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“Owners and occupants of earlier dates, From graves forgotten stretch their dusty hands, And hold in mortmain still their old estates.”

– From Haunted Houses by Henry Wadsworth Longfellow

In the world of Game of Thrones, they’re called “wights.” To the wizarding world of Harry Potter, they were known as “Inferi.” But most often, they’re known as zombies. These creepy creatures have populated (infested?) books, TV shows, and movies for decades. This week, the world learned about a different kind of zombie—one that’s not made of bones or flesh. This kind of zombie is made of DNA, and it may be playing an important role in the evolution of elephants. It could also be helping humans grow large brains.

Over the past few weeks, two research articles have set off a storm of headlines. One talked about the death of a gene in marine mammals that may have left them vulnerable to the toxic effects of pesticides. The other describes a “zombie” gene that may be helping elephants fight cancer. Central to both findings is the idea that genes have a life cycle, of sorts. In its “alive” state, the gene provides a function to its host. Death befalls a gene when its DNA sequence changes—due to heritable variants—in such a way that it is prevented from doing its job of producing a protein. Rather than call these genes “dead,” scientists usually call them pseudogenes.

In the case of marine mammals like dolphins, whales, and some seals, their PON1 gene has suffered multiple changes in its DNA sequence that led to its demise (or pseudogenization). PON1 produces a protein that helps protect our heart and blood vessels from oxygen radicals—short lived oxygen molecules that can damage the structure of fats, proteins, and DNA within cells [1]. Research also shows that PON1 can help metabolize certain toxins that are present in the bloodstream, including some that are found in pesticides [2]. Exactly why it happened is unclear, but the evidence suggests that the death of PON1 in some aquatic mammals gave them an evolutionary advantage that may relate to oxygen regulation during deep sea diving [2].

Do humans have genes that zombified?
In short, yes

For the time being, the PON1 gene seems to be dead in these select aquatic species, but genetic studies have found that some genes are capable of having a life after death—so-called “zombie genes.” As their name suggests, zombie genes were once pseudogenes whose original function had been lost. Over generations, the gene continued to mutate and its DNA kept changing until the right combination of mutations gave it life once again.

The zombie gene that’s currently making headlines is known as the leukemia inhibitory factor-6 (LIF6). Researchers have found that this gene was resurrected in ancient elephant relatives nearly 60 million years ago, which allowed the evolution of large-bodied mammals like woolly mammoths, the American mastodon, and modern-day elephants [3].

The team who conducted this study showed that when a cell suffers damage which could lead to cancer, it triggers the activation of a gene (TP53) which then turns on the LIF6 gene. LIF6 then acts like a true zombie by helping to kill the potentially cancerous cell. The ability to stop cancer before it starts may have given ancient mammals a survival advantage by allowing them to grow large. Thus, the LIF6 zombie gene found a home in the elephant genome.

Humans also have the PON1 gene and a version of the LIF6 gene (ours is just called LIF). It begs the question: Do humans have genes that are dead or zombified? In short, yes—we have thousands of them!

Scientists have known for some time that it’s hard for functional genes to evolve. Any change to their DNA sequence might cause its protein to stop working correctly. If that protein is supposed to direct the formation of a brain, for example, it would be pretty bad for it to stop working. Scientists believe this is why the majority of changes in the human genome occur in sections of DNA that don’t code for functional proteins.

Tails of the dead

Humans have the remnants of a tail (our sacral bone). Thousands of years ago, we lost most of our tails because they were no longer needed. Without evolutionary pressure to discourage extremely short tails, the length of the tail just deteriorated until it was just a stubble. These relics from the past are known as vestigial structures. Like our tailbone, we also have vestigial genes.

Many pseudogenes are considered vestigial, meaning they just lost their function when they weren’t needed anymore. A good example of this is sweet taste receptors in cats. They have the genes to taste sweet foods, but those genes have died because cats are carnivores and no longer need to taste sugar [8,9].

But occasionally, a gene will accidentally be duplicated, causing there to be two copies a specific gene. With an extra copy, it’s possible for life to experiment a little bit. Changes in the DNA of one copy that alter its function become more tolerable because there’s a backup copy that can still do the needed job [4,5]. This is like having two chefs in the kitchen: While one is doing the necessary cooking, the other is free to experiment and maybe even develop a new skill.

One example of a zombie gene in humans is NOTCH2NL. This gene was duplicated millenia ago from the original NOTCH2 gene in our (very) distant ancestors. Initially, these duplicate copies died and lost their function. But after our ancestors began to diverge from the ancestors of modern gorillas and chimpanzees, mutations resurrected one of the NOTCH2 duplicates. Everyone knows that zombies like brains, and the resurrected NOTCH2 duplicate, NOTCH2NL, seems to be similar in that respect: Researchers found that the NOTCH2NL zombie gene may have helped us grow larger brains [6,7]!

There’s a whole graveyard of dead genes in our genome that could potentially be resurrected one day. Most estimates suggest that there’s more than 10,000 pseudogenes in the human genome [5]. Some are relics from the days when we relied more on smell to sense the world around us, while others may be remnants of old immune system genes. Humans will likely have more genes cease to function (and others brought back to life) in the future, but—like all evolutionary processes—it will take a very long time.

In the movies, people go to great lengths to avoid encountering zombies for fear of becoming one. As this month’s news shows us, zombies aren’t just fiction—they’re in the fabric of our being, and they’re not always bad.

References

1. Macharia, Muiruri, et al. “The Growing Importance of PON1 in Cardiovascular Health.” Journal of Cardiovascular Medicine, vol. 13, no. 7, 2012, pp. 443–453., doi:10.2459/jcm.0b013e328354e3ac.

2. Meyer, Wynn K., et al. “Ancient Convergent Losses OfParaoxonase 1yield Potential Risks for Modern Marine Mammals.” Science, vol. 361, no. 6402, Sept. 2018, pp. 591–594., doi:10.1126/science.aap7714.

3. Vazquez, Juan Manuel, et al. “A Zombie LIF Gene in Elephants Is up-Regulated by TP53 to Induce Apoptosis in Response to DNA Damage.” Dec. 2017, doi:10.1101/187922.

4. Hurles, Matthew. “Gene Duplication: The Genomic Trade in Spare Parts.” PLoS Biology 2.7 (2004): e206. PMC. Web. 15 Aug. 2018.

5. Poliseno, Laura. Pseudogenes: Functions and Protocols. Humana Press, 2014.

6. Suzuki, Ikuo K. “Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation.” Cell. Vol. 173, no. 6, May 2018, pp1370–1384., DOI: https://doi.org/10.1016/j.cell.2018.03.067. Web. 31 May 2018.

7. Fiddes, Ian T. et al. “Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.” Cell. Vol. 173, no. 6, May 2018, pp1356–1369., DOI: https://doi.org/10.1016/j.cell.2018.03.051. Web. 31 May 2018.

8. Risso, Davide et al. “Probing the Evolutionary History of Human Bitter Taste Receptor Pseudogenes by Restoring Their Function.” Molecular Biology and Evolution 34.7 (2017): 1587–1595. PMC. Web. 15 Aug. 2018.

9. Li, Xia et al. “Cats Lack a Sweet Taste Receptor.” The Journal of nutrition 136.7 Suppl (2006): 1932S–1934S. Print.