To unearth new functional regions in the human genome with potential roles in shaping clinically important traits, researchers in the United States searched for how elephants, hibernating bats, orcas, dolphins, naked mole rats, and thirteen-lined ground squirrels changed critical parts of the human genome that are shared with most other mammals. These regions are thought to be important because they are so highly conserved, but to evolve their highly distinctive traits, these seven species had to change how these conserved DNA elements work.
For example, elephants are the largest land mammals and were discovered to have changed several conserved regions associated with DNA repair. This discovery hints at why elephants rarely get cancer despite their large size and may provide clues to the genetics of human cancer. The study appears March 6 in the journal Cell Reports.
"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," says senior author Christopher Gregg (@GreggNeuroLab), a neuroscientist and geneticist at the University of Utah. "By decoding some of the noncoding parts of the genome, these data sets also revealed traits that you wouldn't have thought about in relation to these animals, like bats have enriched pathways involving uterus development and squirrels changed DNA regions related to human pigmentation abnormalities"
After casting a wide net, Gregg and his team looked specifically at their finding related to elephant DNA repair. They found elephant-specific changes near a gene called FANCL, a master regulatory of DNA repair. Then, in collaboration with Joshua Schiffman, a pediatric oncologist at the Huntsman Cancer Institute and University of Utah, the group looked directly at elephant cells exposed to irradiation to identify a DNA damage response program in elephant cells. The researchers discovered that the entire set of DNA damage response genes is changed in the elephant--revealing a composite of candidate elements across the genome that can affect cancer.
"This was exactly what our hypothesis predicted," Gregg says. "The genes that were responding to DNA damage in elephant cells were enriched with elephant accelerated regions all around them, and what'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."
Elephants need to be resistant to mutations because of the amount of cell division required to generate and sustain an organism of an elephant's size and lifespan. Humans are smaller and may have less evolutionary pressure to have similarly enhanced DNA repair mechanisms. Gregg argues that, by understanding the evolution of regulatory elements that contribute to enhanced cancer prevention in elephants, we may learn more about the mechanisms that can prevent cancer in humans.
Gregg's success with the elephant motivated his team to use other extraordinary species to further decode noncoding regions of the human genome. For example, bats evolved pointy ears and webbed fingers and toes, and Gregg's team discovered that the bat changed many noncoding regions near genes linked to Stahl ear, a human morphological disorder in which a person has "Spock-like" ears, and syndactyly, a condition in which a person's fingers are fused together. Naked mole rats, which live completely underground and have lost their vision, evolved changes around genes related to human glaucoma, a form of visual degeneration.
"What we have now is an atlas of new candidate elements for shaping particular phenotypes," Gregg says. "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."
This kind of analysis, which took several years of work led by first author Elliott Ferris, a University of Utah bioinformatician, was made possible by advances in genomic sequencing,
This research was supported by the National Institutes of Health, The Huntsman Cancer Foundation, Ringling Bros. Children's Fund of The Feld Family Foundation and The New York Stem Cell Foundation.
Cell Reports, Ferris et al.: "Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance" http://www.cell.com/cell-reports/fulltext/S2211-1247(18)30176-1
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