Identifying novel constrained elements by exploiting biased substitution patterns
Open accessAbstract
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. Availability: The algorithms are implemented in a Java software package, called SiPhy, freely available at http://www.broadinstitute.org/science/software/. Contact: xhx@ics.uci.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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Comparative genomics analyses (species-tree inference, comparative annotation, selection detection) require genome alignments.
“Comparative genomics analyses, including species-tree inference7,8, comparative annotation9,10, and selection detection11,12, require genome alignments.”
From Progressive Cactus is a multiple-genome aligner for the thousand-genome era (2020) · cites this paper as [12]
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“Conflict of interest: none declared.”
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- Authors
- Garber, M., Guttman, M., Clamp, M., Zody, M. C., Friedman, N., & Xie, X.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Xie, Xiaohui
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-05-27
- Volume
- 25
- Issue
- 12
- Pages
- i54-i62
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- PMC
- PMC2687944
- OpenAlex
- W2155845523
- Cited by
- 370
- References
- 5
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 14 · 2023: 21 · 2022: 31 · 2021: 44 · 2020: 34 · 2019: 35 · 2018: 30 · 2017: 17 · 2016: 33 · 2015: 24 · 2014: 12 · 2013: 14 · 2012: 11
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Bioinformatics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- natural selection, sequence conservation, hidden Markov models, comparative genomics
- MeSH terms
- Algorithms, Base Sequence, Software, Sequence Alignment, Evolution, Molecular, Genomics
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