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1 shtml An Introduction to the Gene Ontology (GO) The Gene Ontology project provides a controlled vocabulary to describe gene and gene product attributes in any organism.

2 tml Search the Gene Ontology Database Search for genes, proteins or GO terms using AmiGO :gene or protein name GO term or ID AmiGO is the official GO browser and search engine. Browse the Gene Ontology with AmiGO. AmiGO Browse the Gene Ontology with AmiGO

3 What does the Gene Ontology Consortium do? Terms in the Gene Ontology Species-specific terms Obsolete terms The Ontologies Cellular component Biological processMolecular functionOntology structure What GO is NOT Annotation and toolsDownloadsBeyond GO Cross- products Mappings to other classification systems Contributing to GOWhat does the Gene Ontology Consortium do? Terms in the Gene Ontology Species-specific terms Obsolete terms The Ontologies Cellular component Biological processMolecular functionOntology structure What GO is NOT Annotation and toolsDownloadsBeyond GO Cross- products Mappings to other classification systems Contributing to GO

4 What does the Gene Ontology Consortium do? Biologists currently waste a lot of time and effort in searching for all of the available information about each small area of research. This is hampered further by the wide variations in terminology that may be common usage at any given time, which inhibit effective searching by both computers and people. For example, if you were searching for new targets for antibiotics, you might want to find all the gene products that are involved in bacterial protein synthesis, and that have significantly different sequences or structures from those in humans. If one database describes these molecules as being involved in 'translation', whereas another uses the phrase 'protein synthesis', it will be difficult for you - and even harder for a computer - to find functionally equivalent terms. The Gene Ontology (GO) project is a collaborative effort to address the need for consistent descriptions of gene products in different databases. The project began as a collaboration between three model organism databases, FlyBase ( Drosophila ), the Saccharomyces Genome Database (SGD) and the Mouse Genome Database (MGD), in FlyBase Saccharomyces Genome Database Mouse Genome Database Since then, the GO Consortium has grown to include many databases, including several of the world's major repositories for plant, animal and microbial genomes. See the GO Consortium page for a full list of member organizations. GO Consortium page

5 The GO project has developed three structured controlled vocabularies (ontologies) that describe gene products in terms of their associated biological processes, cellular components and molecular functions in a species- independent manner. There are three separate aspects to this effort: first, the development and maintenance of the ontologies themselves; second, the annotation of gene products, which entails making associations between the ontologies and the genes and gene products in the collaborating databases; and third, development of tools that facilitate the creation, maintenance and use of ontologies. The use of GO terms by collaborating databases facilitates uniform queries across them. The controlled vocabularies are structured so that they can be queried at different levels: for example, you can use GO to find all the gene products in the mouse genome that are involved in signal transduction, or you can zoom in on all the receptor tyrosine kinases. This structure also allows annotators to assign properties to genes or gene products at different levels, depending on the depth of knowledge about that entity.

6 Terms in the Gene Ontology The building blocks of the Gene Ontology are the terms, so what makes up a GO term? Each entry in GO has a unique numerical identifier of the form GO:nnnnnnn, and a term name, e.g. cell, fibroblast growth factor receptor binding or signal transduction. Each term is also assigned to one of the three ontologies, molecular function, cellular component or biological process. The majority of terms have a textual definition, with references stating the source of the definition. If any clarification of the definition or remarks about term usage are required, these are held in a separate comments field. Many GO terms have synonyms; GO uses 'synonym' in a loose sense, as the names within the synonyms field may not mean exactly the same as the term they are attached to. Instead, a GO synonym may be broader or narrower than the term string; it may be a related phrase; it may be alternative wording, spelling or use a different system of nomenclature; or it may be a true synonym. This flexibility allows GO synonyms to serve as valuable search aids, as well as being useful for applications such as text mining and semantic matching. The relationship of the synonym to the term is recorded within the GO file.

7 The scope of the Gene Ontology overlaps with a number of other databases, and in cases where a GO term is identical in meaning to an object in another database, a database cross reference is added to the term. These cross references can also be downloaded from the mappings to GO page. mappings to GO Species-specific terms The Gene Ontology aims to provide a controlled vocabulary that can be used to describe any organism; nevertheless, many functions, processes and components are not common to all life forms. The convention is to include any term that can apply to more than one taxonomic class of organism. To specify the class of organisms to which a term is applicable, GO uses the designator sensu, 'in the sense of'; for example, trichome differentiation (sensu Magnoliophyta) represents the differentiation of plant hair cells (trichomes). Obsolete terms Occasionally, a term is found that is outside the scope of GO, is misleadingly named or defined, or describes a concept that would be better represented in another way. Rather than delete the term, it is deprecated or made obsolete. The term and ID still exist in the GO database, but the term is marked as obsolete, and a comment added, giving a reason for the obsoletion and recommending alternative terms where appropriate.

8 The Ontologies The three organizing principles of GO are cellular component, biological process and molecular function. A gene product might be associated with or located in one or more cellular components; it is active in one or more biological processes, during which it performs one or more molecular functions. For example, the gene product cytochrome c can be described by the molecular function term oxidoreductase activity, the biological process terms oxidative phosphorylation and induction of cell death, and the cellular component terms mitochondrial matrix and mitochondrial inner membrane.

9 Cellular component A cellular component is just that, a component of a cell, but with the proviso that it is part of some larger object; this may be an anatomical structure (e.g. rough endoplasmic reticulum or nucleus ) or a gene product group (e.g. ribosome, proteasome or a protein dimer). See the documentation on the cellular component ontology for more details. documentation on the cellular component ontology

10 Biological process A biological process is series of events accomplished by one or more ordered assemblies of molecular functions. Examples of broad biological process terms are cellular physiological process or signal transduction. Examples of more specific terms are pyrimidine metabolism or alpha-glucoside transport. It can be difficult to distinguish between a biological process and a molecular function, but the general rule is that a process must have more than one distinct steps.A biological process is not equivalent to a pathway; at present, GO does not try to represent the dynamics or dependencies that would be required to fully describe a pathway.Further information can be found in the process ontology documentation. process ontology documentation

11 Molecular function Molecular function describes activities, such as catalytic or binding activities, that occur at the molecular level. GO molecular function terms represent activities rather than the entities (molecules or complexes) that perform the actions, and do not specify where or when, or in what context, the action takes place. Molecular functions generally correspond to activities that can be performed by individual gene products, but some activities are performed by assembled complexes of gene products. Examples of broad functional terms are catalytic activity, transporter activity, or binding ; examples of narrower functional terms are adenylate cyclase activity or Toll receptor binding. It is easy to confuse a gene product name with its molecular function, and for that reason many GO molecular functions are appended with the word "activity". The documentation on gene products explains this confusion in more depth. The documentation on the function ontology explains more about GO functions and the rules governing them. gene products documentation on the function ontology

12 Ontology structure The terms in an ontology are linked by two relationships, is_a and part_of. is_a is a simple class-subclass relationship, where A is_a B means that A is a subclass of B; for example, nuclear chromosome is_a chromosome. part_of is slightly more complex; C part_of D means that whenever C is present, it is always a part of D, but C does not always have to be present. An example would be nucleus part_of cell ; nuclei are always part of a cell, but not all cells have nuclei. The ontologies are structured as directed acyclic graphs, which are similar to hierarchies but differ in that a child, or more specialized, term can have many parents, or less specialized, terms. For example, the biological process term hexose biosynthesis has two parents, hexose metabolism and monosaccharide biosynthesis. This is because biosynthesis is a subtype of metabolism, and a hexose is a type of monosaccharide. When any gene involved in hexose biosynthesis is annotated to this term, it is automatically annotated to both hexose metabolism and monosaccharide biosynthesis, because every GO term must obey the true path rule : if the child term describes the gene product, then all its parent terms must also apply to that gene product. true path rule

13 What GO is NOT It is important to clearly state the scope of GO, and what it does and does not cover. The ontologies section explains the domains covered by GO; the following areas are outside the scope of GO, and terms in these domains would not appear in the ontologies.Gene products: e.g. cytochrome c is not in the ontologies, but attributes of cytochrome c, such as oxidoreductase activity, are.Processes, functions or components that are unique to mutants or diseases: e.g. oncogenesis is not a valid GO term because causing cancer is not the normal function of any gene.Attributes of sequence such as intron/exon parameters: these are not attributes of gene products and will be described in a separate sequence ontology (see the OBO website for more information).Protein domains or structural features.Protein-protein interactions.Environment, evolution and expression.Anatomical or histological features above the level of cellular components, including cell types.GO is not a database of gene sequences, nor a catalog of gene products. Rather, GO describes how gene products behave in a cellular context.GO is not a dictated standard, mandating nomenclature across databases. Groups participate because of self-interest, and cooperate to arrive at a consensus.GO is not a way to unify biological databases (i.e. GO is not a 'federated solution'). Sharing vocabulary is a step towards unification, but is not, in itself, sufficient. Reasons for this include the following:Knowledge changes and updates lag behind.Individual curators evaluate data differently. While we can agree to use the word 'kinase', we must also agree to support this by stating how and why we use 'kinase', and consistently apply it. Only in this way can we hope to compare gene products and determine whether they are related.GO does not attempt to describe every aspect of biology; its scope is limited to the domains described above. Back to ontologies section OBO website Back to

14 top top Annotation and tools How do the terms in GO become associated with their appropriate gene products? Collaborating databases annotate their genes or gene products with GO terms, providing references and indicating what kind of evidence is available to support the annotations. More information can be found in the GO Annotation Guide.If you browse any of the contributing databases, you'll find that each gene or gene product has a list of associated GO terms. Each database also publishes downloadable files containing these associations; these can be downloaded from the GO annotations page. You can browse the ontologies using a range of web-based browsers. A full list of these, and other tools for analyzing gene function using GO, is available on the GO Tools section.In addition, the GO consortium has prepared GO slims, 'slimmed down' versions of the ontologies that allow you to annotate genomes or sets of gene products to gain a high-level view of gene functions. Using GO slims you can, for example, work out what proportion of a genome is involved in signal transduction, biosynthesis or reproduction. See the GO Slim Guide for more information. GO Annotation Guide GO annotations page GO Tools section GO Slim Guide

15 Beyond GO GO allows us to annotate genes and their products with a limited set of attributes. For example, GO does not allow us to describe genes in terms of which cells or tissues they're expressed in, which developmental stages they're expressed at, or their involvement in disease. It is not necessary for GO to do these things because other ontologies are being developed for these purposes. The GO consortium supports the development of other ontologies and makes its tools for editing and curating ontologies freely available. A list of freely available ontologies that are relevant to genomics and proteomics and are structured similarly to GO can be found at the Open Biomedical Ontologies website. A larger list, which includes the ontologies listed at OBO and also other controlled vocabularies that do not fulfill the OBO criteria is available at the Ontology Working Group section of the Microarray Gene Expression Data (MGED) Network site. Open Biomedical Ontologies website Ontology Working Group Microarray Gene Expression Data (MGED) Network site

16 Download All data from the GO project is freely available. You can download the ontology data in a number of different formats, including XML and mySQL, from the GO Downloads page. For more information on the syntax of these formats, see the GO File Format Guide.If you need lists of the genes or gene products that have been associated with a particular GO term, the Current Annotations table tracks the number of annotations and provides links to the gene association files for each of the collaborating databases is available. GO Downloads page GO File Format Guide Current Annotations table

17 GO term enrichment Hypergeometric SGD : example using LA output

18

19 Transitive functional annotation by shortest-path analysis of gene expression data PNAS | October 1, 2002 | vol. 99 | no. 20 | Xianghong Zhou *, Ming-Chih J. Kao *, and Wing Hung Wong Fig. 1. (A) Application of the shortest-path (SP) algorithm to gene expression data. Nine genes are depicted in the graph. The distance between two genes is a decreasing function of their correlation. For example, there are multiple expression dependence paths leading from gene a to gene e. Among them, the shortest dependence path is a-b-c-d-e, with genes b, c, and d serving as the transitive genes. This is the most parsimonious summary of the expression relationship between the terminal genes a and e. (B) Level 0 (L0) and level 1 (L1) matches of genes on the SP a-b-c-d-e defined according to their relationships in the Gene Ontology (GO) classification tree. With respect to the terminal genes a and e, the transitive gene b is a L0 match because it is annotated in the informative node where a and e are annotated; the transitive gene c is a L1 match because it shares the same direct parent as the two terminal genes; the transitive gene d is neither a L0 nor a L1 match.

20 Current methods for the functional analysis of microarray gene expression data make the implicit assumption that genes with similar expression profiles have similar functions in cells. However, among genes involved in the same biological pathway, not all gene pairs show high expression similarity. Here, we propose that transitive expression similarity among genes can be used as an important attribute to link genes of the same biological pathway. Based on large-scale yeast microarray expression data, we use the shortest-path analysis to identify transitive genes between two given genes from the same biological process. We find that not only functionally related genes with correlated expression profiles are identified but also those without. In the latter case, we compare our method to hierarchical clustering, and show that our method can reveal functional relationships among genes in a more precise manner. Finally, we show that our method can be used to reliably predict the function of unknown genes from known genes lying on the same shortest path. We assigned functions for 146 yeast genes that are considered as unknown by the Saccharomyces Genome Database and by the Yeast Proteome Database. These genes constitute around 5% of the unknown yeast ORFome.

21 Data Processing Saccharomyces cerevisiae gene expression profiles from the Rosetta Compendium ( 6 ), which includes 300 deletion and drug treatment experiments. Genes were annotated by using the biological process ontology of Gene Ontology (GO) ( 7 ) provided by the Saccharomyces Genome Database (SGD) ( 8 ) After removing the genes without GO process annotation and the 20 genes for which there are less than 80 experimental measurements in the Rosetta Compendium, we were left with 266 mitochondrial, 398 cytoplasmic, and 659 nuclear GO-annotated genes. For each of the three sets of genes, we calculated the expression similarities of all gene pairs {a, b} using C a,b, the minimum of the absolute value of leave-one-out Pearson correlation coefficient estimates. This estimate is a measurement robust against single experiment outliers and sensitive to overall similarities in expression patterns.

22 Graph Construction and SP Computation. We constructed three graphs, one for each set of the 266 mitochondrial genes, the 398 cytoplasmic genes, and the 659 nuclear genes. In each graph, two genes were assigned an edge if their absolute expression correlation C a,b was higher than = 0.6. This cut-off, while conservative, nonetheless retains a sufficient number of connected gene pairs in the graph. The edge length between vertices a and b is d a,b = f(C a,b ) = (1 C a,b )k. The powering factor k is used to enhance the differences between low and high correlations. Because the length of a path is the sum of the individual edge lengths, by exaggerating the differences between edge lengths, the SPs will be more likely to cover more transitive genes. Thus by increasing k we gain more power to reveal transitive co-expression. We set k = 6 because for k 6, the numbers of transitive genes stabilizes (detailed results at ). To ensure the quality of SPs, we consider only SPs with total path lengths <

23 Predicting the Functions of Unknown Genes. We use the SP method to classify previously unannotated yeast genes by adding the 3,255 ORFs unknown to SGD into the graphs of known genes in the mitochondrial, cytoplasmic, and nuclear compartments. As before, an edge is constructed between two genes if their absolute expression correlation is higher than 0.6. For all pairs of known genes, we determine the SPs connecting them. For the purpose of functional prediction, we would like to assign a putative function that is as specific as possible to the gene. Given all known genes on a SP, we achieve this by tracing back their annotations along the GO process tree and finding their lowest common ancestor. If the lowest ancestral node is at least 4 levels below the root of the GO tree, that is, it defines a sufficiently specific gene function, we then assign this function to the unknown genes on the SP. Analogous to the L0 and L1 matches, here the L0 prediction then corresponds to the lowest common ancestor, and the L1 prediction to its direct parent. In this way, the function represented by the lowest common ancestor can be more specific than that defined by the informative nodes.. For each predicted gene function, we provide both the number of support SPs from which the prediction was derived and the number of unique known genes on those support SPs (support genes). The more support genes there are, the more confidence we have in the corresponding prediction. Note that a gene can be assigned putative functions in multiple graphs, because many genes are known to function in multiple cellular compartments. Under two circumstances an unknown gene may be assigned with multiple functions: (i) Because known genes on a SP may each have multiple functions, they may share several lowest common ancestors in the GO tree. (ii) An unknown gene may reside in different SPs with different lowest common ancestors


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