May 6, 2004— Hundreds of stretches of DNA may be so critical to life's machinery that they have been “ultra-conserved” throughout hundreds of millions of years of evolution. Researchers have found precisely the same sequences in the genomes of humans, rats, and mice; sequences that are 95 to 99 percent identical to these can be found in the chicken and dog genomes, as well.
Most of these ultra-conserved regions do not appear to code for proteins, but may instead play a regulatory role. Evolutionary theory suggests these sequences may be so central to mammalian biology that even small changes in them would compromise the animal's fitness.
Led by Howard Hughes Medical Institute investigator David Haussler, at the University of California at Santa Cruz, the researchers published their findings online May 6, 2004, in Science Express, the Web counterpart of the journal Science. The lead author on the paper was Gill Bejerano in Haussler's laboratory. Also co-authoring the paper were John Mattick and his colleagues from the University of Queensland in Australia.
The first indication of the existence of ultra-conserved sequence regions was found in the initial comparison of the human and mouse genomes. Previous estimates of the amount of the genome that was "junk DNA" or sequences that are unused turned out to be too high. The amount of conservation of sequence that was found suggested most of the genome that has functionality is not coding for proteins. This argues that the genome contains much more regulatory complexity.
According to Haussler, the researchers were launched on their analysis when initial studies hinted at major regions of conserved DNA sequences. “When we had compared the human and mouse genomes, we found that about five percent of each of these showed some kind of evolutionary selection that partially preserved the sequence,” he said. “We got excited about this because only about 1.5 percent of the human genome codes for protein. So five percent was about three times as much as one might expect from the standard model of the genome, in which it basically codes for proteins, with a little bit of regulatory information on the side, and the rest is nonfunctional or “junk” DNA.
“These initial findings suggested that quite a lot of the genome was performing some kind of regulatory or structural role - doing something important other than coding for proteins,” said Haussler.
Comparison between the genomes of humans, mice, and rats showed many identical sequences. Most of those sequences do not code for proteins. So they are probably regions that regulate expression and translation of genes into proteins.
The comparison of the three genomes revealed 481 such elements that they called “ultra-conserved.” “What really surprised us was that the regions of conservation stretched over so many bases. We found regions of up to nearly 800 bases where there were absolutely no changes among human, mouse and rat.”
Although 111 of these ultra-conserved elements overlapped with genes known to code for proteins, 256 showed no evidence that they overlap genes, and another 114 appeared inconclusively related to genes. In the 111 that overlapped genes, relatively small portions were actually in coding regions. Many were either in untranslated regions of the gene's messenger RNA transcript or in regions that are spliced out before the message is translated into protein.
Many of the complex regulatory mechanism were worked out into their final form at least 300 million years ago. Some of our components are based on very old and proven designs.
“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.
Comparative genomics is turning out to be incredibly useful. Conservation of regions shows which regions are functionally important. The higher the degree of conservation the more likely that a region is involved in some function that is heavily intertwined with many aspects of cellular function or development. Faced with billions of letters of DNA sequence information about conservation of sequences allows scientists to sort through and rapidly choose much smaller key sections for further study.
Comparative genomics is also incredibly useful between humans in part because it allows us to identify where selective pressures were acting on the genome. There are millions of DNA sequence differences between humans. Most have no effects. But others will turn out to be incredibly important for disease risks, differences in rates of aging, intelligence, personality, physical appearances, strength, and other characteristics.
The rate of discovery from comparative genomics is going to continue to increase quite dramatically in the coming years because of declining costs for DNA sequencing and SNP testing.
|Share |||Randall Parker, 2004 May 06 12:07 PM Evolutionary History|