Naked mole rats and elephants offer genetic clues to human diseases
Comparing genomes of seven very different mammals pays dividends. Stephen Fleischfresser reports.
All mammals share a large proportion of their genetic material, and these regions are highly conserved, meaning that they are mostly unchanging in the face of evolution. However, from research into humans, scientists realised that within these conserved elements there were a number of species-specific changes, known as accelerated regions (ARs). There are thousands of these in humans.
ARs almost always appear outside of genes in non-coding DNA, sections of the genome that are concerned with regulating genetic function.
ARs are also responsible for some of the remarkable characteristics of Earth’s unique creatures. Bioinformatician Elliot Ferris and Christopher Gregg, a neuroscientist and geneticist, both from the University of Utah in the US, led a multidisciplinary team that hypothesised that genomic analysis of ARs in species with distinctive traits would reveal exactly how these conserved elements had changed to produce the results.
They also suspected that the traits might help in understanding human diseases, among other things.
The team picked seven unlikely mammals with unique characteristics for their study: the little brown bat (Myotis lucifugus), the big brown bat (Eptesicus fuscus), and the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), all of which must hibernate to survive; the orca (Orcinus orca) and the bottlenose dolphin (Tursiops truncates), both of which are marine mammals adapted for diving; the naked mole rat (Heterocephalus glaber), a blind subterranean mammal; and, importantly, the African elephant (Loxodonta africana), the world’s largest land animal.
The elephant is of particular interest because it is an obvious case of Peto’s paradox. Named after Oxford University epidemiologist Sir Richard Peto, the paradox notes that if the chances of developing cancer were the same for all cells, then large organisms with more cells should develop tumours more often. The rub here is that they don’t – hence the paradox. This has led to the hypothesis that large animals must have evolved unique mechanisms to reduce the risk for cancer-causing mutations in body, or somatic, cells.
Indeed, the team found that there were ARs in the elephant genome near a gene called FANCL, a master regulator of DNA repair, and similar ARs were found in the other large mammal in the study – orcas. The researchers then exposed elephant cells to irradiation and watched as they responded to cancer-causing damage, only to discover that the ARs had modified the genes responsible for DNA repair.
“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.”
Interestingly, recent research suggests that such damage and mutation of somatic cells is an important risk factor in neurological conditions such as autism. The newly discovered elephant ARs responsible for enhanced DNA repair may well shed light on the treatment of such conditions, too.
Ferris and Gregg’s team also found ARs in bats that are implicated in the formation of fingers, toes and ears, possibly shedding light on human conditions such as syndactyly, the fusing of fingers, and Stahl ear, a unique pointing of the ear not unlike that of Mr Spock of Star Trek. In naked mole rats, with a subterranean lifestyle has led to the loss of vision, they found ARs associated with human eyesight.
“What we have now is an atlas of new candidate elements for shaping particular phenotypes,” says Gregg. “But this is just the beginning.”