Elephants Are Protected From Cancer by a Zombie Gene

An estimated 17 percent of humans worldwide die from cancer, but less than five percent of captive elephants — who also live for about 70 years, and have about 100 times as many potentially cancerous cells as humans die from the disease. Elephants and other huge animals have a lower cancer rate than statistically predicted, implying that they have evolved mechanisms to protect themselves against the disease. Elephants do it this way, according to a recent study: An ancient gene that was no longer functioning was recycled from the huge “genome junkyard” to make elephant cells more sensitive to DNA damage, allowing them to detect possibly malignant cells earlier.

Cells in multicellular organisms undergo several growth and division cycles. Every time a cell divides, it copies its complete genome, and a few errors are certain to occur. Cancer can be caused by some of these mutations. It’s natural to believe that animals with bigger bodies and longer lives are more likely to get cancer. When scientists compare animals with a wide range of body sizes, however, they observe something different: The number of cells in an organism or its lifespan do not appear to be related to the occurrence of cancer.

Separate research teams from the University of Chicago and the University of Utah began to investigate why. They were aware that humans, like all other animals, have a single copy of the master tumour suppressor gene p53. This gene allows humans and elephants to detect unrepaired DNA damage, which is a precursor to cancer. The damaged cells are then killed.

Surprisingly, the researchers discovered that elephants have 20 copies of the p53 gene. This makes their cells far more sensitive to damaged DNA and far more likely to commit cellular suicide.

The University of Chicago team describes a second component of this process in the August 14, 2018 issue of the journal Cell Reports: a resurrected anti-cancer gene.

“Genes duplicate all the time,” said Vincent Lynch, PhD, senior author of the study and assistant professor of human genetics at the University of Chicago. “They occasionally make mistakes, resulting in non-functional versions known as pseudogenes. We dismissively refer to these as “dead genes.””

Lynch and colleagues discovered a former pseudogene called leukaemia inhibitory factor 6 (LIF6) that had somehow evolved a new on-switch while studying p53 in elephants. LIF6, once thought to be extinct, had resurrected as a useful working gene. When activated by p53, its function is to kill the cell in response to damaged DNA. The LIF6 gene produces a protein that quickly travels to the mitochondria, the cell’s primary energy source. This protein pierces the mitochondria, causing the cell to die.

“Therefore, zombie,” Lynch explained. “This dormant gene was resurrected. When activated by damaged DNA, it quickly kills the cell. This is advantageous because it acts in response to genetic errors, which occur when the DNA is being repaired. Getting rid of that cell can help you avoid developing cancer in the future.”

There are eight LIF genes in elephants, but only LIF6 is known to be functional. Despite the fact that it was only recently described, it appears to have been assisting elephants and their relatives for quite some time.

“We can use evolutionary tricks to try to figure out when this defunct gene became functional again,” Lynch explained. It appears to have evolved around the time that the fossil record indicates that the small groundhog-sized forefathers of today’s elephants began to grow larger. This began approximately 25 to 30 million years ago. This additional method of cancer suppression may have been a key factor in enabling enormous growth, which eventually led to modern elephants.

Being enormous has significant and long-term benefits. Small animals, such as mice, squirrels, and groundhogs, are constantly eaten, primarily by larger animals. “If you’re enormous, like an elephant or a whale,” Lynch says, “nothing is going to mess with you.”

However, there are tradeoffs. Larger animals have far more cells, and they live for longer periods of time, giving them more time and opportunities to accumulate cancer-causing mutations. When those cells divide, their DNA duplicates itself. However, the copies do not match the original. Errors are introduced, and the repair process is unable to keep up.

“In order to live as long as they do and reach adult sizes, large, long-lived animals must have evolved robust mechanisms to either suppress or eliminate cancerous cells,” said study co-author Juan Manuel Vazquez, a doctoral candidate in the Lynch laboratory.

As a result, these massive animals are more likely to develop cancerous cells. On a smaller scale, this can also occur. Taller people, for example, have a slightly higher incidence of several cancer types than average-sized people, while shorter people have a lower risk for those cancers.

According to the researchers, LIF6 was “reanimated sometime before the demands of maintaining a larger body existed.” It aided in the development of animals as small as a 10-pound groundhog into majestic creatures weighing more than 15,000 pounds. According to the authors, it was “permissive for the origin of large bodies,” but “insufficient.”

However, it is unknown how LIF6 causes apoptosis. The authors stated that this will be the “focus of further research.”

Reference
Vazquez JM, Sulak M, Chigurupati S, Lynch VJ. A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage. Cell Rep. 2018 Aug 14;24(7):1765-1776. doi: 10.1016/j.celrep.2018.07.042. PMID: 30110634.