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Genomic Analysis Points to Three Regulatory Region Expansions During Vertebrate History

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a study appearing online today in Science, an international research team reported that it has identified three periods of gene regulatory innovation during the course of vertebrate evolution.

American and Swedish researchers brought together genome data for 40 vertebrates to see where regulatory elements cropped up over the course of evolution, focusing on conserved non-exonic elements (CNEEs) that are conserved between vertebrates but don't contain sequences coinciding with coding or non-coding transcripts. The team subsequently verified the CNEEs patterns detected through these alignments through comparisons of five species with well-assembled genomes: human, mouse, cow, stickleback, and medaka.

"We re-did all our work using only the species that had been very well assembled into chromosomes," the study's first author Craig Lowe told GenomeWeb Daily News.
"That allowed us to do a more conservative analysis that used fewer species, but the alignments are more reliable, we believe."

Lowe is currently a post-doctoral researcher at Stanford University in co-author David Kingsley's developmental biology lab. The study was initiated when he was a doctoral student in senior author David Haussler's biomolecular science and engineering lab at the University of California at Santa Cruz.

Overall, the researchers found evidence for three evolutionary stretches of regulatory region expansion: an ancient increase in regulatory elements near transcription factors and developmental genes, a later period in which regulatory regions tended to crop up near extra-cellular signaling genes, and, most recently, the proliferation of CNEEs near genes coding for post-translational protein modifiers in mammals.

The work was motivated, in part, by recent studies hinting that gene regulation might be as important as genes themselves in explaining some of the phenotypic or adaptive differences in vertebrate species, Lowe explained.

"That was really the motivation to try to look genome-wide to try to understand what sorts of regulatory elements are in the human genome and other vertebrate genomes," he said, "and to understand the timing of when those regulatory elements came to be."

To do this, Lowe and his colleagues looked at the repertoire of CNEEs within vertebrate genomes. The conservation of these regions, despite their lack of obvious coding function, hints that they are functional and being buffered against mutation, the researchers explained.

After doing whole-genome alignments of 40 vertebrate genomes, representing 31 mammals, two birds, five fish species and individual lizard and amphibian species, the team used software that helped them narrow in on regions with multi-species conservation that were resistant to substitutions, Lowe explained. They then tossed out coding genes and sequences that appeared to contribute to mature gene transcripts.

When they did a similar analysis on the human genome in relation to the mouse, cow, medaka, and stickleback genomes, the researchers found more than 2.9 million CNEEs, which were 28 bases long, on average, covering 2.9 percent of the human genome. And by looking at the alignment in relationship to the vertebrate tree, Lowe said, it was possible to plot the introduction of these CNEEs into the genome over evolutionary time.

For instance, their data suggests that the oldest CNEEs are found near transcription factor coding sequences and basal developmental genes. These ancient CNEEs first appeared in vertebrate genomes an estimated 300 million to 600 million years ago and are thought to have been present in a common ancestor of humans and fish.

Additional regulatory regions apparently arose in the genome around 100 million to 300 million years ago in the amniote ancestor, Lowe said. This second batch of CNEEs typically turn up in distinct parts of the genome compared to the older CNEEs, often occurring near genes for receptor proteins and proteins involved in signaling between cells.

The third and most recent round of gene regulatory gains appears to have happened in the mammalian ancestor within the past 100 million years or so, leading to a marked increase in CNEEs around genes contributing to post-translational protein modifications and intracellular signaling.

"We don't understand the specifics, but it seems like in mammalian evolution, possibly, this set of genes has been very helpful and useful for adapting to our environment," Lowe said.

Lowe cautioned that the regulatory elements identified are still putative and said researchers aren't sure that each individual CNEE they detected has a regulatory role. But, he said, other lines of evidence support the notion that the group as a whole does represent regulatory elements.

In addition, the team's subsequent experiments suggest that the timing of regulatory element gain near mammalian hair development genes appears to coincide with what's known about the evolutionary history of this process. It was possible to look at that trait because of the extensive research that's been done on mouse coat development, Lowe noted, which provided information on the genes that are involved in this process.

As more and more genomes from various vertebrate lineages become available, the team hopes to learn even more about vertebrate regulatory patterns and the timing of their regulatory region expansions within these lineages. "Further sequencing of additional vertebrate species will make it possible to determine the pervasiveness of these trends and to look for additional functional categories that may be associated with epochs of evolutionary change in particular lineages," they wrote.

In a perspectives article in Science, Duke University biologist Gregory Wray commented on the study, calling the team's method "a clever approach to document what may be among the first examples of long-term, macroevolutionary trends in genome function."

And although the periods of regulatory innovation identified don't seem to share a clear cause-and-effect relationship with the three evolutionary waves or faunas proposed from fossil evidence, Wray said it is still "exciting to think that, in time, it may become possible to integrate information from the fossil and genomic records to better understand major events in the history of life, such as the radiation of the vertebrates."

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