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Doctor in a cell “The sci-fi vision of a molecular medical team that Alu elements — a can be injected into a patient, coursing through his bloodstream to diagnose a complex affair disease and treat it, has taken a step nearer to reality” (AFP Discovery Channel). Formerly described as junk and para- showed that ~5% of human alter- On 28th April 2004, Ehud sitic, who would have expected that natively spliced exons are derived Shapiro and colleagues, from the Weizmann Institute, transposable elements would help us from Alu elements — short - reported online in Nature the out from a potential evolutionary specific , of which creation of the first molecular embarassment — the low gene num- have ~1.4 million copies. computer that could have ber in the ? Ast and These Alu exons (AExs) have evolved medical use. This computer colleagues have shown that inclusion from intronic Alu elements. But how exploits the base-pairing of Alu elements in exons promotes can a ‘free’ intronic Alu element turn showed that positions 2 and 5 in the properties of DNA to detect alternative splicing and therefore into an exon that is alternatively intron are those that matter. mRNAs that are diagnostic for disease and then destroys genome diversity. Using bioinformatic spliced? But how is the alternative splic- them by releasing antisense and experimental approaches, they To answer that, the authors com- ing of AExs regulated? Using site- DNA molecules. The now identify the mutational steps that pared AEx sequences with those of directed mutagenesis, the authors computer is “so small that create 5′-splice sites in alternatively their intronic ancestors. They focused found that alternative splicing of about a trillion can fit in a drop spliced Alu elements. on the 5′-splice site: >98% of human AEx is possible because C at position of water” (The Telegraph) and The surprisingly low gene num- introns begin with GT and very 2 of the 5′-splice site unpairs from “is listed in the 2004 Guinness Book of World ber and much higher protein number few with GC, although these are the U1 small nuclear RNA (snRNA); Records as the world’s made alternative splicing an obvious the ones that are supposed to be its interaction with the 5′-splice site is smallest biological computing process that could account for our bio- mainly involved in alternative splic- crucial for constitutive splicing. device” (The Guardian). logical complexity. Mouse and human ing. Strikingly, the most significant Moreover, it seems that positions 3 “The computer has two sequence comparisons have indicated change in AExs was at position 2 of and 4 of the intron control the level states, ‘yes’ and ‘no’, and that alternative splicing is often asso- the intron, where a C→T transition of exon inclusion, whereas G at posi- changes from one to the ′ ′ other on the basis of a single ciated with recent exon creation creates a canonical GT 5 -splice site. tion 5 ensures that the 5 -splice site is variable, like the presence or and/or loss. The authors previously Comparing over 300,000 sequences selected. absence of the RNA it is looking for. If at the end of a series of steps it is in the ‘yes’ state, the diagnosis is T ECHNOLOGY the stability of positive” (The New York a gene’s mRNA. Times). Their aim was to What do the experts think? find defined ‘“I think it’s very elegant — changes in the 3′ almost like a beautiful Three prime mice mathematical proof,” said UTR that would George Church. “But it’s not allow the expression working in human cells yet”’ Modelling quantitative traits in these often subtle changes is of a gene to be altered (The New York Times). mice has just got easier thanks to a usually left to rather crude in situ in a predictable The molecular computer new technique, reported by Masao manipulations. In mice, for way. proved its worth in the Kakoki and colleagues, that allows example, the expression of To test their idea, they optimal conditions of the the expression of a gene to be transgenes that are microinjected created mouse embryonic laboratory: “To actually track subtly modified by tweaking the into a one-cell embryo is stem (ES) cells in which a GFP gene down and disable cancer sequences at its 3′ end. Gene unpredictable as it depends on how was inserted into an endogenous cells in a human body, it expression can be many copies are integrated into the locus. Altering the 3′ sequences of would have to survive the hurly-burly of proteins, lipids, varied over a genome and where in the genome the transgene allowed them to ′ polysaccharides and nucleic 100-fold range, the integration occurs. To obtain a assess the effect of various 3 acids, any of which could without moving the gene more predictable and less regions on GFP expression by block or disable it” (The from its normal chromosomal intrusive means of monitoring the level of Guardian). But, Professor position, or altering its controlling gene fluorescence emitted by the cells. Shapiro is upbeat: ‘“Only two promoters or introns. expression, Kakoki Protein expression (which years ago we predicted that it Methods for mapping the and colleagues turned correlated with mRNA levels) would take another 10 years genetic alterations that to the 3′-untranslated varied over a 100-fold range to reach the point we have underlie complex traits are region (UTR), which according to whether the 3′ reached today”’ (The getting ever more has been shown many Guardian). sequences were derived from say, sophisticated, but modelling times before to influence the Fos gene, which has a very Tanita Casci

406 | JUNE 2004 | VOLUME 5 www.nature.com/reviews/genetics