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Published online on January 27, 2003, 10.1073/pnas.0337561100
PNAS | February 4, 2003 | vol. 100 | no. 3 | 1140-1145


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Genetics
 Comparison of mouse and human genomes followed by experimental verification yields an estimated 1,019 additional genes

Roderic Guigó*,dagger , Emmanouil T. Dermitzakisdagger ,Dagger , Pankaj Agarwal§, Chris P. Ponting, Genís Parra*, Alexandre ReymondDagger , Josep F. Abril*, Evan Keibler||, Robert LyleDagger , Catherine UclaDagger , Stylianos E. AntonarakisDagger , and Michael R. Brent||,**

* Research Group in Biomedical Informatics, Institut Municipal d'Investigació Mèdica/Universitat Pompeu Fabra/Centre de Regulació Genòmica, E08003 Barcelona, Catalonia, Spain; Dagger  Division of Medical Genetics, University of Geneva Medical School and University Hospitals, 1211 Geneva, Switzerland; § GlaxoSmithKline, UW2230, 709 Swedeland Road, King of Prussia, PA 19406;  Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; and || Department of Computer Science, Washington University, One Brookings Drive, St. Louis, MO 63130

Communicated by Robert H. Waterston, Washington University School of Medicine, St. Louis, MO, December 11, 2002 (received for review October 21, 2002)

A primary motivation for sequencing the mouse genome was to accelerate the discovery of mammalian genes by using sequence conservation between mouse and human to identify coding exons. Achieving this goal proved challenging because of the large proportion of the mouse and human genomes that is apparently conserved but apparently does not code for protein. We developed a two-stage procedure that exploits the mouse and human genome sequences to produce a set of genes with a much higher rate of experimental verification than previously reported prediction methods. RT-PCR amplification and direct sequencing applied to an initial sample of mouse predictions that do not overlap previously known genes verified the regions flanking one intron in 139 predictions, with verification rates reaching 76%. On average, the confirmed predictions show more restricted expression patterns than the mouse orthologs of known human genes, and two-thirds lack homologs in fish genomes, demonstrating the sensitivity of this dual-genome approach to hard-to-find genes. We verified 112 previously unknown homologs of known proteins, including two homeobox proteins relevant to developmental biology, an aquaporin, and a homolog of dystrophin. We estimate that transcription and splicing can be verified for >1,000 gene predictions identified by this method that do not overlap known genes. This is likely to constitute a significant fraction of the previously unknown, multiexon mammalian genes.

dagger R.G. and E.T.D. contributed equally to this work.

** To whom correspondence should be addressed. E-mail: brent{at}cse.wustl.edu.

www.pnas.org/cgi/doi/10.1073/pnas.0337561100
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