Elephants very, very rarely develop cancer. This makes them very unique, as cancer is a common cause of death for most species, yet only 4.8 percent of known elephant deaths are caused by the disease. Because random genetic mutations that occur during cell division can lead to cancer, it seems counterintuitive that such large bodies stay relatively cancer-free since the cells in a large, long-lived animal divide many more times than the cells in a small, short-lived animal. On Tuesday, scientists stumped by the conundrum reported in Cell that they’ve figured out how elephants do it.
In the paper, the researchers report that elephants are protected by certain genes — many of which they share with humans. This is good news for scientists trying to understand the genetics of human cancer.
“This was exactly what our hypothesis predicted,” senior author and assistant professor in Neurobiology and Anatomy at University of Utah Health Christopher Gregg, Ph.D., said in a statement. “The genes that were responding to DNA damage in elephant cells were enriched with elephant accelerated regions all around them, and what’s exciting in those elements were conserved across mammals. They exist in humans, which means they may be relevant for shaping DNA damage responses in human cells.”
Research in the field has shown that elephants’ protection against cancer definitely has a genetic basis. Previous studies showed that elephants have 20 copies of a gene called p53 (the “tumor suppressor gene”) that responds to irradiation by mitigating DNA damage. Other mammals, including humans, have just one copy of that gene. In the new study, scientists determined that elephants also have distinct versions of DNA repair genes called FANCL, VRK2 and BCL11A, which they discovered after exposing elephant cells to radiation and examining how the DNA responded to the damage.
On the elephant genome, all of these genes lie in the region that resulted from “accelerated evolution” — that is, the part of the genome that evolved rapidly, leading to the development of many distinct traits.
These findings aren’t just relevant to elephants, though. Because mammals like humans, elephants, and mice share a common ancestor that lived approximately 80 million years ago, the genomes of all mammals are at least somewhat similar. For example, while each of us are 99.9 percent genetically similar to another human, we are 96 percent genetically similar to a chimpanzee and 85 percent similar to a mouse. With that in mind, we may not have the version of FANCL that helps elephants resist mutations in the face of the amount of cell division it takes to generate and sustain their size, but other mammals have the gene, too. Learning about how it changed could help us understand how we could manipulate our own genomes to do the same in the future.
That’s why studies like the current one can potentially teach us so much about humankind. By examining animals that share our genes yet have distinctive traits that we don’t have, scientists can pinpoint what elements of the mammalian genome have changed — and, more importantly, how. This process, the scientists write, “could be relevant for understanding human disease.”
In addition to elephants, the researchers also analyzed the genomes of six other animals to help identify the genetic roots of their unique (and desirable) traits. For instance, bats, with their pointy ears, have changes in noncoding regions near genes linked to Stahl’s ear, a morphological disorder that causes human ears to become Vulcan-like. Blind, naked mole rats, meanwhile, have evolved changes in genes that could shed light on how human glaucoma develops.
“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 use before,” says Gregg.
“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.”