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 approximately 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 
approximately 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.