For example, said Haussler, the many conserved elements that are not in genes still tend to cluster in groups at certain places on the chromosomes. These clusters are often next to or surrounding genes that are known to play a role in regulating the activity of other genes in embryonic development. The conserved elements in the cluster can be up to a million bases away from the gene, however. The fact that conserved elements are hanging around the most important development genes suggests that they have some role in regulating the process of development and differentiation, said Haussler, even though they are often far away from the gene itself.

What really surprised us was that when we included the chicken genome in this comparison, we found that nearly all these regions still showed amazingly high levels of conservation, he said. In 29 cases it was 100%. This, despite the fact that the common ancestor of chickens, rodents, and humans is thought to have lived about 300 million years ago, he said.

However, the researchers found these regions to be significantly less conserved in the genome of the fish called fugu. And when they extended their comparisons to the even more ancient genomes of the sea squirt, fruit fly and roundworm, they found very little evidence of these conserved elements. The sea squirt exhibits a simple spinal cord early in its life cycle, and so it is more closely related to vertebrates than are flies or worms.

The most exciting thing for me is that the ultra-conserved regions we have identified do represent evolutionary innovations that must have happened sometime during vertebrate development, because we see such large pieces that no longer match in fish, and almost nothing in sea squirt. They must have evolved rather rapidly while our ancestors were still in the ocean, with some further evolution when animals first started to colonize land; after that they must have essentially frozen evolutionarily.

This suggests that these were foundational innovations that were very important to the species, and since the conserved elements are different from one another, that each one was important in some particular way. It is possible that further innovations in other interacting elements created so many dependencies that these foundational elements couldn't be mutated any more without disrupting something vital, said Haussler.

Besides the fact that the purpose of the non-coding ultra-conserved elements remains unknown, said Haussler, the researchers also do not understand the molecular mechanism of their action that requires them to be so faithfully preserved. A major question is what molecular mechanism would demand such a relentless conservation over hundreds of bases, he said. There is still the possibility that these regions are not so vital to the function of the organism, but in fact change very slowly for some other reason, such as lack of susceptibility to mutation, or hyper-repair. But it is even harder to imagine a mechanism for that.

Further studies, said Haussler, will involve not only more detailed comparisons of the conserved elements, but also laboratory studies exploring their functionality.

hhmi