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Title: On the necessity of dissecting sequence similarity scores into segment-specific contributions for inferring protein homology, function prediction and annotation
Authors: Wong, W.-C
Maurer-Stroh, S 
Eisenhaber, B
Eisenhaber, F 
Keywords: Dissection
Hidden Markov models
Protein domains
Protein function annotation
Protein sequences
Sequence homology
Sequence similarity
Similarity scores
amino acid sequence
computer program
molecular genetics
nucleotide sequence
sequence alignment
sequence homology
Amino Acid Sequence
Conserved Sequence
Molecular Sequence Data
Sequence Alignment
Sequence Homology, Amino Acid
Issue Date: 2014
Publisher: BioMed Central Ltd.
Citation: Wong, W.-C, Maurer-Stroh, S, Eisenhaber, B, Eisenhaber, F (2014). On the necessity of dissecting sequence similarity scores into segment-specific contributions for inferring protein homology, function prediction and annotation. BMC Bioinformatics 15 (1) : 166. ScholarBank@NUS Repository.
Abstract: Background: Protein sequence similarities to any types of non-globular segments (coiled coils, low complexity regions, transmembrane regions, long loops, etc. where either positional sequence conservation is the result of a very simple, physically induced pattern or rather integral sequence properties are critical) are pertinent sources for mistaken homologies. Regretfully, these considerations regularly escape attention in large-scale annotation studies since, often, there is no substitute to manual handling of these cases. Quantitative criteria are required to suppress events of function annotation transfer as a result of false homology assignments.Results: The sequence homology concept is based on the similarity comparison between the structural elements, the basic building blocks for conferring the overall fold of a protein. We propose to dissect the total similarity score into fold-critical and other, remaining contributions and suggest that, for a valid homology statement, the fold-relevant score contribution should at least be significant on its own. As part of the article, we provide the DissectHMMER software program for dissecting HMMER2/3 scores into segment-specific contributions. We show that DissectHMMER reproduces HMMER2/3 scores with sufficient accuracy and that it is useful in automated decisions about homology for instructive sequence examples. To generalize the dissection concept for cases without 3D structural information, we find that a dissection based on alignment quality is an appropriate surrogate. The approach was applied to a large-scale study of SMART and PFAM domains in the space of seed sequences and in the space of UniProt/SwissProt.Conclusions: Sequence similarity core dissection with regard to fold-critical and other contributions systematically suppresses false hits and, additionally, recovers previously obscured homology relationships such as the one between aquaporins and formate/nitrite transporters that, so far, was only supported by structure comparison. © 2014 Wong et al.; licensee BioMed Central Ltd.
Source Title: BMC Bioinformatics
ISSN: 14712105
DOI: 10.1186/1471-2105-15-166
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