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Downloaded from Placed in a Duplication Node More Closely Related to the the Gene Ontology’S Archive of MGI Gafs [52] Christie and Blake Cilia (2018) 7:3 https://doi.org/10.1186/s13630-018-0057-0 Cilia RESEARCH Open Access Sensing the cilium, digital capture of ciliary data for comparative genomics investigations Karen R. Christie*† and Judith A. Blake† Abstract Background: Cilia are specialized, hair-like structures that project from the cell bodies of eukaryotic cells. With increased understanding of the distribution and functions of various types of cilia, interest in these organelles is accelerating. To efectively use this great expansion in knowledge, this information must be made digitally accessible and available for large-scale analytical and computational investigation. Capture and integration of knowledge about cilia into existing knowledge bases, thus providing the ability to improve comparative genomic data analysis, is the objective of this work. Methods: We focused on the capture of information about cilia as studied in the laboratory mouse, a primary model of human biology. The workfow developed establishes a standard for capture of comparative functional data relevant to human biology. We established the 310 closest mouse orthologs of the 302 human genes defned in the SYSCILIA Gold Standard set of ciliary genes. For the mouse genes, we identifed biomedical literature for curation and used Gene Ontology (GO) curation paradigms to provide functional annotations from these publications. Results: Employing a methodology for comprehensive capture of experimental data about cilia genes in structured, digital form, we established a workfow for curation of experimental literature detailing molecular function and roles of cilia proteins starting with the mouse orthologs of the human SYSCILIA gene set. We worked closely with the GO Consortium ontology development editors and the SYSCILIA Consortium to improve the representation of ciliary biol- ogy within the GO. During the time frame of the ontology improvement project, we have fully curated 134 of these 310 mouse genes, resulting in an increase in the number of ciliary and other experimental annotations. Conclusions: We have improved the GO annotations available for mouse genes orthologous to the human genes in the SYSCILIA Consortium’s Gold Standard set. In addition, ciliary terminology in the GO itself was improved in col- laboration with GO ontology developers and the SYSCILIA Consortium. These improvements to the GO terms for the functions and roles of ciliary proteins, along with the increase in annotations of the corresponding genes, enhance the representation of ciliary processes and localizations and improve access to these data during large-scale bioinfor- matic analyses. Keywords: Gene Ontology, Cilia, Ciliopathy, Ciliary-related disease, Flagella, Curation Background Notably, there has been a surge in the number of publi- Interest in cilia has increased dramatically over the last cations reporting advances in our understanding of cili- 10 years as it has become clear that ciliopathies are an ary biology. However, in this era of comparative genome underlying cause of numerous human diseases [1–5]. analysis and bioinformatics, the data need to be available in a structured, digital format that is accessible to compu- *Correspondence: [email protected] tational analysis in order to get the most out these recent †Karen R. Christie and Judith A. Blake—The Gene Ontology Consortium insights into ciliary biology. To this end, we focused on (http://geneontology.org) The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA functional annotation of ciliary genes for the laboratory © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Christie and Blake Cilia (2018) 7:3 Page 2 of 18 mouse using the Gene Ontology (GO), and participated understand the genes involved in these human diseases. in a collaborative efort with the SYSCILIA Consor- In cases of PCD, where a mutation in a specifc gene leads tium and the Gene Ontology Consortium to expand and to a loss of ciliary motility, but not loss of cilia entirely, it improve the formal, digital representation of ciliary biol- may be possible to characterize the ciliary defect in cells ogy within the GO [6–8]. from afected human patients. However, it is not always Sperm and various types of epithelial cells have long possible to fnd human mutations relevant to the study been known to possess motile cilia. Ten, since the of a particular gene, particularly if loss of that function 1970s, we learned that defects in ciliary motility are asso- results in embryonic lethality. Tus, mouse models can ciated with numerous dysfunctional phenotypes that are play a key role in developing our understanding of the now characterized as Primary Ciliary Dyskinesia or PCD, role of cilia in development throughout the embryo [24] including chronic respiratory and sinus infections, male and in increasing our understanding of ciliary function in infertility, and reversal in the left/right organization of many human disease syndromes [36]. Te ability to gen- the body [9–11]. Te motile cilia present on many types erate mice with gene knockouts specifcally targeted for of multiciliated epithelial cells are essential for movement specifc tissues or embryonic stages allows researchers of fuids across tissues [12] and play important roles in to address questions that are not possible any other way. the development and function of many organs including However, for the wealth of experimental data generated the brain [13], nasal and respiratory passages [14], and by these mouse models to be most useful, this informa- fallopian tubes [15]. tion must be made digitally available for analysis of large- While it has been known for over 100 years that many scale experiments such as enrichment analyses of gene mammalian cell types possess a single non-motile cilum, lists resulting from high-throughput expression or phe- also referred to as a primary cilium, these primary cilia notypic studies, or for comparative genome analyses. were thought, until fairly recently, to be functionless evo- To further the availability and utility of the experimen- lutionary relics [1, 16]. It is now clear that primary cilia tal work on cilia, we initiated a project to comprehen- are sensory organelles critical to the regulation of many sively annotate experimentally characterized ciliary genes signaling pathways including Sonic hedgehog (Shh)—a of the laboratory mouse using Gene Ontology (GO) major regulator of early developmental patterning [1–4, terms to describe their molecular functions, biological 16, 17]. Tere is evidence that motile cilia also possess roles, and cellular locations [6, 37]. Here, we describe sensory functions [18]. Te motile primary cilia of the our progress, including how our workfow provides a embryonic node play another key role in early develop- model for targeted annotation of genes from a model ment as they are required for the initial generation of organism relevant to a specifc human disease or health left/right asymmetry in the embryo and thus are required issue. Inspired by the publication of the SYSCILIA Con- for proper morphogenesis of asymmetric anatomical sortium’s Gold Standard set of known human ciliary structures such as the heart and the digestive tract. Spe- components, we initiated our work on the mouse equiva- cialized cilia are part of structures required for detecting lents of these known human ciliary components as tar- sensory input, such as the kinocilia at the center of ste- gets for comprehensive GO annotation of mouse ciliary reocilia bundles in cochlear hair cells; the cilia of olfac- genes. We subsequently became aware of other excellent tory sensory neurons within olfactory epithelium; and resources that have compiled sets of ciliary genes, such the modifed cilia of photoreceptor cells [16, 19, 20]. as Cildb [38], and these other genes may be part of other With this greater understanding of the diversity of both annotation projects in the future. As part of the curation the structures and the roles of cilia [21], we are devel- process, we also updated the Gene Ontology as needed oping a greater understanding of the underlying com- to best represent our understanding of ciliary biology mon role of defects in ciliary function in developmental [8]. Our experimental annotations to mouse genes gain defects in right/left symmetry including situs inversus additional value as they are propagated via phyloge- [22], brain development defects including hydrocephaly netic methods to several related taxa including rat and [13], congenital heart defects [23, 24], and craniofacial human [39, 40]. Tis inference process improves the abil- defects [25], and also with many diseases that manifest ity of researchers to identify a common ciliary role in the after birth or later in life, such as obesity [26–28], recur- sets of genes identifed in their research, regardless of rent sinus and respiratory tract infections [9, 14, 22], whether they are looking at lists of human genes, or, by hearing loss [29], vision
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