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Thursday, January 25, 2007

Too much complexity!
Science this week has an interesting paper, interesting in that it gives me a headache and I wish life would find simpler solutions to problems. It doesn't though. I think I'm going to take the creationist route soon though and just blame everything on a fickle creator who existed solely to deceive and atagonize molecular biologists.

Anyway, in biology there is what is called the "Central Dogma of Molecular Biology" and it has to do with the way information is stored, propogated, and used to express a phenotype in a cell. The most basic expression of this "Dogma" (one based on evidence at least) is that DNA is the heritable information in a cell, it is transcribed to make RNA, and then is translated into protein. DNA, in this simple explanation, is merely a storage medium. RNA is then a messenger and enabler shuttling materials between the genomic information storage space and the molecular assembler known as the ribosome. Each 3 base pairs of the messenger RNA (mRNA) correspond to a single amino acid, the basic building blocks of proteins. The 64 different potential codons correspond to 20 amino acids (multiple codons correspond to the same amino acid), and are shuttled in on transfer RNAs (tRNA) that then are assembled by the ribosome into a chain based the coding sequence of the mRNA sequence. Protein is the ultimate goal of this information transfer, and is responsible for carrying out all the responsibilities of the cell.

This is what you learn in highschool, and it seems a little complicated but reasonable. You may ask questions at the time, like why do we have 64 codons when there are only 20 amino acids? If only it ended there. Here is an image from the Wikipedia article showing a more accurate representation of the current state of knowledge of how information is transferred in biological systems.

This image is already inaccurate because RNA-Dependent RNA polymerase activity has been found to be associated within higher eukaryotes (c. elegans) and siRNA, so it's already off. Still, you can see how complicated the "dogma" has become. You have viruses going every which way, plants doing weird stuff, crazy lab experiments bypassing RNA etc.

This week in Science, the picture becomes even more complicated. Researchers have found that in humans, the multi-drug resistance gene (MDR-1) is sensitive to single nucleotide polymorphisms (that means changes in a single DNA base pair), that are "synonymous" which means that the mutation doesn't lead to a change in the protein sequence. So you have 64 codons, which correspond to 20 amino acids and are responsible for assembling the primary sequence of a protein. But now we're learning that when one codon in the mRNA is exchanged for another codon that corresponds to the exact same amino acid, the protein function can be drastically altered. This is pretty extraordinary.

Evidence from within the paper suggests that the "mutated" protein assumes a different conformation despite having an identical primary sequence as the "wild-type" protein. Clearly something interesting is happening at the ribosome in response to different codons, and the evidence is that the kinetics of translation is altered, such that the presence of the synonymous codon leads to a greater or shorter time of passage of the RNA through the ribosome, thus altering the kinetics of protein folding as the amino acids exit the ribosome. The increased or decreased times through the ribosome may lead to protein conformations which would not otherwise be energetically favored.

It is questionable whether this is a mechanism that evolved to create greater complexity of expression in cells, or whether this is some kind of emergent property of a complex system. Either way, this is an interesting result which does a lot to explain the so called "preferred" codon usage in higher animals, which is the observation that codons that encode the same amino acid are present at differing frequencies in various animals, which would suggest some advantage for using one codon over another, despite being synonymous. And the reason why I bring up the Central Dogma of Molecular Biology in a discussion of this isn't because there's a new pathway of information transfer. Rather, this paper suggests that in addition to transporting sequence information from DNA to protein, the mRNA codon preference encodes a piece of kinetic information which can ultimately alter phenotype. The evidence is clear that the raw amino acid sequence is not responsible for these changes in the MDR-1 phenotype. There's a new angle to explore and it's entirely possible that both rare and common codons have specific usages that ultimately may effect the phenotype of cells, the pathogenesis of genetic diseases, as well as creating an unexpected source of variation between individuals.

Also the parthenogenic stem cells paper that was published online about a month ago is out. We blogged about it previously.



Ted said...

Hey, interesting stuff.

BTW, Larry Summers got your back Rev Dr.

He thinks we need to protect the scientific class although the rabble in the comments seems to want to throw you folk out into the cold.

10:33 PM, January 28, 2007


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