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BIOLOGICAL SCIENCES / GENETICS
Distinguishing protein-coding and noncoding genes in the human genome
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*Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; ¶Department of Biology and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142; and ||Department of Systems Biology, Harvard Medical School, Boston, MA 02115
Contributed by Eric S. Lander, October 3, 2007 (received for review August 1, 2007)
Although the Human Genome Project was completed 4 years ago, the catalog of human protein-coding genes remains a matter of controversy. Current catalogs list a total of 
24,500 putative protein-coding genes. It is broadly suspected that a large fraction of these entries are functionally meaningless ORFs present by chance in RNA transcripts, because they show no evidence of evolutionary conservation with mouse or dog. However, there is currently no scientific justification for excluding ORFs simply because they fail to show evolutionary conservation: the alternative hypothesis is that most of these ORFs are actually valid human genes that reflect gene innovation in the primate lineage or gene loss in the other lineages. Here, we reject this hypothesis by carefully analyzing the nonconserved ORFs—specifically, their properties in other primates. We show that the vast majority of these ORFs are random occurrences. The analysis yields, as a by-product, a major revision of the current human catalogs, cutting the number of protein-coding genes to 20,500. Specifically, it suggests that nonconserved ORFs should be added to the human gene catalog only if there is clear evidence of an encoded protein. It also provides a principled methodology for evaluating future proposed additions to the human gene catalog. Finally, the results indicate that there has been relatively little true innovation in mammalian protein-coding genes.
comparative genomics
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709013104/DC1.
To whom correspondence may be addressed. E-mail: mclamp{at}broad.mit.edu or lander{at}broad.mit.edu
© 2007 by The National Academy of Sciences of the USA
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