xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation
Background: While the local-mode HMMER3 is notable for its massive speed improvement, the slower glocal-mode HMMER2 is more exact for domain annotation by enforcing full domain-to-sequence alignments. Since a unit of domain necessarily implies a unit of function, local-mode HMMER3 alone remains insu...
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sg-ntu-dr.10356-846772020-03-07T11:48:57Z xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation Yap, Choon-Kong Eisenhaber, Birgit Eisenhaber, Frank Wong, Wing-Cheong School of Computer Science and Engineering Sequence homology Hidden Markov model Background: While the local-mode HMMER3 is notable for its massive speed improvement, the slower glocal-mode HMMER2 is more exact for domain annotation by enforcing full domain-to-sequence alignments. Since a unit of domain necessarily implies a unit of function, local-mode HMMER3 alone remains insufficient for precise function annotation tasks. In addition, the incomparable E-values for the same domain model by different HMMER builds create difficulty when checking for domain annotation consistency on a large-scale basis. Results: In this work, both the speed of HMMER3 and glocal-mode alignment of HMMER2 are combined within the xHMMER3x2 framework for tackling the large-scale domain annotation task. Briefly, HMMER3 is utilized for initial domain detection so that HMMER2 can subsequently perform the glocal-mode, sequence-to-full-domain alignments for the detected HMMER3 hits. An E-value calibration procedure is required to ensure that the search space by HMMER2 is sufficiently replicated by HMMER3. We find that the latter is straightforwardly possible for ~80% of the models in the Pfam domain library (release 29). However in the case of the remaining ~20% of HMMER3 domain models, the respective HMMER2 counterparts are more sensitive. Thus, HMMER3 searches alone are insufficient to ensure sensitivity and a HMMER2-based search needs to be initiated. When tested on the set of UniProt human sequences, xHMMER3x2 can be configured to be between 7× and 201× faster than HMMER2, but with descending domain detection sensitivity from 99.8 to 95.7% with respect to HMMER2 alone; HMMER3’s sensitivity was 95.7%. At extremes, xHMMER3x2 is either the slow glocal-mode HMMER2 or the fast HMMER3 with glocal-mode. Finally, the E-values to false-positive rates (FPR) mapping by xHMMER3x2 allows E-values of different model builds to be compared, so that any annotation discrepancies in a large-scale annotation exercise can be flagged for further examination by dissectHMMER. Conclusion: The xHMMER3x2 workflow allows large-scale domain annotation speed to be drastically improved over HMMER2 without compromising for domain-detection with regard to sensitivity and sequence-to-domain alignment incompleteness. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2016-12-20T09:25:51Z 2019-12-06T15:49:20Z 2016-12-20T09:25:51Z 2019-12-06T15:49:20Z 2016 Journal Article Yap, C.-K., Eisenhaber, B., Eisenhaber, F., & Wong, W.-C. (2016). xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation. Biology Direct, 11(63), 1-17. https://hdl.handle.net/10356/84677 http://hdl.handle.net/10220/41906 10.1186/s13062-016-0163-0 en Biology Direct © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated 17 p. application/pdf |
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Sequence homology Hidden Markov model Yap, Choon-Kong Eisenhaber, Birgit Eisenhaber, Frank Wong, Wing-Cheong xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
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Background: While the local-mode HMMER3 is notable for its massive speed improvement, the slower glocal-mode HMMER2 is more exact for domain annotation by enforcing full domain-to-sequence alignments. Since a unit of domain necessarily implies a unit of function, local-mode HMMER3 alone remains insufficient for precise function annotation tasks. In addition, the incomparable E-values for the same domain model by different HMMER builds create difficulty when checking for domain annotation consistency on a large-scale basis.
Results: In this work, both the speed of HMMER3 and glocal-mode alignment of HMMER2 are combined within the xHMMER3x2 framework for tackling the large-scale domain annotation task. Briefly, HMMER3 is utilized for initial domain detection so that HMMER2 can subsequently perform the glocal-mode, sequence-to-full-domain alignments for the detected HMMER3 hits. An E-value calibration procedure is required to ensure that the search space by HMMER2 is sufficiently replicated by HMMER3. We find that the latter is straightforwardly possible for ~80% of the models in the Pfam domain library (release 29). However in the case of the remaining ~20% of HMMER3 domain models, the respective HMMER2 counterparts are more sensitive. Thus, HMMER3 searches alone are insufficient to ensure sensitivity and a HMMER2-based search needs to be initiated. When tested on the set of UniProt human sequences, xHMMER3x2 can be configured to be between 7× and 201× faster than HMMER2, but with descending domain detection sensitivity from 99.8 to 95.7% with respect to HMMER2 alone; HMMER3’s sensitivity was 95.7%. At extremes, xHMMER3x2 is either the slow glocal-mode HMMER2 or the fast HMMER3 with glocal-mode. Finally, the E-values to false-positive rates (FPR) mapping by xHMMER3x2 allows E-values of different model builds to be compared, so that any annotation discrepancies in a large-scale annotation exercise can be flagged for further examination by dissectHMMER.
Conclusion: The xHMMER3x2 workflow allows large-scale domain annotation speed to be drastically improved over HMMER2 without compromising for domain-detection with regard to sensitivity and sequence-to-domain alignment incompleteness. |
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School of Computer Science and Engineering |
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School of Computer Science and Engineering Yap, Choon-Kong Eisenhaber, Birgit Eisenhaber, Frank Wong, Wing-Cheong |
format |
Article |
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Yap, Choon-Kong Eisenhaber, Birgit Eisenhaber, Frank Wong, Wing-Cheong |
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Yap, Choon-Kong |
title |
xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
title_short |
xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
title_full |
xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
title_fullStr |
xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
title_full_unstemmed |
xHMMER3x2: Utilizing HMMER3’s speed and HMMER2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
title_sort |
xhmmer3x2: utilizing hmmer3’s speed and hmmer2’s sensitivity and specificity in the glocal alignment mode for improved large-scale protein domain annotation |
publishDate |
2016 |
url |
https://hdl.handle.net/10356/84677 http://hdl.handle.net/10220/41906 |
_version_ |
1681041443841376256 |