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Tag: human genome

  • What If There’s a Secret Benefit to Getting Asian Glow?

    What If There’s a Secret Benefit to Getting Asian Glow?

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    At every party, no matter the occasion, my drink of choice is soda water with lime. I have never, not once, been drunk—or even finished a full serving of alcohol. The single time I came close to doing so (thanks to half a serving of mulled wine), my heart rate soared, the room spun, and my face turned stop-sign red … all before I collapsed in front of a college professor at an academic event.

    The blame for my alcohol aversion falls fully on my genetics: Like an estimated 500 million other people, most of them of East Asian descent, I carry a genetic mutation called ALDH2*2 that causes me to produce broken versions of an enzyme called aldehyde dehydrogenase 2, preventing my body from properly breaking down the toxic components of alcohol. And so, whenever I drink, all sorts of poisons known as aldehydes build up in my body—a predicament that my face announces to everyone around me.

    By one line of evolutionary logic, I and the other sufferers of so-called alcohol flush (also known as Asian glow) shouldn’t exist. Alcohol isn’t the only source of aldehydes in the body. Our own cells also naturally produce the compounds, and they can wreak all sorts of havoc on our DNA and proteins if they aren’t promptly cleared. So even at baseline, flushers are toting around extra toxins, leaving them at higher risk for a host of health issues, including esophageal cancer and heart disease. And yet, somehow, our cohort of people, with its intense genetic baggage, has grown to half a billion people in potentially as little as 2,000 years.

    The reason might hew to a different line of evolutionary logic—one driven not by the dangers of aldehydes to us but by the dangers of aldehydes to some of our smallest enemies, according to Heran Darwin, a microbiologist at New York University. As Darwin and her colleagues reported at a conference last week, people with the ALDH2*2 mutation might be especially good at fighting off certain pathogens—among them the bug that causes tuberculosis, or TB, one of the greatest infectious killers in recent history.

    The research, currently under review for publication at the journal Science, hasn’t yet been fully vetted by other scientists. And truly nailing TB, or any other pathogen, as the evolutionary catalyst for the rise of ALDH2*2 will likely be tough. But if infectious disease can even partly explain the staggering size of the flushing cohort—as several experts told me is likely the case—the mystery of one of the most common mutations in the human population will be one step closer to being solved.

    Read: Tuberculosis got to South America through … seals?

    Scientists have long been aware of aldehydes’ nasty effects on DNA and proteins; the compounds are carcinogens that literally “damage the fabric of life,” says Ketan J. Patel, a molecular biologist at the University of Oxford who studies the ALDH2*2 mutation and is reviewing the new research for publication in Science. For years, though, many researchers dismissed the chemicals as the annoying refuse of the body’s daily chores. Our bodies produce them as part of run-of-the-mill metabolism; the compounds also build up during infection or inflammation, as byproducts of some of the noxious chemicals we churn out. But then aldehydes are generally swept away by our molecular cleanup systems like so much microscopic trash.

    Darwin and her colleagues are now convinced that the chemicals deserve more credit. Dosed into laboratory cultures, aldehydes can kill TB within days. In previous research, Darwin’s team also found that aldehydes—including ones produced by the bacteria themselves—can make TB ultra sensitive to nitric oxide, a defensive compound that humans produce during infections, as well as copper, a metal that destroys many microbes on contact. (For what it’s worth, the aldehydes found in our bodies after we consume alcohol don’t seem to much bother TB, Darwin told me. Drinking has actually been linked to worse outcomes with the disease.)

    The team is still tabulating the many ways in which aldehydes are exerting their antimicrobial effects. But Darwin suspects that the bugs that are vulnerable to the chemicals are dying “a death by a thousand cuts,” she told me at the conference. Which makes aldehydes more than worthless waste. Maybe our ancestors’ bodies wised up to the molecules’ universally destructive powers—and began to purposefully deploy them in their defensive arsenal. “It’s the immune system capitalizing on the toxicity,” says Joshua Woodward, a microbiologist at the University of Washington who has been studying the antibacterial effects of aldehydes.

    Specific cells show hints that they’ve caught on to aldehydes’ potency. Sarah Stanley, a microbiologist and an immunologist at UC Berkeley, who has been co-leading the research with Darwin, has found that when immune cells receive certain chemical signals signifying infection, they’ll ramp up some of the metabolic pathways that produce aldehydes. Those same signals, the researchers recently found, can also prompt immune cells to tamp down their levels of aldehyde dehydrogenase 2—the very aldehyde-detoxifying enzyme that the mutant gene in people like me fails to make.

    If holstering that enzyme is a way for cells to up their supply of toxins and brace for inevitable attack, that could be good news for ALDH2*2 carriers, who already struggle to make enough of it. When, in an extreme imitation of human flushers, the researchers purged the ALDH2 gene from a strain of mice, then infected them with TB, they found that the rodents accumulated fewer bacteria in their lungs.

    The buildup of aldehydes in the mutant mice wasn’t enough to, say, render them totally immune to TB. But even a small defensive bump can make for a massive advantage when combating such a deadly disease, Russell Vance, an immunologist at UC Berkeley who’s been collaborating with Darwin and Stanley on the project, told me. Darwin is now curious as to whether TB’s distaste for aldehyde could be leveraged during infections, she told me—by, for instance, supplementing antibiotic regimens with a side of Antabuse, a medication that blocks aldehyde dehydrogenase, mimicking the effects of ALDH2*2.

    Tying those results to the existence of ALDH2*2 in half a billion people is a larger leap, several experts told me. There are clues of a relationship: Darwin and Stanley’s team found, for instance, that in a cohort from Vietnam and Singapore, people carrying the mutation were less likely to have active cases of TB—echoing patterns documented by at least one other study from Korea. But Daniela Brites, an evolutionary geneticist at the Swiss Tropical and Public Health Institute, told me that the connection still feels a little shaky. Other studies that have searched for genetic predispositions to TB, or resistance to it, she pointed out, haven’t hit on ALDH2*2—a sign that any link might be weak.

    The team’s general idea could still pan out. “They are definitely on the right track,” Patel told me. Throughout most of human history, infectious diseases have been among the most dramatic influences over who lives and who dies—a pressure so immense that it’s left obvious scars on the human genome. A mutation that can cause sickle cell anemia has become very common in parts of the African continent because it helps guard people against malaria.

    Read: A history of humanity in which humans are secondary

    The story with ALDH2*2 is probably similar, Patel said. He’s confident that some infectious agent—perhaps several of them—has played a major role in keeping the mutation around. TB, with its devastating track record, could be among the candidates, but it wouldn’t have to be. A few years ago, work from Woodward’s lab showed that aldehydes can also do a number on the bacterial pathogens Staphylococcus aureus and Francisella novicida. (Darwin and Stanley’s team have now shown that mice lacking ALDH2 also fare better against the closely related Francisella tularensis.) Che-Hong Chen, a geneticist at Stanford who’s been studying ALDH2*2 for years, suspects that the culprit might not be a bacterium at all. He favors the idea that it’s, once again, malaria, acting on a different part of our genome, in a different region of the world.

    Other tiny perks of ALDH2*2 may have helped the mutation proliferate. As Chen points out, it’s a pretty big disincentive to drink—and people who abstain (which, of course, isn’t all of us) do spare themselves a lot of potential liver problems. Which is another way in which the consequences of my genetic anomaly might not be so bad, even if at first flush it seems more trouble than it’s worth.

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    Katherine J. Wu

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  • The Fatal Error of an Ancient, HIV-Like Virus

    The Fatal Error of an Ancient, HIV-Like Virus

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    Many, many millions of years ago, an HIV-like virus wriggled its way into the genome of a floofy, bulgy-eyed lemur, and got permanently stuck.

    Trapped in a cage of primate DNA, the virus could no longer properly copy itself or cause life-threatening disease. It became a tame captive, passed down by the lemur to its offspring, and by them down to theirs. Today, the benign remains of that microbe are still wedged among a fleet of lemur genes—all that is left of a virus that may have once been as deadly as HIV is today.

    Lentiviruses, the viral group that includes HIV, are an undeniable scourge. The viruses set up chronic, slow-brewing infections in mammals, typically crippling a subset of immune cells essential to keeping dangerous pathogens at bay. And as far as scientists know, these viruses are pretty uniformly devastating to their hosts—or at least, that’s true of “all the lentiviruses that we know of,” says Aris Katzourakis, an evolutionary virologist at the University of Oxford. Which means, a long time ago, that lemur lentivirus was likely devastating too. But somewhere along the way, the strife between lemur and lentivirus dissipated enough that their genomes were able to mix. It’s proof, says Andrea Kirmaier, an evolutionary virologist at Boston College, that lentivirus and host “can coexist, that peace can be made.”

    Détentes such as these have been a fixture of mammals’ genomic history for countless millennia. Scientists have stumbled across lentiviruses embedded in the DNA of not just lemurs, but rabbits, ferrets, gliding mammals called colugos, and most recently, rodents—all of them ancient, all of them quiescent, all of them seemingly stripped of their most onerous traits. The infectious versions of those viruses are now extinct. But the fact that they posed an infectious threat in the past can inform the strategies we take against wild lentiviruses now. Finding these defunct lentiviruses tells us which animals once harbored, or might still harbor, active ones and could potentially pass them to us. Their existence also suggests that, in the tussle between lentivirus and host, the mammal can gain the upper hand. Lemurs, rabbits, ferrets, colugos, and rodents, after all, are still here; the ancient lentiviruses are not. Perhaps humans could leverage these strange genetic alliances to negotiate similar terms with HIV—or even extinguish the modern virus for good.

    When viruses assimilate themselves into animal genomes in a heritable way, a process called endogenization, scientists generally see it as “kind of a mistake,” says Daniel Blanco-Melo, a virologist at the Fred Hutchinson Cancer Center. Once cemented into one host, the virus can no longer infect others; much of its genome may even end up degrading over time, which is “certainly not what it evolved to do.” The blunders usually happen with retroviruses, which have RNA-based genomes that they convert into DNA once they enter cells. The flip allows the viruses to plug their genetic material into that of their host, which is then forced to manufacture its pathogen’s proteins alongside its own. Sometimes, a retrovirus will inadvertently stitch itself into the genome of a sperm or an egg, and its blueprints end up passed to its host’s progeny. If the melding doesn’t kill the animal, the once-pathogen can become a permanent fixture of the creature’s DNA.

    Over time, the human genome has amassed a horde of these viral hitchhikers. Our DNA is so riddled with endogenous retroviruses, ERVs for short, that they technically occupy more space in our genomes than bona fide, protein-manufacturing genes do. But on the long list of ERVs that have breached our borders, lentiviruses are conspicuously absent, in both our genomes and those of other animals; up until the mid-aughts, some scientists thought lentiviruses might not endogenize at all. It wasn’t a totally wonky idea: Lentiviruses have complex genomes, and are extremely picky about the tissues they invade; they’re also quite dangerous, not exactly the kind of tenant that most creatures want occupying their cellular real estate. Or perhaps, some researchers posited, lentiviruses were endogi-capable, but simply too young. If they had only begun infecting mammals within the past few hundreds of thousands of years, there might not have been time for such accidents to occur.

    Then, some 15 years ago, a team led by Katzourakis and Rob Gifford, an evolutionary virologist at the University of Glasgow, discovered an endogenous lentivirus called RELIK in the genomes of rabbits and then in hares, a hint that it had lodged itself in the animals’ mutual ancestor at least 12 million years before. In an instant, the lentivirus timeline stretched, and in the years since has kept growing. Scientists have now identified endogenous lentiviruses in a wide enough array of mammals, Gifford told me, to suspect that lentiviruses may have been a part of our history for at least 100 million years—entering our very distant ancestors’ genomes before the demise of the dinosaurs, before the rise of primates, before the land masses of North and South America kissed. “That tells us just how long virus and host have been connected,” Katzourakis told me. Through those eons, lentiviruses and the mammals they afflict have been evolving in concert—the pathogen always trying to infect better, the animal always trying to more efficiently head its enemy off.

    Knowing that lentiviruses are so deeply laced into our past can help us understand how other mammals are faring against the ones that are still around today. Two species of monkeys, sooty mangabeys and African green monkeys, have spent so much evolutionary time with a lentivirus called SIV—the simian version of HIV—that they’ve grown tolerant of it. Even when chock-full of virus, the monkeys don’t seem to suffer the severe, immunocompromising disease that the pathogen induces in other primates, says Nikki Klatt, a microbiologist and an immunologist at the University of Minnesota. The key seems to be in the monkeys’ ultra-resilient, fast-healing guts, as well as their immune systems, which launch more muted attacks on SIV, keeping the body from destroying itself as it fights. Such immunological shrugs could enable certain retroviruses to eventually endogenize, says Lucie Etienne, an evolutionary virologist at the International Center for Infectiology Research, in Lyon, France.

    Many mammals have also developed powerful tools to prevent lentiviruses from reproducing in their bodies in the first place—proteins that can, for instance, mess with viral entry or replication, or prevent new viral particles from busting out of already infected cells. Viruses, too, can mutate and evolve, far faster than animals can. That’s given the pathogens plenty of chances to counteract these defenses; HIV, for instance, has no trouble sidestepping or punching through many of the shields that human cells raise against it.

    Read: Could genetics be the key to never getting the coronavirus?

    But take the equivalent immune-defense protein from a monkey, and HIV “cannot degrade that,” says Michael Emerman, a virologist at the Fred Hutchinson Cancer Center. Other primates have had different infectious histories from ours, which have shaped their immune evolution in distinct ways. Studying those primates’ genomes—or maybe even the genomes of mammals that are carrying lentiviruses as neutered genetic cargo—might eventually inspire therapies that “augment our immunity,” Emerman told me. At the very least, such experiments could point scientists to lentiviruses’ common weak spots: the parts of the virus that ancient immune systems once targeted successfully enough that their hosts survived to tell the tale. “Evolution has already taught us the best places to target retroviruses,” says Maria Tokuyama, a virologist at the University of British Columbia. “Why not push for the types of interactions that we already know have worked?”

    Another, perhaps more radical idea might yet give way to an HIV cure: speeding the path toward endogenization—allowing lentiviruses to tangle themselves into our genomes, in the hopes that they’ll stay permanently, benignly put. “We could figure out a way to silence the virus, such that it’s there but we don’t care about it,” says Oliver Fregoso, a virologist at UCLA. One of the holy grails of HIV research has always been cooking up a vaccine that could prevent infection—an extraordinarily difficult thing to do. But if some sort of gentle armistice can be reached, Boston College’s Kirmaier told me, “maybe we don’t need to go that far.”

    Cedric Feschotte and Sabrina Leddy, virologists at Cornell, are among those pushing for such an intervention. They’re capitalizing on HIV’s tendency to go dormant inside cells, where it can hide from some of our most powerful antiretroviral drugs. The virus essentially “plays dead,” Leddy told me, then reawakens when the coast is clear. But if HIV could be silenced stably, its rampage would end when it jammed itself into the genome. “We’re hoping to emulate this natural path that ERVs have taken,” where they’re effectively locked in place, Leddy said. The imprisoned viruses could then be excised from cells with gene editing.

    The idea’s ambitious and still a way off from yielding usable treatments. But if it works, it could produce an additional perk. After setting up shop inside us, our viral tenants can start to offer their landlord benefits—such as fighting off their own active kin. In recent years, researchers have found that some animals, including cats, chickens, mice, primates, sheep, and even humans, have been able to co-opt proteins from certain endogenous retroviruses to create blockades against incoming viruses of similar ilk. Blanco-Melo and Gifford were part of a team that made one such discovery in 2017, describing an ERV that ancient monkeys and apes might have used to strip viral entryways off the surfaces of their cells. When encountering an ERV-ed-up host, the infectious, still-pathogenic version of that ERV would no longer have been able to get in.

    Eventually, the active retrovirus “just went extinct,” Blanco-Melo told me—an outcome that he thinks could be attributable to the antics of its endogenous counterpart. It’s a devious move, essentially a way to “turn the virus against itself,” Kirmaier said. This sort of friendly-fire tactic may already be at work among lentiviruses, duking it out inside and outside host genomes: Species with endogenous lentiviruses usually aren’t bedeviled by active lentiviruses, at least none that has been identified yet, Fregoso told me. With any luck, the same could someday be true for HIV, the virus little more than a memory—or an idle fragment in our cells.

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    Katherine J. Wu

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