post.queensu.ca/~forsdyke/introns.htm
Defects in the receptor for this chemokine decrease the severity of AIDS, transplant rejection, asthma, rheumatoid arthritis and multiple sclero sis (see Lancet 2001. Splicing of the human G0S19 (MIP1-alpha/CC3) gene to form messenger RNA,part of which is then translated to form the chemokine protein whose rec eptor (CCR5) is also a HIV1 coreceptor.
gif (4546 bytes) Introns Introduction In the 1960s non-bacterial (eukaryotic) ribosomal RNAs (rRNAs) were found to be synthesized as a long precursor RNA which was subsequently proces sed by the removal of apparently functionless internal "spacer" sequence s Since bacterial (prokaryotic) rRNAs were more compactly organized, it was reasonable to ask whether the first rRNAs to evolve had the spacer sequences, which subsequently decreased in prokaryotes, or whether the s pacer sequences were later acquired in eukaryotes. In the 1960s a similar processing was found to apply to eukaryotic pr ecursor messenger RNAs (pre-mRNAs; In the mid 197 0s it was found that the some of the internal sequences interrupted the protein-encoding part of the corresponding mRNAs. The internal sequences which were removed were named "introns", and what remained in the proce ssed mRNA constituted the "exons". Since the phenomenon had already been described for rRNA it should have been no big deal to find that it also applied to other RNAs, but many, including the author of these pages, w ere surprised that protein-encoding regions were interrupted. If introns could be dispensed with in bacteria, then perhaps they had no function. Alternatively, whatever function introns had, either was n ot necessary in bacteria, or might be achieved in other ways by bacteria . Since members of many bacterial species appeared to be under intense p ressure to streamline their genomes to facilitate rapid replication, if it were possible they would have dispensed with any preexisting introns and/or would have been reluctant to acquire them. On the other hand, if introns played a role and/or did not present too great a selective burde n, eukaryotes would have tended to retain preexisting introns, or could have acquired them. Knowing the function of introns seemed critical for sorting out these issues. Some thought introns wer e just another example of the apparently non-utile "junk" DNA which litt ered the DNA of many eukaryotes. However, some principles to guide inves tigation of a possible error-checking role were presented (Forsdyke 1981 ), and there is now growing evidence that introns play such a role (Fors dyke 1995a,b), although the mechanism may be somewhat different to that originally proposed (Liebovitch et al. It appears that the order of bases in nucleic acids might have been und er evolutionary pressure to develop the potential to form stem-loop stru ctures which would facilitate "in-series" or "in-parallel" error-correct ion by recombination. Although the genetic code is degenerate (more than one codon per amin o acid so that there is some flexibility as to which base occupies a par ticular position), there is still room for conflict between the "desires " of a sequence to encode both a protein (or non-messenger RNA) and stem -loop potential. The conflict would be particularly apparent in the case of genes under very strong positive phenotypic (Darwinian ) selection, as in the case of genes affected by "arms races" with predators or prey. For example, snake venom may decrease the rodent population (prey) un til a venom-resistant rodent line develops and expands. Now, while the r odent population increases, the snake population (predators) decreases, because it cannot obtain sufficient food. This decrease continues until a line of snakes arises with more active venom, which overcomes the resi stance. This line of snakes now increases, and the rodent population beg ins to fall again. This cycle constitutes an "arms race", and influences particular genes. The part of the venom protein which is important for toxicity is required to change so very rapidly in response to this stron g phenotypic pressure from the environment, that the corresponding gene can no longer afford the "luxury" of trying to encode both the best prot ein and the best stem-loops. So the stem-loop role is left to the intron s Here, paradoxically, sequence conservation is high, whereas in the ex ons, sequence conservation is low (Forsdyke 1995b). Similar pressures ma y be acting of the peptide binding regions of the genes encoding major h istocompatibility antigens (Forsdyke 1996b). Subsequent to the publication of the latter papers, another "player" in the conflict between protein-encoding potential and stem-loop potent ial emerged. Most mRNAs are "purine-loaded" in the loop regions of stem- loop structures (reviewed in Forsdyke & Mortimer, 2000). The selection p ressure for this appears to operate primarily at the cytoplasmic level. Consequently, the purine-loading may not optimally serve the postulated genomic role of stem-loops. There may be a conflict between "AG-pressure " (the pressure to purine-load) and stem-loop pressure. To resolve this, stem-loop potential would be moved to a region where AG-pressure does n ot operate, the introns. gif (2362 bytes) Are Introns In-series Error-detecting Sequences?
The probability of the accurate transmission of a message sequen ce can be increased by the addition of non-message sequences which permi t errors in the message sequence to be detected and corrected. It is pro posed that sequences in introns (or in other non-message genomic regions ) serve this function with respect to the transmission of genetic inform ation. Speculation on t he possible role of introns has included the view that they are examples of "junk" or "selfish" DNA, which does not contribute positively to cel l function (Doolittle & Sapienza, 1980; However, t he notion of message sequences interrupted by non-message sequences is q uite familiar to those working on noise affecting signal transmission in electrical systems. In these systems the non-message sequences have an error-checking function and permit the receiver to detect and correct er rors in the message sequence (Hamming, 1980). Some principles which may guide investigations of a possible error-checking role for introns are o utlined in this paper. When suggesti ng the duplex structure of DNA, Watson & Crick (1953) pointed out that t he sequence of one strand could be derived from the parallel strand, giv en the algorithm that purines pair only with pyrimidines (adenine with t hymine and guanine with cytosine). Thus, a duplex with correct base-pair ing can be written: RRYRYRRYY YYRYRYYRR If there were "noise" due to an abnormal base (Z ) in one strand of the d uplex, then the error could be corrected using information provided by t he parallel complementary strand. RRZRYRRYY YYRYRYYRR Remove abnormal base RR RYRRYY YYRYRYYRR Insert correct base RRYRYRRYY YYRYRYYRR In this example the error-checking system recognizes Z as abnormal so that it is excised. However, if the n oise were due to a normal base in the wrong position, then the error-che cking system would not know which strand contained the correct sequence. There would only be a 50% probability of correcting the error. RRRRYRRYY YYRYRYYRR Replace base in top or bottom strand, resulting in either a corrected seq uence RRYRYRRYY YYRYRYYRR or a mutation RRRRYRRYY YYYYRYYRR In this example the error-checking system recognizes that R-with-R pairin g is incorrect and changes either the R in the top strand (error correct ed) or the R in the bottom strand (error compounded). In a diploid organ ism containing two homologous parallel copies of duplex DNA it should be possible to correct noise due to a normal base in the wrong position wi th 100% probability of success. Duplex with error RRRRYRRYY YYRYRYYRR + Homologous duplex RRYRYRRYY YYRYRYYRR Results in: RRYRYRRYY YYRYRYYRR + RRYRYRRYY YYRYRYYRR In this example the error-checking system determines which of the two strands contains the error by comparing the duplex with the error with the homologous duplex. However, if the error were due to a switch in a b ase pair so that both strand...
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