Tiny snippets of the genome known as microRNA were long thought to be genomic refuse because they were transcribed from so-called "junk DNA," sections of the genome that do not carry information for making proteins responsible for various cellular functions. Evidence has been building since 1993, however, that microRNA is anything but genetic bric-a-brac. Quite the contrary, scientists say that it actually plays a crucial role in switching protein-coding genes on or off and regulating the amount of protein those genes produce.
Now, researchers from Dartmouth College in Hanover, N.H., and the University of Bristol in England report in Proceedings of the National Academy of Sciences USA that these tiny genetic segments could be responsible for the evolution of animals with backbones, noting that they found a surfeit of microRNA in the genomes of the earliest vertebrates, such as lampreys (jawless fish), when compared with invertebrates like sea squirts.
"There's this dramatic increase in microRNAs that were fixed in the genome of vertebrates and were rarely secondarily lost," says study co-author Kevin Peterson, an associate professor of biological sciences at Dartmouth. "If a human has a microRNA that's also found in zebra fish, we [typically] find it in lamprey but we don't find it in any invertebrate," implying that that piece of genetic material is unique to vertebrates
Peterson says that scientists previously believed that the jump in complexity from invertebrates to vertebrates was due to genome-duplication events, during which large swaths of new genetic material were made (by some unknown mechanism) that randomly mutated and ultimately evolved into new species. In 2005 some researchers believed they had uncovered compelling evidence that two of these so-called duplication events had taken place when they compared the genomes of vertebrates with those of sea squirts, and between to vertebrate lineages: bony fish (lungfish and Atlantic blue marlin) and sharks.
But the Human Genome Project, completed in 2003, punched holes in their theory. The reason: if two duplication events had occurred, scientists would expect the resulting vertebrates to have four times as many genes as their spineless predecessors. Yet, among other things revealed by the genome project, was that humans have between 20,000 and 25,000 genes, which is less than two times the number carried by mere fruit flies.
"Given that most of the genes [from the genome-duplication events] were lost," Peterson says, "we thought maybe it's a red herring in thinking about the origin of vertebrate complexity." So, Peterson and his colleagues instead turned their focus to microRNA.
Beginning with mammals, like humans and mice, the team worked backward through time scanning genomes for microRNAidentified by its characteristic hairpin shape and 21- to 23-nucleotide (structural unit) length. The researchers compared shark, lamprey and sea squirt genomes and found much more microRNA in lampreys than in sea squirts. (Sharks, of course, are more complex than lampreys, and thereby also had more microRNA than the lowly squirts.) More interesting, this expansion of microRNA from the sea squirt to the lamprey predates the genome-duplication events that were thought to have created vertebrates.
The scientists also found that the majority of new microRNA was centered around genes responsible for the development of organs unique to vertebrates, such as the liver, pancreas and brain, says co-author Philip Donoghue, a senior lecturer in Bristol University's Department of Earth Sciences. "Therefore," he adds, "the origin of vertebrates and the origin of these genes is no coincidence."
Peter Stadler, a professor of bioinformatics at the University of Leipzig in Germany, believes it is plausible that microRNAs, given their known role in gene regulation, could be responsible for the complex changes that took place between invertebrates and vertebrates. He is, however, not sure that they acted alone. "I would be reluctant to rely solely on gene phylogenies of a small number of microRNAs, given that there is still no definitive information on the relative timing of the lampreygnathostome [vertebrates with jaws] split and the two rounds of vertebrate-specific genome duplications," he says. "With more genomes becoming available for basal chordates [proto-vertebrates, like the sea squirt], it will be very interesting to elucidate in detail the interplay of genome duplications, protein innovations and restructuring of the microRNA inventory."
