Multiple evidence strands suggest that there may be as few as 19 000 human protein-coding genes
Iakes Ezkurdia1,†, David Juan3,†, Jose Manuel Rodriguez4, Adam Frankish5, Mark Diekhans6, Jennifer Harrow5, Jesus Vazquez2, Alfonso Valencia3,4,* and Michael L. Tress3,*
Author Affiliations
1Unidad de Proteómica and,
2Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Melchor Fernández Almagro, 3, 28029, Madrid, Spain,
3Structural Biology and Bioinformatics Programme and,
4National Bioinformatics Institute (INB), Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain,
5Wellcome Trust Sanger Institute, Wellcome Trust Campus, Hinxton, Cambridge CB10 1SA, UK and
6Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz (UCSC), 1156 High Street, Santa Cruz, CA 95064, USA
↵*To whom correspondence should be addressed at: Structural Biology and Bioinformatics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. Tel: 
+34 917328000; Fax: +34 912246976; Email: mtress@cnio.es (M.T.); Tel: +34 917328000; Fax: +34 912246976; Email: valencia@cnio.es (A.V.)
+34 917328000; Fax: +34 912246976; Email: mtress@cnio.es (M.T.); Tel: +34 917328000; Fax: +34 912246976; Email: valencia@cnio.es (A.V.)
Received February 25, 2014.
Revision received May 30, 2014.
Accepted June 12, 2014.
Abstract
Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein-coding potential is the detection of cellular protein expression through peptide mass spectrometry (MS) experiments. Here, we mapped peptides detected in seven large-scale proteomics studies to almost 60% of the protein-coding genes in the GENCODE annotation of the human genome. We found a strong relationship between detection in proteomics experiments and both gene family age and cross-species conservation. Most of the genes for which we detected peptides were highly conserved. We found peptides for >96% of genes that evolved before bilateria. At the opposite end of the scale, we identified almost no peptides for genes that have appeared since primates, for genes that did not have any protein-like features or for genes with poor cross-species conservation. These results motivated us to describe a set of 2001 potential non-coding genes based on features such as weak conservation, a lack of protein features, or ambiguous annotations from major databases, all of which correlated with low peptide detection across the seven experiments. We identified peptides for just 3% of these genes. We show that many of these genes behave more like non-coding genes than protein-coding genes and suggest that most are unlikely to code for proteins under normal circumstances. We believe that their inclusion in the human protein-coding gene catalogue should be revised as part of the ongoing human genome annotation effort.
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