Tandem chimerism as a means to increase protein complexity in the human genome

Abstract

The "one-gene, one-protein" rule, coined by Beadle and Tatum, has been fundamental to molecular biology. The rule implies that the genetic complexity of an organism depends essentially on its gene number. The discovery, however, that alternative gene splicing and transcription are widespread phenomena dramatically altered our understanding of the genetic complexity of higher eukaryotic organisms; in these, a limited number of genes may potentially encode a much larger number of proteins. Here we investigate yet another phenomenon that may contribute to generate additional protein diversity. Indeed, by relying on both computational and experimental analysis, we estimate that at least 4%-5% of the tandem gene pairs in the human genome can be eventually transcribed into a single RNA sequence encoding a putative chimeric protein. While the functional significance of most of these chimeric transcripts remains to be determined, we provide strong evidence that this phenomenon does not correspond to mere technical artifacts and that it is a common mechanism with the potential of generating hundreds of additional proteins in the human genome.

Figure 1.

Flowchart depicting the protocol used to infer EST-supported TICs.

Figure 2.

The three computationally predicted chimeras in the ENCODE regions verified by RT-PCR. (A) chimera ENm013_GCL+006; (B) chimera ENr331_GCL+002; (C) chimera ENm005_GCL-002. Only one had known chimeric mRNAs before our experiments. One of the chimeras—ENm005_GCL-002—still lacks known mRNAs. The results of the RT-PCR validation in 12 of the 24 tissues tested are shown. Asterisks mark positive amplimers. The tissues are (1) brain, (2) heart, (3) kidney, (4) spleen, (5) liver, (6) colon, (7) small intestine, (8) muscle, (9) lung, (10) stomach, (11) testis, and (12) placenta. Chimeras were tested in 12 additional tissues (not shown here).