ConVarT: a search engine for matching human genetic variants with variants from non-human species

Abstract

The availability of genetic variants, together with phenotypic annotations from model organisms, facilitates comparing these variants with equivalent variants in humans. However, existing databases and search tools do not make it easy to scan for equivalent variants, namely “orthologous variants,” between humans and other organisms. Therefore, we developed an integrated search engine called ConVarT (http://www.convart.org/) for orthologous variants between humans, mice, and C. elegans. ConVarT incorporates annotations (including phenotypic and pathogenic) into variants, and these previously unexploited phenotypic OrthoVars from mice and C. elegans can give clues about the functional consequence of human genetic variants. Our analysis shows that many phenotypic variants in different genes from mice and C. elegans, so far, have no counterparts in humans, and thus, can be useful resources when evaluating a relationship between a new human mutation and a disease.Graphical Abstract

Ectocytosis prevents accumulation of ciliary cargo in C. elegans sensory neurons

“…C. elegans bears 20 tetraspanin genes (TSP-1–20). Using a reciprocal best hit approach, TSP-6 and TSP-7 appeared orthologous to CD9 and CD63, respectively ( Figure 2A ; Hemler, 2005 ; Moreno-Hagelsieb and Latimer, 2008 ; Pir et al, 2021 ). As potential ciliary EVs markers for the amphid neurons, we selected TSP-6, which is strongly expressed in the ciliated neurons, and TSP-7, which is broadly expressed in the nervous system but not in ciliated neurons ( Hammarlund, 2018 ; Lorenzo et al, 2020 ; Figure 2A ).…”

MSABrowser: dynamic and fast visualization of sequence alignments, variations, and annotations

“…MSABrowser is the most recently created tool that allows the visualization of MSAs, genetic variations, posttranslational modifications, and protein domains at the same time. MSABrowser makes it much easier to display orthologous variants between different species (Pir et al, 2021). Importantly, it does not require the installation of any software as it runs on any modern browser that is pre-installed on computers.…”

“…MSABrowser introduces four major novelties: first, the pliable annotation of genetic variants (c.88C>G or p.Pro30Ala), orthologous variants (OrthoVars), or posttranslational modifications (PTMs) (ubiquitination at Lysine 2563; K2563-ub) into the respective sequence positions on the PSA and MSA (Fig. 2A and B) (Pir et al, 2021); second, multiple annotations, such as protein domains (SH3 domains) and/or user-specified intervals can be added at the same time to the corresponding positions; third, the variant-specific annotations, including phenotypic data, variant ID, and allele frequency, can be integrated into the corresponding positions. For example, p.R79Q in ARL13B (Protein ID = NP_001167621.1) has several variant-specific annotations, including variant ID (rs121912606), an allele frequency (3.98e-6), predicted as a pathogenic variant, and disease association (causing Joubert syndrome) (Karczewski et al, 2020;Cantagrel et al, 2008), and all of these annotations can easily be co-viewed at the respective sites.…”

mutscan - a flexible R package for efficient end-to-end analysis of multiplexed assays of variant effect data

“…However, the phenotypic consequences of a large fraction of variants identified in the human genome remain elusive (2), which is why these variants have been termed variants of uncertain significance (VUS). For example, 41.8 % of variants currently listed in ClinVar are characterized as VUS (3). Therefore, a pressing objective has been to find ways to annotate these variants in an efficient way.…”