The recent sequencing of the complete human genome has made it clear that gene number is not the sole determinant of human complexity. Humans possess about 32,000 genes, only about 50% more than a worm and far less than the number of human proteins, estimated to exceed 90,000. Alternative splicing selectively chooses different parts of a gene and diversifies the genetic message by producing more than one type of messenger RNA molecule (and thus protein), from a single gene. Bioinformatic studies show that 32-59% of all human genes participate in alternative splicing; which may well explain the gene/protein disparity and human complexity. Some alternatively spliced events are specific to developmental or cell-cycle events, or to a certain type of cancer.
Dr. Gil Ast of the TAU Department of Human Genetics and Molecular Medicine, Prof. Dan Graur of the TAU Department of Zoology and their colleagues have recently shown that 5.2% of all alternatively spliced human exons originated from a mobile Alu sequence, while none of the normally spliced exons are Alu-derived. Exons are the parts of the genome that encode proteins; in contrast, introns do not.
Alu elements are short mobile sequences of DNA, consisting of two sections separated by a poly-adenine tail, which can make additional copies of themselves by reverse transcription from their corresponding messenger RNA. Alternatively spliced Alu sequences seem to have first entered intron regions and only later, via a process called "exonization," became new exons. Since Alu sequences are found only in primate genomes, Alu-derived exons, and the proteins they encode, may contribute to some characteristically human features. In fact, mobile genetic elements, such as Alu sequences, make up over 45% of the human genome (exons constitute only 2%). Since such elements continue to multiply, over the last 60 million years, approximately 1.4 million copies of Alu elements have accumulated in the primate genome. Humans seem to have more Alu elements in their genome (11% of the whole genome) than other primates; and they are also more susceptible to AIDS, cancer and other diseases. Thus better understanding the genetic basis of these differences may help elucidate the origin of such diseases and increase our ability to control them.
The TAU investigators are now examining the linkage between the appearance ("birthing") of new Alu exons and specific cancer cell types, in an effort to develop a novel series of diagnostic tests. They find that a significant number of alternatively spliced RNA molecules which contain Alu elements are indeed associated with ovary, brain, head-neck, lung, kidney and prostate cancers. To validate their computer predictions, the investigators studied one gene, HSACD ("High Similarity to Acyl-CoA Dehydrogenase") in detail. They found six alternatively spliced HSACD messenger RNA variants (isoforms) which contained the Alu exon and which were found only in human ovarian cancer cells. Examining 16 different ovarian cancer tissue samples, the researchers found that 50% contained more than one alternatively spliced HSACD messenger RNA isoforms. Work on this promising new approach continues.
