Finding protein-coding genes through human polymorphisms.

Human gene catalogs are fundamental to the study of human biology and medicine. But they are all based on open reading frames (ORFs) in a reference genome sequence (with allowance for introns). Individual genomes, however, are polymorphic: their sequences are not identical. There has been much research on how polymorphism affects previously-identified genes, but no research has been done on how it affects gene identification itself. We computationally predict protein-coding genes in a straightforward manner, by finding long ORFs in mRNA sequences aligned to the reference genome. We systematically test the effect of known polymorphisms with this procedure. Polymorphisms can not only disrupt ORFs, they can also create long ORFs that do not exist in the reference sequence. We found 5,737 putative protein-coding genes that do not exist in the reference, whose protein-coding status is supported by homology to known proteins. On average 10% of these genes are located in the genomic regions devoid of annotated genes in 12 other catalogs. Our statistical analysis showed that these ORFs are unlikely to occur by chance.