It is generally believed that signi®cant ribosomal frameshifting during translation does not occur without a functional purpose. The distribution of two frameshift-prone sequences, A_AAA_AAG and CCC_TGA, in coding regions of Escherichia coli has been analyzed. Although a moderate level of selection against the ®rst sequence is evident, 68 genes contain A_AAA_AAG and 19 contain CCC_TGA. The majority of those tested in their genomic context showed >1% frameshifting. Comparative sequence analysis was employed to assess a potential biological role for frameshifting in decoding these genes. Two new candidates, in pheL and ydaY, for utilized frameshifting have been identi®ed in addition to those previously known in dnaX and nine insertion sequence elements. For the majority of the shift-prone sequences no functional role can be attributed to them, and the frameshifting is likely erroneous. However, none of frameshift sequences is in the 306 most highly expressed genes. The unexpected conclusion is that moderate frameshifting during expression of at least some other genes is not suf®ciently harmful for cells to trigger strong negative evolutionary pressure.

A bioinformatics approach to finding new cases of ؊1 frameshifting in the expression of human genes revealed a classical retroviruslike heptanucleotide shift site followed by a potential structural stimulator in the paraneoplastic antigen Ma3 and Ma5 genes. Analysis of the sequence 3 of the shift site demonstrated that an RNA pseudoknot in Ma3 is important for promoting efficient ؊1 frameshifting. Ma3 is a member of a family of six genes in humans whose protein products contain homology to retroviral Gag proteins. The ؊1 frameshift site and pseudoknot structure are conserved in other mammals, but there are some sequence differences. Although the functions of the Ma genes are unknown, the serious neurological effects of ectopic expression in tumor cells indicate their importance in the brain.Although nonoverlapping triplet reading of mRNA codons is the essence of genetic decoding, dynamic nonstandard events at specific sites can permit product diversity and provide regulatory options. One of these recoding events involves shifting to an alternative reading frame by a proportion of ribosomes, thereby changing the linearity of readout. Such utilized frameshifting commonly features both a "shifty site" in the mRNA and an appropriately positioned structural feature in the mRNA that acts to enhance the level of frameshifting, i.e. it is programmed. Although the shift involved can be to either alternative frame, a shift to the Ϫ1 frame often involves tRNAs in both the A and P sites detaching from their codons and re-pairing to mRNA at the two overlapping Ϫ1 frame codons (1, 2). This tandem detachment and re-pairing usually occurs on a "slippery" heptanucleotide sequence that follows the general pattern of X XXY YYZ where the A and P site tRNAs detach from the zero frame codons XXY YYZ and re-pair after shifting 1 nucleotide to XXX YYY. The spacer region between the shift site and the 3Ј structural element is commonly 6 -8 nt 2 (3). The most common 3Ј recoding signals for Ϫ1 frameshifting are pseudoknots (4, 5) with distinct features (6, 7). A less common type of pseudoknot is the kissing stem-loop found in the human coronavirus, HCV229E (8), but bioinformatic studies suggest that it may be involved for transmissible gastroenteritis virus frameshifting also (9).Examples of genes that require Ϫ1 frameshifting for expression are well known in viral genomes. There is only one demonstrated case of Ϫ1 frameshifting in a mammalian cellular gene (10, 11), but it does not display the phylogenetic breadth of the ϩ1 frameshifting utilized in decoding antizyme mRNA, conserved from mammals to yeasts (12). Frameshifting near the end of a coding sequence often allows a proportion of ribosomes to access an ORF that extends beyond the zero frame terminator so that the transframe (coupled ORF) protein is longer than that of standard decoding. The easiest class of Ϫ1 programmed frameshift events to search for is one that has conserved architecture of two ORFs that partially overlap and contains a defined shift site. In these cases conser...

To find a length of slippage-prone sequences at which selection against transcriptional slippage is evident, the transcription of repetitive runs of A and T of different lengths in 108 bacterial genomes was analyzed. IS element genes were found to exploit transcriptional slippage for regulation of gene expression.

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