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Bioinformatics DOI:10.1093/bioinformatics/btp190

Identifying novel constrained elements by exploiting biased substitution patterns.

Publication TypeJournal Article
Year of Publication2009
AuthorsGarber, M, Guttman, M, Clamp, M, Zody, MC, Friedman, N, Xie, X
Date Published2009 Jun 15
KeywordsAlgorithms, Base Sequence, Evolution, Molecular, Genomics, Sequence Alignment, Software

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

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Alternate JournalBioinformatics
PubMed ID19478016
PubMed Central IDPMC2687944