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We present PhyloCSF, a novel comparative genomics method that analyzes a multispecies nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models.<\/jats:p><jats:p>Results: We show that PhyloCSF's classification performance in 12-species Drosophila genome alignments exceeds all other methods we compared in a previous study. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE, and as interest grows in long non-coding RNAs, often initially recognized by their lack of protein coding potential rather than conserved RNA secondary structures.<\/jats:p><jats:p>Availability and Implementation: The Objective Caml source code and executables for GNU\/Linux and Mac OS X are freely available at http:\/\/compbio.mit.edu\/PhyloCSF<\/jats:p><jats:p>Contact: \u00a0mlin@mit.edu; manoli@mit.edu<\/jats:p>","DOI":"10.1093\/bioinformatics\/btr209","type":"journal-article","created":{"date-parts":[[2011,6,17]],"date-time":"2011-06-17T23:32:32Z","timestamp":1308353552000},"page":"i275-i282","source":"Crossref","is-referenced-by-count":931,"title":["PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions"],"prefix":"10.1093","volume":"27","author":[{"given":"Michael F.","family":"Lin","sequence":"first","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"},{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irwin","family":"Jungreis","sequence":"additional","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"},{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolis","family":"Kellis","sequence":"additional","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"},{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street 32-D510, Cambridge, MA 02139 and 2The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,6,14]]},"reference":[{"key":"2023012512134139000_B1","first-page":"7","article-title":"State of the art in eukaryotic gene prediction","volume-title":"Modern Genome Annotation: the BioSapiens Network","author":"Alioto","year":"2009"},{"key":"2023012512134139000_B2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/molbev\/msn232","article-title":"Investigating protein-coding sequence evolution with probabilistic codon substitution models","volume":"26","author":"Anisimova","year":"2008","journal-title":"Mol. 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