Genetic Variations and Diseases in UniProtKB/Swiss‐Prot: The Ins and Outs of Expert Manual Curation

Abstract

During the last years, next-generation sequencing (NGS) technologies have accelerated the detection of genetic variants resulting in the rapid discovery of new disease-associated genes. However, the wealth of variation data made available by NGS alone is not sufficient to understand the mechanisms underlying disease pathogenesis and manifestation. Multidisciplinary approaches combining sequence and clinical data with prior biological knowledge are needed to unravel the role of genetic variants in human health and disease. In this context, it is crucial that these data are linked, organized and made readily available through reliable online resources. The Swiss-Prot section of the Universal Protein Knowledgebase (UniProtKB/Swiss-Prot) provides the scientific community with a collection of information on protein functions, interactions, biological pathways, as well as human genetic diseases and variants, all manually reviewed by experts. In this article, we present an overview of the information content of UniProtKB/Swiss-Prot to show how this knowledgebase can support researchers in the elucidation of the mechanisms leading from a molecular defect to a disease phenotype.

MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search

“…Given the importance of gene-disease associations, much research attention has been directed to improved algorithms for generating such connections (5,20,30,31). In order to evaluate MalaCards performance in this context, we performed a comparison to six other disease data sources.…”

Text Mining Genotype-Phenotype Relationships from Biomedical Literature for Database Curation and Precision Medicine

“…UniProtKB–the Universal Protein Resource Knowledge Base–is a database of protein sequence and annotation data produced in Switzerland through collaboration between the European Bioinformatics Institute (EMBL-EBI), the Swiss Institute of Bioinformatics (SIB) and the Protein Information Resource (PIR) [38]. Its scope includes all human genes and function-altering gene variants along with any diseases caused by those variants [39]. Data collection from UniProtKB is explained in detail in the supplementary material, S4 Text.…”

UniProt Genomic Mapping for Deciphering Functional Effects of Missense Variants

“…The mappings described here contain additional annotation including isoform sequences from Swiss-Prot and also sequences and features from the TrEMBL section of UniProtKB. UniProtKB/TrEMBL contains additional isoforms and predicted genes not currently in UniProtKB/Swiss-Prot and automated annotation provided by a combination of automated prediction algorithms with human curated rules (Vasudevan et al 2010;Dimmer et al 2012;Famiglietti et al 2014;Pedruzzi et al 2015). This includes sequence features such as active sites, binding sites and functional domains.…”

“…Some tools such as PolyPhen-2 (Adzhubei et al 2013) predict the effects of variants using a subset of protein annotation from UniProtKB, such as active sites, in their score and including additional annotations in such tools should improve predictive capabilities. UniProtKB represents decades of effort in capturing protein and gene names, function, catalytic activity, cofactors, pathway information, subcellular location, protein-protein interactions, patterns of expression, and phenotypes or diseases associated with variants in a protein (Famiglietti et al 2014) using literature-based and semi-automated expert curation. Included in this information are sequence positional features such as enzyme active sites; modified residues; binding domains; protein isoforms; glycosylation sites; protein variations and more.…”