title: Targeted discovery of novel human exons by comparative genomics.
abstract: A complete and accurate set of human protein-coding gene annotations is perhaps the single most important resource for genomic research after the human-genome sequence itself, yet the major gene catalogs remain incomplete and imperfect. Here we describe a genome-wide effort, carried out as part of the Mammalian Gene Collection (MGC) project, to identify human genes not yet in the gene catalogs. Our approach was to produce gene predictions by algorithms that rely on comparative sequence data but do not require direct cDNA evidence, then to test predicted novel genes by RT-PCR. We have identified 734 novel gene fragments (NGFs) containing 2188 exons with, at most, weak prior cDNA support. These NGFs correspond to an estimated 563 distinct genes, of which >160 are completely absent from the major gene catalogs, while hundreds of others represent significant extensions of known genes. The NGFs appear to be predominantly protein-coding genes rather than noncoding RNAs, unlike novel transcribed sequences identified by technologies such as tiling arrays and CAGE. They tend to be expressed at low levels and in a tissue-specific manner, and they are enriched for roles in motor activity, cell adhesion, connective tissue, and central nervous system development. Our results demonstrate that many important genes and gene fragments have been missed by traditional approaches to gene discovery but can be identified by their evolutionary signatures using comparative sequence data. However, they suggest that hundreds-not thousands-of protein-coding genes are completely missing from the current gene catalogs.
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York 14853, USA. acs4@cornell.edu
authors.forename: Adam
authors.initials: A
authors.lastname: Siepel
authors.forename: Mark
authors.initials: M
authors.lastname: Diekhans
authors.forename: Brona
authors.initials: B
authors.lastname: Brejová
authors.forename: Laura
authors.initials: L
authors.lastname: Langton
authors.forename: Michael
authors.initials: M
authors.lastname: Stevens
authors.forename: Charles L G
authors.initials: CL
authors.lastname: Comstock
authors.forename: Colleen
authors.initials: C
authors.lastname: Davis
authors.forename: Brent
authors.initials: B
authors.lastname: Ewing
authors.forename: Shelly
authors.initials: S
authors.lastname: Oommen
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Yu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Roe
authors.forename: Phil
authors.initials: P
authors.lastname: Green
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Gary
authors.initials: G
authors.lastname: Temple
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brent
mesh_terms: D000818:Animals; D001483:Base Sequence; D002645:Chickens / Q000235:genetics; D019295:Computational Biology; D005091:Exons / Q000235:genetics*; D020224:Expressed Sequence Tags; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D051379:Mice; D011237:Predictive Value of Tests; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics