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Identifying novel constrained elements by exploiting biased substitution patterns

Garber, Manuel and Guttman, Mitchell and Clamp, Michele and Zody, Michael C. and Friedman, Nir and Xie, Xiaohui (2009) Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics, 25 (12). i54-i62. ISSN 1367-4803. PMCID PMC2687944.

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Motivation: Comparing the genomes from closely related species provides a powerful tool to identify functional elements in a reference genome. Many methods have been developed to identify conserved sequences across species; however, existing methods only model conservation as a decrease in the rate of mutation and have ignored selection acting on the pattern of mutations. Results: We present a new approach that takes advantage of deeply sequenced clades to identify evolutionary selection by uncovering not only signatures of rate-based conservation but also substitution patterns characteristic of sequence undergoing natural selection. We describe a new statistical method for modeling biased nucleotide substitutions, a learning algorithm for inferring site-specific substitution biases directly from sequence alignments and a hidden Markov model for detecting constrained elements characterized by biased substitutions. We show that the new approach can identify significantly more degenerate constrained sequences than rate-based methods. Applying it to the ENCODE regions, we identify as much as 10.2% of these regions are under selection.

Item Type:Article
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URLURL TypeDescription CentralArticle
Garber, Manuel0000-0001-8732-1293
Guttman, Mitchell0000-0003-4748-9352
Friedman, Nir0000-0002-9678-3550
Additional Information:© 2009 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Published: 27 May 2009. We thank M. Kamal, T. Mikkelsen and Or Zuk for insightful comments on the article; M. Kellis, P. Kheradpour, E. Lander, M. Lin, K. Lindblad-Toh, M. Rasmussen and A. Stark for helpful discussions. Funding: UCI (to XX); NHGRI (to MG, MC and MZ); Israel Science Foundation (to NF). Availability: The algorithms are implemented in a Java software package, called SiPhy, freely available at Conflict of interest: none declared.
Funding AgencyGrant Number
University of California, IrvineUNSPECIFIED
National Human Genome Research InstituteUNSPECIFIED
Israel Science FoundationUNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC2687944
Record Number:CaltechAUTHORS:20161122-081912441
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Official Citation:Manuel Garber, Mitchell Guttman, Michele Clamp, Michael C. Zody, Nir Friedman, Xiaohui Xie; Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 2009; 25 (12): i54-i62. doi: 10.1093/bioinformatics/btp190
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72235
Deposited By: Tony Diaz
Deposited On:22 Nov 2016 18:12
Last Modified:21 Dec 2020 21:06

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