Genetic variations and diseases in UniProtKB/Swiss-Prot: the ins and outs of expert manual curation

Abstract

During the last few 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.

Keywords: UniProtKB/Swiss-Prot; controlled vocabulary; database; disease; functional annotation; genetic variants; manual curation.

Figure 1

Flowchart of variant annotation in UniProtKB/Swiss-Prot. Variant annotation is based on published experimental data. The first step is to select a relevant article. This is achieved using several complementary approaches, including browsing specialized journals, alerts from literature databases and text mining. Users are also invited to take part in this process by contacting us to draw our attention on obsolete entries and/or to interesting publications. Articles linking protein information with medical disorders are critically reviewed by expert curators, and variant identification, disease description, and/or protein functional characterization are annotated based on supporting evidence. This annotation is submitted to various manual and automated checks before final integration into UniProtKB/Swiss-Prot. The disease nomenclature is based on OMIM, if available. If the disorder is not reported in OMIM, names and acronyms are created by the UniProtKB/Swiss-Prot staff on the basis of published reports.

Figure 2

Excerpt from UniProtKB/Swiss-Prot entry Q5HYA8 representing human Meckelin (TMEM67). The “Sequence annotation (Features)” section describes the sequence and sequence variants at the single residue level. Note the presence of three types of variants: a neutral polymorphism at position 261, disease variants associated with ciliopathies MKS3, COACHS, and NPHP11, and VUS at positions 245 and 296. Note that disease-linked variant p.Asn242Thr affects a predicted N-glycosylation site (see subsection “Amino acid modifications”). Disease-linked variant p.Gln376Pro perturbs protein subcellular location.

Figure 3

UniProtKB/Swiss-Prot page for human Meckelin (TMEM67) variant p.Asn242Thr.

Figure 4

Excerpt from the “General annotation (Comments)” section in Q5HYA8, containing functional annotations based on publications. TMEM67 mutations are involved in several ciliopathies, including Meckel syndrome 3 (MKS3), Joubert syndrome 6 (JBTS6), Bardet–Biedl syndrome (BBS), COACH syndrome (COACHS), and nephronophthisis 11 (NPHP11). The precise type of association with the disease, i.e. confirmed or probable pathological role, susceptibility to disease or disease modification, is indicated in the “Note” using a controlled vocabulary.