One Gene, Many Proteins

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See related article, pages 874–883 When the human genome sequence was first drafted in 2000, researchers were shocked by the low number of genes found. Humans make ≈90 000 different types of protein, so estimates were that at least a similar number of genes would be found. The logic was that, given the structural and functional complexity of the human body, we ought to have more genes than the simpler corn ( zea mays , ≈40 000 genes) or the puny worm Caenorhabditis elegans (≈19 500 genes). So, when the final number of human genes was established to be fewer than 25 000, researchers immediately realized the gene:protein mismatch, reaffirmed the notion that the axiom “one gene, one protein” was inaccurate, and began looking for the evolutionary mechanisms that increase diversity and complexity from a relatively simple genetic makeup. The answer, it seems, is alternative gene splicing. When a segment of DNA (gene) is transcribed, the resulting RNA (tRNA) contains meaningful (exons) and nonmeaningful (introns) sequences that must be edited to produce a coherent message (mRNA). This cut-and-paste process where exons are retained and introns are discarded is called gene splicing and constitutes the normal processing of genes. However, as it was first discovered some 25 years ago,1 “alternative splicing” occurs, a highly regulated process that confers sophistication to the manufacturing of proteins by frequently “violating the rules” and leaving pieces of introns or excising parts of exons in the final mRNA. The resultant protein, a splice variant, thus contains segment(s) of distinct amino acid sequence that presumably leads to functional diversity. The relevance of alternative splicing cannot be overemphasized. In one extreme example, alternative splicing is largely responsible for determining whether a cell continues to live or whether it programs its death by expressing a promoter of apoptosis …