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Cross-Species Genome Comparison Uncovers Regulatory Elements With Ties to Clinical Phenotypes

NEW YORK (GenomeWeb) – A cross-species analysis centered on parts of the genome that have undergone speedier-than-usual evolution has uncovered potential functional elements with ties to species-specific phenotypes and human disease.

Researchers from the University of Utah, the Huntsman Cancer Institute, and the New York Stem Cell Foundation compared the genomes of seven mammals with environmental, disease, and lifestyle adaptations: the African elephant, microbat, big brown bat, orca, bottlenose dolphin, naked mole rat, and thirteen-lined ground squirrel. The study, appearing online today in Cell Reports, led to candidate functional elements at sites that are highly conserved in most mammals but show enhanced evolution in a given species.

By cross-referencing this collection of so-called accelerated regions (ARs) with mouse and human genomes, the team identified tens of thousands of apparent regulatory elements neighboring genes with ties to specific traits or diseases.

"What we have now is an atlas of new candidate elements for shaping particular phenotypes," senior author Christopher Gregg, a neurobiology, anatomy, and human genetics researcher affiliated with the University of Utah and the New York Stem Cell Foundation, said in a statement. "But this is just the beginning. We need functional studies to determine what the elements we discovered actually do, and whether they do have important functional roles in shaping clinically relevant phenotypes."

The analysis centered on seven mammalian species, some living on land or underground, and others adapted to marine environments, the researchers explained. Three of the species — the microbat, big brown bat, and ground squirrel — are known to hibernate, for example, while elephants and naked mole rats are far less prone to somatic mutations and cancer development than most mammals, including humans.

"What we've done is use animals with extraordinary traits to reveal new elements in the human genome that we think are important, but were hidden to us before," Gregg said.

From some 660,851conserved regions in the mammalian genomes, the researchers tracked down almost 3,500 ARs in the African elephant. The microbat and big brown bat genomes contained 18,000 and 19,152 ARs, respectively. The researchers also uncovered 2,608 ARs in the orca genome and 2,408 dolphin ARs, along with 4,440 ARs in the naked mole rat and 6,704 ARs in the squirrel genome.

Nearly 70 percent of ARs overlapped in the microbat and big brown bat genome, they reported, while the orca and dolphin shared more than one third of their ARs, providing clues to adaptations in these lineages.

All told, the team tracked down 33,283 candidate functional elements across the seven mammal genomes, which were subsequently cross-referenced with coding and non-coding sites in human and mouse cells, among other analyses.

In elephants, the researchers highlighted ARs enriched near a DNA repair pathway component, for example, perhaps explaining the low cancer rates in the large mammal. Indeed, their follow-up experiments suggested primary peripheral lymphocytes from elephants show distinct DNA damage responses when exposed to ionizing irradiation in the lab.

"The genes that were responding to DNA damage in elephant cells were enriched with elephant accelerated regions all around them," Gregg explained. "[W]hat's exciting is, those elements are conserved across mammals. They exist in humans, which means they may be relevant for shaping DNA damage responses in human cells."

And there were other apparent ties to human conditions: in bats, the team saw ARs falling near genes implicated in a human condition called Stahl ear, marked by pointier-than-usual ears and fused fingers. And the genomes of naked mole rats, which lost their sense of sight while adapting to life underground, contained ARs in regions near human glaucoma-related genes.

More unexpectedly, the researchers uncovered candidate functional elements with potential impacts on less obvious animal traits. In parts of the bat genome, for example, they uncovered ARs associated with genes related to uterine development, while enhanced evolution occurred in regions of the squirrel genome that may impact pigmentation.

"The results are expected to advance our understanding of the genetic basis of different mammalian phenotypes, including human clinical phenotypes," Gregg and co-authors wrote.