the nature and relations of being 1606 1700s

  3. What is the Gene Ontology? • Allows biologists to make queries across large numbers of genes without researching each one individually

  4. So what does that mean? From a practical view, ontology is the representation of something we know about. “Ontologies" consist of a representation of things, that are detectable or directly observable, and the relationships between those things. is part of

  5. Car? Ontology -definition

  6. Gene Ontology (GO) Consortium • Formed to develop a shared language adequate for the annotation of molecular characteristics across organisms; a common language to share knowledge. • Seeks to achieve a mutual understanding of the definition and meaning of any word used; thus we are able to support cross-database queries. • Members agree to contribute gene product annotations and associated sequences to GO database.

  7. How does GO work? • What does the gene product do? • Where and does it act? • Why does it perform these activities? What information might we want to capture about a gene product?

  8. What is the Gene Ontology? • Set of standard biological phrases (terms) which are applied to genes/proteins: • protein kinase • apoptosis • membrane

  9. GO represents three biological domains Molecular Function = elemental activity/task • the tasks performed by individual gene products; examples are carbohydrate binding and ATPase activity Biological Process = biological goal or objective • broad biological goals, such as mitosis or purine metabolism, that are accomplished by ordered assemblies of molecular functions Cellular Component= location or complex • subcellular structures, locations, and macromolecular complexes; examples include nucleus, telomere, and RNA polymerase II holoenzyme

  10. The GO is Actually Three Ontologies Cellular Component GO term: mitochondrion GO id: GO:0005739 Definition: A semiautonomous, self replicating organelle that occurs in varying numbers, shapes, and sizes in the cytoplasm of virtually all eukaryotic cells. It is notably the site of tissue respiration. Biological Process GO term: tricarboxylic acid cycle Synonym: Krebs cycle Synonym: citric acid cycle GO id: GO:0006099 Molecular Function GO term: Malate dehydrogenase. GO id: GO:0030060 (S)-malate + NAD(+) = oxaloacetate + NADH.

  11. Cellular Component • where a gene product acts

  12. Cellular Component

  13. Cellular Component

  14. Cellular Component • Enzyme complexes in the component ontology refer to places, not activities.

  15. Molecular Function • activities or “jobs” of a gene product glucose-6-phosphate isomerase activity

  16. Molecular Function insulin binding insulin receptor activity

  17. Molecular Function • A gene product may have several functions • Sets of functions make up a biological process.

  18. cell division Biological Process a commonly recognized series of events

  19. Biological Process transcription

  20. Biological Process regulation of gluconeogenesis

  21. Biological Process limb development

  22. Ontology Structure • Terms are linked by two relationships • is-a  • part-of 

  23. cell membrane chloroplast mitochondrial chloroplast membrane membrane is-a part-of Ontology Structure

  24. Ontology Structure • Ontologies are structured as a hierarchical directed acyclic graph (DAG) • Terms can have more than one parent and zero, one or more children

  25. Ontology Structure Directed Acyclic Graph (DAG) - multiple parentage allowed cell membrane chloroplast mitochondrial chloroplast membrane membrane

  26. A (machine) interpretable representation of some aspect of biological reality Optic placode sense organ eye develops from is_a part_of lens A biological ontology is: • what kinds of things exist? • what are the relationships between these things?

  27. GO Definitions: Each GO term has 2 Definitions A definition written by a biologist: necessary & sufficient conditions written definition (not computable) Graph structure: necessary conditions formal (computable)

  28. Appropriate Relationships to Parents • GO currently has 2 relationship types • Is_a • An is_a child of a parent means that the child is a complete type of its parent, but can be discriminated in some way from other children of the parent. • Part_of • A part_of child of a parent means that the child is always a constituent of the parent that in combination with other constituents of the parent make up the parent.

  29. Placement in the Graph: Selecting Parents • To make the most precise definitions, new terms should be placed as children of the parent that is closest in meaning to the term. • To make the most complete definitions, terms should have all of the parents that are appropriate. • In an ontology as complicated as the GO this is not as easy as it seems.

  30. nucleus Part_of relationship True Path Violations Create Incorrect Definitions ..”the pathway from a child term all the way up to its top-level parent(s) must always be true". chromosome

  31. Is_a relationship Mitochondrial chromosome True Path Violations ..”the pathway from a child term all the way up to its top-level parent(s) must always be true". chromosome

  32. nucleus Part_of relationship Is_a relationship Mitochondrial chromosome True Path Violations ..”the pathway from a child term all the way up to its top-level parent(s) must always be true". A mitochondrial chromosome is not part of a nucleus! chromosome

  33. nucleus chromosome mitochondrion Part_of relationship Part_of relationship Is_a relationships Nuclear chromosome Mitochondrial chromosome True Path Violations ..”the pathway from a child term all the way up to its top-level parent(s) must always be true".

  34. The Development Node (some example for consistent definitions)

  35. Cell level [i] y cell differentiation ---[p] y cell fate commitment ------[p] y cell fate specification ------[p] y cell fate determination ---[p] y cell development ------[p] y cellular morphogenesis during differentiation ------[p] y cell maturation

  36. y cell differentiation The process whereby a relatively unspecialized cell acquires specialized features of a y cell. [i] y cell differentiation ---[p] y cell fate commitment ------[p] y cell fate specification ------[p] y cell fate determination ---[p] y cell development ------[p] y cellular morphogenesis during differentiation ------[p] y cell maturation http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed6.figgrp.41173

  37. y cell fate commitment The process whereby the developmental fate of a cell becomes restricted such that it will develop into a y cell. [i] y cell differentiation ---[p] y cell fate commitment ------[p] y cell fate specification ------[p] y cell fate determination ---[p] y cell development ------[p] y cellular morphogenesis during differentiation ------[p] y cell maturation

  38. y cell fate specification The process whereby a cell becomes capable of differentiating autonomously into a y cell in an environment that is neutral with respect to the developmental pathway. Upon specification, the cell fate can be reversed. [i] y cell differentiation ---[p] y cell fate commitment ------[p] y cell fate specification ------[p] y cell fate determination ---[p] y cell development ------[p] y cellular morphogenesis during differentiation ------[p] y cell maturation

  39. y cell fate determination The process whereby a cell becomes capable of differentiating autonomously into a y cell regardless of its environment; upon determination, the cell fate cannot be reversed. [i] y cell differentiation ---[p] y cell fate commitment ------[p] y cell fate specification ------[p] y cell fate determination ---[p] y cell development ------[p] y cellular morphogenesis during differentiation ------[p] y cell maturation

  40. Gene Ontology widely adopted AgBase

  41. Terms are defined graphically relative to other terms

  42. The Gene Ontology (GO) • Build and maintain logically rigorous and biologically accurate ontologies • Comprehensively annotate reference genomes • Support genome annotation projects for all organisms • Freely provide ontologies, annotations and tools to the research community

  43. Building the ontologies • The GO is still developing daily both in ontological structures and in domain knowledge • Ontology development workshops focus on specific domains needing experts • 2 workshops / year • Metabolism and cell cycle • Immunology and defense response • Early CNS development • Peripheral nervous system development • Blood Pressure Regulation • Muscle Development

  44. Fatty acid biosynthesis ( Swiss-Prot Keyword) EC:6.4.1.2 (EC number) IPR000438: Acetyl-CoA carboxylase carboxyl transferase beta subunit (InterPro entry) GO:Fatty acid biosynthesis (GO:0006633) GO:acetyl-CoA carboxylaseactivity (GO:0003989) GO:acetyl-CoA carboxylase activity (GO:0003989) Mappings files

  45. Building the ontology: Immune System Process 725 new terms related to immunology 127 new terms added to cell type ontology Red part_of Blue is_a

  46. GO:0047519 P05147 GO:0047519 IDA PMID:2976880 PMID: 2976880 IDA Annotating Gene Products using GO P05147 Gene Product Reference GO Term Evidence

  47. Gene protein inherits GO term • There is evidence that this gene product can be best classified using this term • The sourceof the evidence and other information is included • There is agreement on the meaning of the term

  48. Annotations are assertions Annotations for APP: amyloid beta (A4) precursor protein

  49. We use evidence codes to describe the basis of the annotation • IDA: Inferred from direct assay • IPI: Inferred from physical interaction • IMP: Inferred from mutant phenotype • IGI: Inferred from genetic interaction • IEP: Inferred from expression pattern • IEA: Inferred from electronic annotation • ISS: Inferred from sequence or structural similarity • TAS: Traceable author statement • NAS: Non-traceable author statement • IC: Inferred by curator • RCA: Reviewed Computational Analysis • ND: no data available Direct Experiment in organism NO Direct Experiment Inferred from evidence

  50. GO structure • GO isn’t just a flat list of biological terms • terms are related within a hierarchy

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