Abstract
Next-generation sequencing advances are rapidly expanding the number of human mutations to be analyzed for causative roles in genetic disorders. Our Human Protein Mutation Viewer (HPMV) is intended to explore the biomolecular mechanistic significance of non-synonymous human mutations in protein-coding genomic regions. The tool helps to assess whether protein mutations affect the occurrence of sequence-architectural features (globular domains, targeting signals, post-translational modification sites, etc.). As input, HPMV accepts protein mutations - as UniProt accessions with mutations (e.g. HGVS nomenclature), genome coordinates, or FASTA sequences. As output, HPMV provides an interactive cartoon showing the mutations in relation to elements of the sequence architecture. A large variety of protein sequence architectural features were selected for their particular relevance to mutation interpretation. Clicking a sequence feature in the cartoon expands a tree view of additional information including multiple sequence alignments of conserved domains and a simple 3D viewer mapping the mutation to known PDB structures, if available. The cartoon is also correlated with a multiple sequence alignment of similar sequences from other organisms. In cases where a mutation is likely to have a straightforward interpretation (e.g. a point mutation disrupting a well-understood targeting signal), this interpretation is suggested. The interactive cartoon can be downloaded as standalone viewer in Java jar format to be saved and viewed later with only a standard Java runtime environment. The HPMV website is: http://hpmv.bii.a-star.edu.sg/ .
Highlights
Genome sequencing is rapidly becoming a routine tool for investigating medical disorders with an underlying genetic basis.[1,2,3] Next-generation sequencing is poised to revolutionize the investigation of rare genetic disorders caused by individual mutations and, generally, the in°uence of specic mutations and gene variants on thedelity of physiological functions and on pathogenesis.The dramatic decrease in sequencing prices, coupled with technologies that allow sequencing from saliva and other easy-to-collect samples, make it feasible to sequence a®ected individuals as well as their una®ected family members
Human Protein Mutation Viewer (HPMV) processes arbitrary labels where therst number in the label is interpreted as the sequence position
All the multiple sequence alignment (MSA) can be colored according to sequence conservation or the standard Clustal color scheme
Summary
Genome sequencing is rapidly becoming a routine tool for investigating medical disorders with an underlying genetic basis.[1,2,3] Next-generation sequencing is poised to revolutionize the investigation of rare genetic disorders caused by individual mutations and, generally, the in°uence of specic mutations and gene variants on thedelity of physiological functions and on pathogenesis. Analyses attempting to relate mutations to biomolecular mechanisms are quite time consuming and there is a pressing need for software to facilitate this process Tools such as ANNOVAR,[25] SeattleSeq Annotation,[26] and Ensembl's Variant E®ect Predictor[27] are helpful for therst annotational step of lists of mutations as they link mutations with gene annotational features. No other tool available directly compares wild-type and mutant protein sequences and assesses the e®ect on the existence of diverse sequence-architectural features These features were chosen for their particular relevance to mutation interpretation based on extensive experience in computational protein function prediction and include both characteristics of globular domains and 3D structures as well as a variety of non-globular segments (Table 1). Phobius UniProt UniProt PeroPS/PTS1 (metazoan) UniProt BigPI3.2 (metazoa) MyrPS/NMT PrePS-FT PrePS-GGT1 PrePS-GGT2 UniProt SEG (windows 12&25) IUPred (long disorder) SAPS (charge clusters) HMMER3 against Pfam Ssearch against PDB
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