title: Identifying novel constrained elements by exploiting biased substitution patterns.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  The algorithms are implemented in a Java software package, called SiPhy, freely available at http://www.broadinstitute.org/science/software/.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Biology, Broad Institute of MIT and Harvard, 7 Cambridge Center, MIT, Cambridge, MA 02142, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.forename: Mitchell
authors.initials: M
authors.lastname: Guttman
authors.forename: Michele
authors.initials: M
authors.lastname: Clamp
authors.forename: Michael C
authors.initials: MC
authors.lastname: Zody
authors.forename: Nir
authors.initials: N
authors.lastname: Friedman
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xie
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D019143:Evolution, Molecular; D023281:Genomics / Q000379:methods*; D016415:Sequence Alignment / Q000379:methods*; D012984:Software