Mapping Molecular Pathways
 James Deshler: Genetic GPS
Biologist James Deshler says that after the genomes of humans and other primates were sequenced, he was surprised at the high degree of their overall similarity. The chimpanzee genome, for example, differs from the human genome by only a few percent. “The big question I wanted to ask was, ‘What genetic sequences make us so different from other primates?’ If our genes are so similar, then what is it that makes us human?” Deshler says he now thinks that the answer, at least concerning cognitive abilities, may lie in part where messenger RNA (mRNA) is located within cells.
 Around the time that Deshler finished his post-doctoral research in the mid-1990s, the prevailing idea was that mRNA is randomly distributed within the cytoplasm to relay messages from genes encoded by DNA in the nucleus. “Everyone thought mRNA just floated around the cytoplasm and directed the assembly of proteins without much organization,” he says. Experiments on embryonic development in frogs and other species, however, revealed that some mRNAs prefer one side of the egg over the other, indicating that mRNA can sort itself in the cytoplasm.
Further work revealed that the location of mRNA determines how proteins are positioned in the cell, a process critical to embryonic development and for the growth of polarized cells, like neurons. “A highly evolved mechanism of RNA localization allows neurons to grow appropriately during development and learning,” says Deshler. Proteins (and their respective mRNAs) control the growth of neuronal axons during embryonic development and the reinforcement of connections necessary for learning in adults. The distinction between humans and chimps, therefore, might lie in the relative amounts of proteins and RNA that gather at synapses, the connections between neurons. Higher-order cognitive functions might be genetically hardwired in the unique way synapses are regulated in humans.
In earlier work with mRNAs known to localize within cells, Deshler had noticed short repeating sections in the non-coding portion of the RNA, corresponding to so-called “junk” sequences. Experiments showed that those “words,” which repeated in the sequence more often than expected, were necessary for mRNAs to recruit the accessory proteins needed to move themselves around the cell. Without these words, the mRNAs floated around, lacking any apparent ability to sense direction. Deshler refers to these repeating words as the GPS (global positioning system) of the cell, while others in the field prefer to call them zip codes.
 He originally discovered repeated GPS codes with his own eyes, visually scanning a sequence for repeating words, but now he harnesses computer power. Researchers in his lab designed a program called REPFIND which scans one gene for words that repeat more than twice and produces a list of those potential GPS codes. He uses REPFIND to search neuronal genes for repeated words, and then tests whether those words are actually GPS codes by conducting cellular lab experiments. He also wanted the ability to search the genomes of other organisms to see if certain codes are repeated in them as well, reasoning that if a word shows up frequently in many genomes, it may represent a fundamental language for mRNA localization. Because each gene takes about 30 seconds to scan in REPFIND, however, it would take several days to look for a single repeating word among the thousands of genes in each organism.
To speed up the process, Deshler recruited Ben Kennedy and In Lim, bioinformatics graduate students taking Gary Benson’s Biological Databases course. They created an online database of all repeating words and their probabilities, called GeneFinder. Researchers can use the database to see how many genes contain repeats of a particular word and then test in the lab whether those words are GPS codes. Deshler plans to use GeneFinder to crack the genetic code for mRNA localization, and potentially discover what sets us apart from our fellow primates.
For further information, see www.bu.edu/biology/faculty_staff/jdeshler.html.
To try REPFIND for yourself, visit http://zlab.bu.edu/repfind/.
— by Leah Eisenstadt |
