Variation Ontology for annotation of variation effects and mechanisms

Abstract

Ontology organizes and formally conceptualizes information in a knowledge domain with a controlled vocabulary having defined terms and relationships between them. Several ontologies have been used to annotate numerous databases in biology and medicine. Due to their unambiguous nature, ontological annotations facilitate systematic description and data organization, data integration and mining, and pattern recognition and statistics, as well as development of analysis and prediction tools. The Variation Ontology (VariO) was developed to allow the annotation of effects, consequences, and mechanisms of DNA, RNA, and protein variations. Variation types are systematically organized, and a detailed description of effects and mechanisms is possible. VariO is for annotating the variant, not the normal-state features or properties, and requires a reference (e.g., reference sequence, reference-state property, activity, etc.) compared to which the changes are indicated. VariO is versatile and can be used for variations ranging from genomic multiplications to single nucleotide or amino acid changes, whether of genetic or nongenetic origin. VariO annotations are position-specific and can be used for variations in any organism.

Figure 1.

Organization of sublevels in VariO. Examples of terms in the different levels. The three central levels are DNA, RNA, and protein, to which modifier attributes add further versatility. On each major level certain details are shown to illustrate the organization of VariO and types of terms.

Figure 2.

Variation types at the DNA, RNA, and protein levels. Terms with “is a” relation are indicated by lines with arrowheads, and those with “part of” relation are indicated by a dashed line.

Figure 3.

Example of data analysis with VariO annotations. Wiskott-Aldric syndrome protein (WASP) variations are involved in four conditions including Wiskott-Aldrich syndrome (WAS; red), the most severe disease; X-linked thrombocytopenia (XLT; green), a somewhat milder disorder; intermittent XLT (IXLT; black); and congenital neutropenia (XLN; blue). Annotations are shown only for relevant features of variation type, protein abundance, protein stability, and protein activity. The cases are grouped based on variation types to indicate genotype–phenotype correlations. The less severe disorders typically have less drastic changes—mainly amino acid substitutions—while the more severe diseases such as XLT and especially WAS contain protein truncations and splice-site-affecting alterations. The protein abundance follows this trend, being unaffected in XLN and IXLT, while in XLT it is mainly decreased and in WAS mainly missing.