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Why It’s Crucial the New Superbug Was in a Urinary Tract Infection

Escherichia coli bacteria live in the intestines of humans and are a common cause of urinary tract infections.
Escherichia coli bacteria live in the intestines of humans and are a common cause of urinary tract infections.
Janice Haney Carr, Centers for Disease Control and Prevention

The alarm over the arrival of a grave new superbug in the United States is obscuring part of the story that is crucial to understanding what might happen next. Here it is: The woman who was carrying an E. coli containing resistance to the last-resort antibiotic colistin went for medical care because she had what felt like a routine urinary tract infection, a UTI for short.

The discovery of colistin-resistant bacteria is worrisome: Researchers have been watching for the arrival of this new superbug  for several months. But that it was found in  urine sample puts the discovery into a larger context. Highly drug resistant urinary tract infections happen potentially hundreds of thousands of times a year just in the United States. A small, dedicated corps of researchers has been trying for years to emphasize that these infections represent a serious danger, an unexamined conduit of bacterial resistance from agriculture and meat into the human population, and have mostly been dismissed.

Now that the new-new superbug has thrown light on the problem, will someone listen?

The Centers for Disease Control and Prevention weighed in Tuesday with a statement and a press briefing with health officials from Pennsylvania, where, last week, military researchers said they found the mcr-1 gene in an E. coli bacterium carried by a woman living there.

There are up to 8 million urinary-tract infections in the U.S. each year, and probably at least 10 percent, or 800,000, are antibiotic-resistant.

The MCR gene is important because it represents a breach in the last line of antibiotic defense: It confers protection against colistin, one of the oldest antibiotics out there, and one of the few that continues to work even against bacteria that resist multiple other drugs. Colistin was seldom used in people until recently because it is toxic, but agriculture has been using it enthusiastically for decades, which has seeded resistance through the bacterial world.

And those highly drug-resistant bacteria are turning up in urinary-tract infections. Why UTIs? Because E. coli bacteria are carried in feces, which can easily spread to the urethra and cause urinary-tract infections, especially in women. I’ve written about this several times; the long version in MORE magazine, and, even longer, in a collaborative investigation between the Food and Environment Reporting Network, the Atlantic, and ABC News.

The short version is this: Up to 8 million urinary-tract infections occur in the United States each year, and each year, a growing and significant proportion—hard to measure, but probably at least 10 percent, or 800,000—are antibiotic-resistant.

This has been happening with such frequency that it has actually changed medical practice. Medical specialty societies have been advising doctors for several years now that they should always do a test to determine which antibiotic will work for a UTI, rather than prescribing based on a standard checklist.

But only a few researchers have investigated why that tide of resistance is rising. What they have found is that these resistant UTIs infections are not random and singular, but instead constitute a focused epidemic, caused by particular sets of E. coli that bear the same resistance signatures as ones found in meat animals given antibiotics.

This idea has had difficulty gaining traction, because UTIs are usually dismissed as a minor problem, something that causes a few days of annoyance and requires a few days of antibiotics to fix. (And, not coincidentally, because they overwhelmingly happen to women.) But when UTIs go untreated—which is effectively what happens when the antibiotic administered for them doesn’t work —they climb up the urinary system from the bladder, into the kidneys, and thence into the bloodstream.

At that point, the minor problem becomes literally life-threatening. And resistant UTIs are not only a problem for the individual sufferer: They also pose the possibility of infecting others, if the original victim goes into a hospital for treatment and carries the resistant organism unrecognized in their system.

One reason it has taken so long to recognize this problem is that there is no single surveillance network that could capture all the resistance patterns in all those UTI sufferers, and compare them. There is also the problem of belief: It’s just difficult to imagine that something as minor as a UTI could be the signal of something as grave as a widespread epidemic.

Because of that, the MCR finding in Pennsylvania could end up being fortunate—no only for detecting a grave development early, but also for shining a light on a danger that has been growing, unrecognized, for a while.

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Flies Could Falsely Place Someone at a Crime Scene

The Australian sheep blowfly doesn't just eat nectar. It has a taste for a particular human body fluid—and it’s not blood.
The Australian sheep blowfly doesn’t just eat nectar. It has a taste for a particular human body fluid—and it’s not blood.

This might be the grossest science experiment I’ve ever written about—which is really saying something on a blog called Gory Details—but it’s also one of the most fascinating. It has to do with the taste a certain type of fly has for human bodily fluids.

Blowflies, in case you’re not familiar with them, are the flies of death. As I learned when rats died in my ceiling, these big shiny flies have an amazing ability to appear seemingly out of nowhere within moments of blood being spilled or at the slightest whiff of decay.

So, a lot of blowflies are sometimes found buzzing around a gory crime scene. That got forensic expert Annalisa Durdle wondering: With all those flies doing what flies do—flying around and pooping on stuff—could they be contaminating crime scenes?

“Interestingly, fly poo can also look very similar to blood spatter,” says Durdle, who studied forensic science at La Trobe University in Melbourne, Australia.

“Anyhow,” she e-mailed in response to my indelicate questions about her research, “it turns out that you can get full human DNA profiles from a single piece of fly poo. (I tend to refer to poo rather than vomit because in my experience flies tend to eat their vomit and most of what you have left is poo—although they do eat that too!)”

Clearly, blowflies are gross.

But could they falsely incriminate someone? To find out, Durdle needed to know what blowflies would really eat at a crime scene.  

So she did the experiment. Her team offered Australian sheep blowflies a crime scene buffet, with body fluids collected from volunteers—blood, saliva, and semen—plus other snacks that flies might find in a victim’s home: pet food, canned tuna, and even honey.

“You draw more flies with honey,” my mother always told me. But in this case, she was wrong.

What you draw more flies with, it turns out, is semen.

“It’s the crack cocaine of the fly world,” Durdle says. “They gorge on it; it makes them drunk (they stumble around, partly paralyzed—I’ve even seen one fly give up hope of cleaning itself properly and sit down on its bum!). Then they gorge some more and then it kills them. But they die happy!”

Video: Meet Annalisa Durdle, the coolest fly-poop scientist ever.

The flies liked pet food too, but weren’t much into blood, and they were really uninterested in saliva. Maybe they go for semen’s higher protein content—it contains more than 200 different proteins, at much higher levels than in blood. (Update: or maybe not. Protein levels vary, and Annalisa Durdle notes that “flies are like people—they don’t necessarily eat what is good for them!” Flies are attracted to various aromas, including sulphur-based ones, so it may be that semen is simply more alluring than other food sources.)

Another thing semen has plenty of: DNA.

Durdle tested flies’ poop after various meals. “If the flies had fed on semen or a combination with semen in it, then you got a full human DNA profile almost every time. With blood, it was maybe a third of the time and with saliva, never.”

“It was also interesting to find the flies generally preferred dry blood or semen to wet blood or semen,” Durdle says. “This could be important, because it means flies could continue to cause problems at a scene long after the biological material had dried.”

How big a deal is this? Durdle says, “You really need to look at the probabilities… the chances that a fly might feed on some poor guy’s semen (after he’s had some innocent quiet time to himself), and then fly into a crime scene and poo, potentially incriminating him.”

There’s also the chance that a forensic investigator could sample fly poop thinking it’s blood spatter, she says, and find DNA that’s not from the victim.

A fly might occasionally be helpful to the cause of criminal justice. If a fly eats bodily fluids from a crime scene and then flies away into another room and poops there, it might save a sample of DNA from the perpetrator’s attempts to clean up.

Flies aren’t the only potential problem for interpreting DNA. As the technology used in forensic labs has become more sensitive, there’s greater risk of picking up tiny bits of DNA transferred to a crime scene, forensic scientist Cynthia Cale argued last year in Nature.

In fact, Cale showed that one person can transfer another person’s DNA to a knife handle after two minutes of holding hands. (Next she says she’ll try shorter times, to see if even a brief encounter could transfer DNA.)  

The fly-poop research is interesting, Cale says. Blowflies would probably be more likely to transfer DNA within a crime scene rather than bringing it in from outside, but even that could confuse the reconstruction of a crime.

“I think the biggest impact might be when a defense lawyer uses it to raise doubt in the mind of a jury,” Durdle says.  


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Snake Genomes Reveal Shared Plans for Making Legs, Penises

This is a post about penis enhancers, although not the kind that are advertised on the internet. Let me explain.

Penises and limbs are clearly very different (exaggerated references to third legs aside), but they develop in similar ways. They both involve long bits of tissue that grow out from a small embryonic bud, under the direction of very similar proteins, and molecules. For example, in 1997, Takashi Kondo from the University of Geneva showed that two genes that direct the development of legs in mice are also important for building genitals.

Now, Carlos Infante and Douglas Menke from the University of Georgia has shown that similar enhancers—sequences that switch genes on or off—are also at work in both organs.

Other scientists had already catalogued hundreds of enhancers that control the development of limbs in humans and mice. So Menke’s team wondered: what do these limb enhancers do in a creature without limbs? Have they changed beyond recognition, or become repurposed for other roles, or disappeared entirely?

Infante searched the recently sequenced genomes of three snakes—the boa constrictor, Burmese python, and king cobra—and found counterparts of 65 mammalian limb enhancers. These sequences are still there, and still recognisable, even though their owners have been slithering on their bellies for some 150 million years. So if these enhancers aren’t enhancing limbs, what are they doing instead?

To find out, Infante returned to mice, and found that around half of these enhancers are active in the genitals as well as in limbs. And that turned out to be a general pattern: limb enhancers are also often active in the genitals, but not the eyes, skeleton, or brain. They’re more like all-purpose “appendage enhancers” rather than limb-specific ones, turning on similar suites of genes in arms, legs, and penises alike.

Next, the team focused on just one of these enhancers, known as HLEB. When they deleted it from mouse embryos, the rodents grew up with smaller hips and a smaller baculum or penis bone. An anole lizard’s version of HLEB works equally well in a mouse: stick it in a mouse genome, and it will switch on genes in the rodent’s limbs and genitals. The same can’t be said for the cobra and python versions of HLEB: they can only control the activity of genes in a mouse’s genitals, and not its legs. They retain some of their ancestral functions, but have lost others that are no longer necessary.

Then again, the python HLEB also switches on some genes in the noses of mouse embryos, so perhaps this builder of limbs and penises has evolved a new snake-specific role that no one knows about yet.

PS: “Although the phallus differs from limbs in both form and function…” begins the paper. I’m glad science is around to tell us these things.

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Fast-Evolving Human DNA Leads to Bigger-Brained Mice

Between 5 and 7 million years of evolution separate us humans from our closest relatives—chimpanzees. During that time, our bodies have diverged to an obvious degree, as have our mental skills. We have created spoken language, writing, mathematics, and advanced technology—including machines that can sequence our genomes. Those machines reveal that the genetic differences that separate us and chimps are subtler: we share between 96 and 99 percent of our DNA.

Some parts of our genome have evolved at particularly high speed, quickly accumulating mutations that distinguish them from their counterparts in chimps. You can find these regions by comparing different mammals and searching for stretches of DNA that are always the same, except in humans. Scientists started identifying these “human-accelerated regions” or HARs about a decade ago. Many turned out to be enhancers—sequences that are not part of genes but that control the activity of genes, telling them when and where to deploy. They’re more like coaches than players.

It’s tempting to think these fast-evolving enhancers, by deploying our genes in new formations, drove the evolution of our most distinguishing traits, like our opposable thumbs or our exceptionally large brains. There’s some evidence for this. One HAR controls the activity of genes in the part of the hand that gives rise to the thumb. Many others are found near genes involved in brain development, and at least two are active in the growing brain. So far, so compelling—but what are these sequences actually doing?

To find out, J. Lomax Boyd from Duke University searched a list of HARs for those that are probably enhancers. One jumped out—HARE5. It had been identified but never properly studied, and it seemed to control the activity of genes involved in brain development. The human version differs from the chimp version by just 16 DNA ‘letters’. But those 16 changes, it turned out, make a lot of difference.

Boyd’s team introduced the human and chimp versions of HARE5 into two separate groups of mice. They also put these enhancers in charge of a gene that makes a blue chemical. As the team watched the embryos of their mice, they would see different body parts turning blue. Those were the bits where HARE5 was active—the areas where the enhancer was enhancing.

Embryonic mice start building their brains on their ninth day of life, and HARE5 becomes active shortly after. The team saw that the human version is more strongly active than the chimp one, over a larger swath of the brain, and from a slightly earlier start.

HARE5 seems to be particularly active in stem cells that produce neurons in the brain. The human version of the enhancer makes these stem cells divide faster—they take just 9 hours to split in two, compared to the usual 12. So in a given amount of time, the mice with human HARE5 developed more neural stem cells than those with the chimp version. As such, they accumulated more neurons.

And they developed bigger brains. On average, their brains were 12 percent bigger than those of their counterparts. “We weren’t expecting to get anything that dramatic,” says Debra Silver, who led the study.

“Ours stands as among the first studies to demonstrate any functional impact of one of these HARs,” she adds. “It shows that just having a few changes to our DNA can have a big impact on how the brain is built. We’ve only tested this in a mouse so we can’t say if it’s relevant to humans, but there’s strong evidence for a connection.”

“I’m really excited that people are following up [on these HARs] and finding out what they do,” says Katherine Pollard from the Gladstones Institutes, who was one of the scientists who first identified these sequences. “It’s been really daunting to figure out what the heck these things do. Each one takes years. These guys went the extra mile beyond what everyone else has been doing, by showing changes in the cell cycle and in brain size.”

“It’s a very clever use of mice as readouts for human-chimp differences,” says Arnold Kriegstein from the University of California, San Francisco. “The [brain] size difference isn’t terribly big, but it’s certainly in the correct direction.”

Eddy Rubin from the Joint Genome Institute is less convinced. His concern is that the team’s methods could have saddled the mice with multiple copies of HARE5 in various parts of their genome. As such, it’s not clear if the differences between the two groups are due to these factors, rather than to the 16 sequence differences between the human and chimp enhancers. “[That] casts major shadow on the conclusions,” says Rubin. “This is an interesting study pursuing an important issue, but the results should be taken with a grain of salt.”

Regardless, Silver’s team are now continuing to study HARE5. Now that their mice have grown up, they are designing tests to see if the adults behave differently thanks to their larger brains. This is important—bigger brains don’t necessarily mean smarter animals. They’re also looking into a few other enhancers. One of them, for example, seems to a control a gene that affects the growth of neurons.

“I think HARE5 is just the tip of the iceberg,” says Silver. “It is probably one of many regions that explain why our brains are bigger than those of chimps. Now that we have an experimental paradigm in place, we can start asking about these other enhancers.”

Reference: Boyd, Skove, Rouanet, Pilaz, Bepler, Gordan, Wray & Silver. 2015. Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex. Current Biology http://dx.doi.org/10.1016/j.cub.2015.01.041

More on enhancers:

Did a gene enhancer humanise our thumbs?

RNA gene separates human brains from chimpanzees

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There’s No Plague on the NYC Subway. No Platypuses Either.

There is no good evidence that Yersinia pestis—the bacterium that causes plague—is riding aboard the New York City subway. That’s the message from several microbiologists, in response to a wave of news stories that emerged last Friday.

“Plague, anthrax and cheese? Scientists map bacteria on New York subway,” said the Guardian. “From beetles to bubonic plague: Bizarre DNA found in NYC subway stations,” proclaimed the Washington Post. “Terrifying microbe map of New York’s subway system reveals superbugs, anthrax and bubonic plague,” blathered the Daily Mail, duly retaining its crown as the champions of scaremongering.

All of these stories were based on a census of some of New York City’s smallest residents—its microbes. Over the course of 18 months, a team of scientists led by Christopher Mason from Weill Cornell Medical College swabbed surfaces all over the city, including every open subway station (see a video about their subway sampling here). They then analysed the DNA in their samples to identify the microbes that lived on each surface.

There were plenty of interesting results. For example, the bacteria from South Ferry Station, which was flooded by Hurricane Sandy in 2012, were closer to marine microbes than to those in the rest of the subway. But the team’s most notable claims were that they found DNA from the plague bacterium Yersinia pestis in three samples, and from the anthrax bacterium Bacillus anthracis in two. These nuggets predictably wound their way into every major news story.

The researchers downplayed the significance of these results, saying that if Y.pestis was present, it was unlikely to be “active and causing disease in people”. As Mason told the New York Times, “We’re saying there’s evidence for these things… but no one should worry.”

But several microbiologists think that even this statement goes too far. “[They] have not provided persuasive evidence that the agents that cause plague or anthrax are present anywhere in the New York City subway system,” says Ian Lipkin, a well-respected virus hunter from Columbia University. “The genetic footprints they report are not specific for the agents that cause anthrax or plague; they are also found in other common bacteria that are not associated with disease.”

The team arrived at their conclusions after compiling the DNA in each sample, breaking it down into smaller pieces, and then sequencing the fragments. They then searched for these sequences—or “reads”—in a public database of genes from all known organisms. If they found many matches for a given microbe, they concluded that said microbe was present in their samples.

“This method is notoriously unreliable,” says Willem van Schaik from Utrecht University, who studies antibiotic-resistant bacteria. As Lipkin also noted, it’s prone to false alarms, because a given read could match DNA that’s found in many other bacteria besides Y.pestis.

Rob Knight, formerly at the University of Colorado Boulder, showed just how ludicrous this problem can get last year. His colleague, Andrea Ottesen at the FDA, swabbed tomato plants in a field in Virginia, and Knight analysed the DNA in those samples. He found matches to the duck-billed platypus—an Australian animal, not known to live in Virginia. They then analysed over 19,000 publicly available microbiome samples from around the world; around a third threw up matches for platypus DNA. Either the platypus secretly rules the world or, more likely, this was a hilarious case of false positives gone mad. The team, including Antonio González Peña, even created a programme called Platypus Conquistador to rectify the problem.

There are signs of similar problems in the subway paper. In the case of Y.pestis, the team found several reads that matched a plasmid—a free-floating ring of DNA that sits outside the bacterium’s main genome. They highlighted one particular section of the plasmid in one of their figures. Based on this, Van Schaik did his own search and found that sequences in this section are also found in at least three other bacterial species.

Mason’s team also identified DNA from many eukaryotes—that’s animals, plants, and other complex organisms—and listed the top species in one of their tables. They were, starting from the top: the mountain pine beetle, which lives in the west coast of North America; the Mediterranean fruit fly, which does not exist in the continental US; the cucumber; and humans. Hmm. The fly, in particular, is a major agricultural pest and the subject of intensive surveillance. Its presence in New York is “so unlikely that I think the approach they used is just flawed,” says Van Schaik.

Unlike the fly, Y.pestis does exist in the US, but in the southwest where it infects rodents. It is a stranger to New York. Lipkin’s team have done extensive surveys of the city’s rats and failed to find Y.pestis in any of them.

To convince their critics, Mason’s team would have to show that reads from the subway analysis map to the entirety of the Y.pestis plasmid. Then again, plasmids can easily move from one bacterium to another, so it would be even more convincing to show reads that map to Y.pestis’s actual chromosome. “Even better would be to prove the existence of Y. pestis through some independent means, such as culture,” says Nick Loman from the University of Birmingham, who studies the genomes of disease-causing microbes. By “culture”, he means trying to actually grow bacteria from collected samples.

I contacted Chris Mason about these criticisms and he is preparing a blog post to address them, and others that he has received. [Update 18 Feb: Mason has published the post and it is humble, informative, detailed, and introspective]

As I mentioned, the paper has other interesting results and it might seem churlish to pick on this one. But it symbolises some of the problems in the study of microbiomes—the collections of bacteria that live in specific animals or environments. Microbiome research is among the hottest fields in biology and is attracting hordes of enthusiastic scientists. This is great—(disclosure: I’m writing a book on animal microbiomes)—but the field also risks throwing up a lot of misleading and false conclusions if methods aren’t applied properly and results aren’t analysed cautiously. (Last November, I wrote about another common problem that might lead to false positives in a lot of microbiome studies.)

One could argue that these issues come out in the wash, and that science corrects itself. Indeed, Mason told the New York Times that not reporting the fragments of anthrax and plague “would have been irresponsible”. Then again, readers were hit with a wave of headlines that raised the possibility of plague on the subway. “If I wasn’t a microbiologist, I would be scared by this and rightfully so,” says Van Schaik.

Marc Lipsitch, an epidemiologist from the Harvard School of Public Health, agrees, and adds that panic-quelling follow-up stories, like this one, don’t help matters. “Stories that present a highly hedged finding as news, but then say “Don’t worry”, make scientists seem like we aren’t telling the whole truth,” he says. “Either it is news, or we shouldn’t worry, but it’s tough to see how both could be true.”

Update: Nick Loman has put up a short post illustrating one of the problems I talked about in this post. He took E.coli, shred its DNA, sequenced the pieces, and then matched them up to databases. By right, 100% of the reads should come out as E.coli. In fact, just 61% of them did.

Reference: Afshinnekoo et al., Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics. 2015. Cell Systems http://dx.doi.org/10.1016/j.cels.2015.01

Correction: The article was amended to note that Andrea Ottesen swabbed the tomato plants, rather than Rob Knight himself.

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Jumping DNA and the Evolution of Pregnancy

About a decade ago, Vincent Lynch emailed Frank Grutzner to ask for a tissue sample from a pregnant platypus. He got a polite brush-off instead.

Then, around eight years later, Grutzner got back in touch. His team had collected tissues from a platypus that had been killed by someone’s dog. They had some uterus. Did Lynch still want some?

“Hell yes!”

The platypus was the final critical part of a project that Lynch, now at the University of Chicago, had longed to do since he was a graduate student. He wanted to study the evolution of pregnancy in mammals, and specifically the genetic changes that transformed egg-laying creatures (like platypuses) into those that give birth to live young (like us).

The platypus enjoys a short pregnancy. Its embryo sits in the uterus for just 2-3 weeks, surrounded by a thin eggshell, and nourished by a primitive placenta. It then emerges as an egg. Marsupials, like kangaroos and koalas, also have short pregnancies. But mothers give birth to live young, which live in a pouch until they’re big enough. Other mammals—the placentals, or eutherians—keep their babies in the uterus for as long as possible, nourishing them through a complex placenta. Their pregnancies can be marathons—up to two years in an elephant.

The move from egg-laying to live-bearing was huge. Mammals had to go from holding a shell-covered embryo for weeks to nourishing one for months. To understand how they made the leap, Lynch compared 13 different animals, including egg-layers like the platypus, marsupials like the short-tailed opossum, and eutherians like the dog, cow, and armadillo. He catalogued all the genes that each species switches on in its uterus during pregnancy. He then compared these different sets to work out when mammals started (or stopped) using those genes during reproduction.

He found thousands of differences, many more than he anticipated. For example, hundreds of genes are involved in making eggshell minerals; they’re active in the uterus of a platypus but silent in those of other live-bearing mammals. Conversely, the marsupials and eutherians started activating hundreds of genes involved in suppressing the immune system, and in passing hormonal signals between the mother and foetus.

This all makes sense. A platypus embryo, during its brief stay in the uterus, is separated from its mother—and its mother’s immune system—by a shell. “It’s like the embryo has a cloak,” says Lynch. When mammals evolved live births, the cloak disappeared and a problem arose. Every foetus shares only half of its genes with its mother, so mum’s immune system should recognise this lump of growing tissue as a potential threat. To dispense with eggs, early marsupials and eutherians had to evolve ways of tamping down their immune responses, and only in the uterus. They also needed ways of exchanging signals with their embryos. “The foetus needs to say, Hey I’m here, and the mum needs to say, Oh, that’s okay,” says Lynch.

His study shows that they did so by repurposing a vast array of genes that already had roles in other organs, like the guts, brains, and bloodstream. But how? How does an animal deploy a gene—or thousands of genes—in a different organ?

The answer involves jumping DNA. Many bit of the genome can cut themselves away from the surrounding DNA and paste themselves in elsewhere. Others can copy themselves and insert the duplicates into new spots. These sequences are genomic parasites—they reproduce, often at the expense of their host. If they disrupt other genes when they land, they can cause cancer and other diseases. But sometimes, they settle somewhere useful.

Think of the jumping DNA as the infrared sensor in your television. The sensor recognises a stimulus—the signal from your remote control—and switches on the TV. Imagine that the sensor makes thousands of copies of itself, and somehow wires these into appliances all over your house. Now, when you press the remote control, your TV whirrs into life, but your lights also flicker on, your washing machine starts up, your computer boots, and your radio starts playing. By duplicating and spreading the sensor, you ensure that the same stimulus now turns on a multitude of things.

This is what happened during the evolution of pregnancy except there, the stimulus isn’t an infrared signal but a hormone called progesterone. In the ancestor of eutherian mammals, jumping DNA littered the genome with sequences that progesterone can recognise. They allowed this one hormone to switch on a vast array of new genes in the uterus. And they did so in a very short span of time by evolutionary standards—just a million years or so, by Lynch’s reckoning.

Craig Lowe from Stanford University says that, for decades, scientists have theorised that jumping DNA could do something like this, but Lynch has shown that they actually have. Lowe also suspects that other scientists will use the same methods to study the evolution of traits like pregnancy, which seem overwhelmingly complicated at first pass.

Indeed, that’s what motivated Lynch originally. He’s interested in how evolution produces radically new structures. “We don’t have a good understanding of how you get something entirely new,” he says. “It’s easy to imagine how you select upon an existing structure to get a slightly different one, like a hand into a flipper or a bat wing. But how do you get the limb to begin with?”

The answer almost certainly involved using existing genes in new and innovative ways. “Does that happen slowly and step-wise, or can you have broad, genome-wide changes that reorganise things in larger jumps? Our work suggests that the larger jumps are possible.”

Reference: Lynch, Nnamani, Kapusta, Brayer, Plaza, Mazur, Emera, Shehzad, Sheikh, Grutzner, Bauersachs, Graf, Young, Lieb, DeMayo, Feschotte & Wagner. 2015. Ancient Transposable Elements Transformed the Uterine Regulatory Landscape and Transcriptome during the Evolution of Mammalian Pregnancy. Cell Reports. http://dx.doi.org/10.1016/j.celrep.2014.12.052

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The Long War Against the Iron Pirates

Disease is an act of piracy. When microbes infect us, they steal our resources so they can thrive at our expense. We fight them off with direct attacks, using an army of immune cells and antibodies. But we also have subtler countermeasures: we can, for example, deprive them of the nutrients they need.

Iron is one such nutrient. Many of the most important enzymes only work when they embrace iron atoms, and that’s true for blue whales and bacteria alike. So, when bacteria infect us, they try to scavenge iron from our bodies. We, in turn, try to halt their advances by withholding this nutrient.

Matthew Barber and Nels Elde from the University of Utah School of Medicine have found clear signs of this war over iron in two molecules: transferrin, an animal protein that stores iron in a tight embrace, and TbpA, a bacterial protein that literally snatches iron from transferrin’s grasp.

These proteins have gone through repeated bursts of rapid evolution. Time and again, bacterial TbpAs have evolved to better prise iron from our grasp, while the transferrins of humans and other apes have evolved to clutch the element more tightly. We have been waging this war against iron pirates for millions of years, and neither side shows any side of giving ground.

Elde was interested in evolutionary arms races between infectious microbes and the hosts that they trouble. These conflicts leave their mark on the the genes that drive our immune systems. One such gene, for example, might recognise a telltale molecule on the surface of a virus. The virus adapts by changing those surface molecules to avoid detection, and the gene counter-adapts to spot the virus’s new guise. On and on they go, thrusting and parrying through the generations.

These genes tend to evolve in rapid and repeated bursts—and that’s exactly what Barber and Elde saw when they compared the transferrins of 21 species of primates. “Transferrin was acting as if it was an immunity gene,” says Elde. It was adapting quickly and repeatedly to ever-changing adversaries.

Transferrin acts like a thermostat for iron. It stores the element, keeping it in stock while also stopping toxic levels from building up in our bodies. It looks like a peanut, with two lobes (N and C) that each grasps a single iron ion. Their hold is so delicate that you’d expect the lobes to change very little over time. The N-lobe meets that expectation. It looks the same, “no matter what primate you pull out of the hat,” says Elde.

The C-lobe is different. It has been a hotbed of change, and especially among apes. Barber and Elde found 18 parts of transferrin that have rapidly evolved in primates, and 16 of these are in the C-lobe. On their own, these changes have no obvious purpose. But their significance became clear when the team visualised transferrin next to the TbpA protein from Neisseria meningitidis—a microbe that causes bacterial meningitis.

TbpA is shaped like a claw. It seizes transferrin, prises it apart, and relieves it of its iron. This only works because the shape of the claw conforms exactly to the shape of its transferrin target. The molecules touch each other at several specific points and, sure enough, these are exactly the same parts of transferrin that evolve most rapidly. The protein changes shape to avoid getting snatched.

TbpA (silver) grabs transferrin (gold). The blue dots show the parts of transferrin that are rapidly evolving, and the red/purple dots show the parts of TbpA that are rapidly evolving. Credit: Barber & Elde, 2014.
TbpA (silver) grabs transferrin (gold). The blue dots show the parts of transferrin that are rapidly evolving, and the red/purple dots show the parts of TbpA that are rapidly evolving. Credit: Barber & Elde, 2014.

But TbpA fights back. Barber and Elde compared TbpA genes in several strains of N.gonorrhoeae, which causes gonorrhoea, and Haemophilius influenzae, which causes flu-like symptoms. These bacterial proteins showed the same signs of recurring rapid evolution, especially in the parts that recognise and grab transferrin. Their ‘prey’ changes shape to slip through their grasp, but they adapt by changing their hold.

This evolutionary arms race has played out over 40 million years at least. Barber and Elde demonstrated this by the purifying transferrins from humans, gorillas, chimps, orang-utans, gibbons and baboons, and pitting them against TbpAs from N.gonorrhoeae and H.influenzae. These bacterial proteins recognised transferrins from humans and gorillas, but not the other species. This means that their owners can steal iron from human cells, but not from chimp cells—a striking difference, considering that chimps are our closest relatives.

“Once we saw the difference with chimps, we thought: We should really look at human diversity,” says Elde. “And we didn’t have to look far.” It turned out that not all transferrins are created equal. Humans have two major types: the C1 version, which is the most common, and the C2 version, which is found in 6 to 26 percent of people. Scientists have known about these two versions for a long time, but no one really knew why they co-existed. They differ by a single DNA letter and they certainly both bind iron with equal vigour.

Once again, this mystery became clearer once Barber and Elde pitted the transferrins against iron-stealing microbes. They found that N.meningitidis and N.gonorrhoeae recognise both the C1 and C2 transferrins, but H.influenzae struggles to capture the C2 version. So the number of people who carry the C1 or C2 versions will depend on how common and how deadly these various microbes are.

All of these results suggest that transferrin is part of a nutritional immune system—a set of molecules that prevent disease by starving microbes of essential nutrients. This is an old concept. The scientists who first purified transferrin in 1946 hinted at it. But Barber and Elde have shown that nutritional immunity is important enough to have left a noticeable evolutionary imprint in our genomes.

It might be possible to use this knowledge for our benefit. At a time when bacteria are becoming increasingly resistant to antibiotics, scientists are looking for alternative ways of killing them. “People have been toying with providing patients with more transferrin,” says Elde. “There might be something to that, but if you’re using transferrin therapy, why not try the C2 version, or the one that arose in chimps, depending on which bug you’re trying to counterarct. We could reach into the genetic medicine cabinet and use solutions that we’ve naturally come up with through millions of years of evolution.”

And I, as per usual, am interested in whether the trillions in bacteria in our guts—the ones that are supposedly beneficial partners—are also iron pirates. Some of these mutualists have TbpA proteins too. Do they try to steal iron from our cells? Do we have ways of stopping them, to ensure a stable relationship? “When do these cross over from beneficial relationships into something more nefarious?” says Elde. “There could be this dynamic undercurrent where one day our friends become our enemies, and vice versa.”

Reference: Barber & Elde. 2014. Escape from bacterial iron piracy through rapid evolution of transferrin. Science http://dx.doi.org/10.1126/science.1259329

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Personhood Week: When Dead Bodies Become Dead People

It’s Personhood Week here on Only Human. Today’s installment is about what it means to give a name to a dead body. Monday’s post was about conception, and yesterday’s about the age of majority. Tomorrow goes to non-human animals, and Friday to neuroscientists who argue that “personhood” is a convenient, if illusory construction of the human brain.

I’d love to hear about how you guys define personhood, and why. Feel free to leave comments on these posts, or jump in to the #whatisaperson conversation on Twitter.


On the night of July 19, 1916, halfway through the First World War, troops from Australia and Great Britain attacked German positions in Fromelles, in northern France. The Germans were prepared. The battled ended the next day, after thousands of Brits and Aussies had died. It was, according to a magazine produced by the Australian government, “the worst 24 hours in Australia’s entire history.”

In 2002, an Australian amateur historian named Lambis Englezos visited Fromelles and noticed that the number of graves was far fewer than the number of soldiers reported missing from the battle. He suspected that the Germans had buried many in mass graves, and over the next few years he convinced reporters at 60 Minutes Australia of his theory. Its eventual broadcast, as well as reports from Red Cross records and aerial photos, led to an official investigation. In 2008 and 2009, archaeologists dug up five mass graves, containing 250 bodies.

Then came the question of identifying them. After more than 90 years, standard identification methods — fingerprints, medical and dental records — weren’t available. But there was DNA, deep inside the bone marrow. So the researchers extracted samples from the remains and then re-buried each body in its own grave.

This launched the Fromelles Identification Project (FIP), a joint effort by the Australian and British governments to find living descendants of the dead soldiers and convince them to donate their own DNA for matching. (The Y chromosome, passed through male descendants, changes very little from one generation to the next; same goes for mitochondrial DNA that is passed down through the female line.) So far 1,000 Australians have donated DNA to the effort, and 144 soldiers have been identified by name. The scientific, ethical and privacy concerns surrounding this project are fascinating. But before digging in to those, I think it’s important to address why people (via their governments) are willing to put so much effort and resources into identifying dead bodies in the first place.

The first answer is practical. Surviving family members often need to confirm a dead person’s identity before having access to their estate, pension, life insurance policy, and so on. Identification is also thought to ease families’ emotional toll. As bioethicist Jackie Leach Scully writes in a study published earlier this year, “the certainty of death is generally thought to be better than the ongoing emotional anguish of fearing but not knowing.”

It’s hard to see how these benefits would be valid for family members 90 years later, though. Nobody’s still settling their great-great grandfather’s estate, after all, and they’re not likely to be mourning his death, either.

But the justification goes beyond practical concerns. In To Know Where He Lies, a book about unidentified bodies from the Bosnian War in the 1990s, anthropologist Sarah Wagner explains how DNA identifications can have larger, more abstract consequences for the community (emphasis mine):

DNA became the critical, entrusted, indeed indispensable proof of individual identity for the thousands of sets of nameless mortal remains… Matching genetic profiles promised to reattach personhood (signposted by a name) to physical remains and, thereby, to reconstitute the identified person as a social — and political — subject.

The FIP smartly decided to conduct a social, ethical, and historical study along with its DNA efforts. Scully’s new paper, published in New Genetics in Society, gives pilot data showing how FIP participations described their motivations for getting involved. It’s a small study — based on email responses of several dozen participants and in-person interviews with five of them — but fascinating all the same. Some of these responses have challenged my own conceptions about the value of historical research, not to mention what it means to be a person.

In her initial emails to FIP participants, Scully simply asked whether they would be interested in being interviewed in the future. She received 116 responses. Of these, about one-third provided additional information about why they wanted to get involved. “These were more than just curiosity about a long-lost relative or interest in being part of a high profile and prestigious national project,” Scully writes. “Many email respondents indicated a powerful emotional investment.”

For instance, one woman said that after she learned she was a direct female descendant of one of the soldier’s sisters, “I literally jumped around the living room for several minutes.” Another participant said, during an in-person interview, “It was like winning the lottery as far as I was concerned. Skin was tingling, hairs standing up.”

Of all of the responses she received, Scully notes, about half said that part of their motivation involved “looking after” or “caring” for the dead or for the family the dead left behind. They said this even when they didn’t believe in any kind of afterlife. Here’s one interview exchange:

Participant: I’m doing it for George.

Interviewer: How does that work?

Participant: I dunno! I’m a bit of an agnostic, I don’t believe in life after death, you know.

That’s a bit hard for my mind to understand. Scully says it might be about respecting the memory of the deceased, which is still alive in the minds of other people. Identifying the body by name, she says, might help ensure “that the biography through which he is remembered has the ending that casts the best backward light on the life that has gone.”

Other participants are involved not to care for the dead, per se, but to honor relatives they had real relationships with. “Two interviewees said that it was ‘for my mother,’ who in both cases was a younger sister of the dead man,” Scully notes. Another participant reached out to their father after a 20-year absence after learning of the project, because it was he who first recounted the story of the dead soldier. This person told Scully that the FIP “helped to bridge a gap between my father and I while, at the same time, allowing us to bridge a gap with our family’s past.”

Soliciting DNA samples for body identifications also raises significant ethical and privacy concerns, similar to those that come up during any kind of genetic genealogy project. Genetic comparisons among family members might reveal long-buried family secrets, such as inaccurate paternity, that can cause unexpected emotional turbulence. Many people may be willing to take that risk, but they should at least know about it before getting involved. Unfortunately, none of the five participants Scully interviewed remembered these issues being mentioned before they signed on.

Then there are the related issues of privacy and consent: What if one family member wants to participate but another, sharing some of the same DNA, does not? A few of the email respondents told Scully that some of their relatives were “skeptical or hostile” about their involvement.

What if relatives have differing opinions about how long the identifications must go on? After the World Trade Center attacks in 2001, for example, body parts were strewn everywhere. Some families wanted to know every time a sample was identified as their relative, whereas others found these constant updates upsetting. “The ability to ‘give a name to’ the tiniest scraps of tissue is a new problem that is unique to DNA-based identification,” Scully notes.

And finally, there’s the more abstract concern that, to my mind, may in the long run pose more problems than the rest: that DNA identification will lead to what Scully calls the “geneticization of family.” The partner of a missing man is not (usually) genetically related to him. The same goes for his adopted children, or children his partner conceived using a sperm donation. Does that mean these relationships are any less familial, or any less important?

In this (albeit subtle) way, DNA identification may be contributing to our society’s growing obsession with biological identity, with biological personhood. This technology, Scully writes, is “likely to reinforce further the status of the genome as the most important, or even only, constituent of both individual and family identity.”

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Uprooted, Again

For me, the hardest part of writing a story is finding the end. It often feels arbitrary, or artificial, or both. A person’s story isn’t necessarily over, after all, just because I’m ready to write it down. But I can’t put it off forever, either. Editors are waiting, and my unpaid bills. So I squeak out an ending and just cross my fingers that a better one — the real one — doesn’t show itself the day after publication.

Earlier this month, I heard the real ending for a story I wrote more than a year ago about people who use DNA to fill in branches of their family tree. It’s a doozy, and has me thinking hard, again, about the profound consequences of so-called “recreational genetics.”

In 2008 the story’s protagonist, 56-year-old Cheryl Whittle from rural Virginia, heard about DNA testing on Oprah. Just for kicks she bought a kit for herself, her husband, and two of her siblings. When the results came back in her email inbox, she discovered that the man who raised her, the man she had thought was her father, wasn’t. He had died in 1989, several years after Cheryl’s mom, and few people were still alive who had known them at the time of Cheryl’s conception. Thus Cheryl began a long, circuitous, frustrating, emotional quest in genetic genealogy to find out who her father really was.

When my story ended (spoiler alert), Cheryl had been through one emotional roller coaster after another. Her search had angered some of her immediate family members, and greatly disappointed a woman who longed to be Cheryl’s biological sister but turned out to be a distant cousin. As of August 2013, when my reporting wound down, Cheryl had made contact with another possible sister who refused to get a DNA test because she was worried about tarnishing the memory of her late father.

After my story was published, Cheryl and I kept in touch on Facebook. She often Liked my articles, and I commented on photos of her new great-grandchild. She patched things up with her immediate family, and seemed to be healing from some of the bruises of genetic genealogy. But despite everything she had been through, she didn’t give up the search for her father.

Long before I met her, Cheryl had used online DNA databases to find a woman estimated to be her second cousin, a fairly close match. (The woman had to be on Cheryl’s father’s side because her DNA didn’t match with one of Cheryl’s half sisters.) This woman was a genealogy buff who had put much of her family research online. So one of the branches on this woman’s tree, Cheryl knew, had to lead to her father.

This July, Cheryl traced one of those lines to Edward Barden of Orange County, Virginia, about 70 miles from where she grew up. Cheryl thought Edward was a little too young to be her father — he would have been about 19, and her mother 26, at the time of her conception. But then again, she thought, you never know.


Cheryl called Edward’s daughter, Edie Growden, figuring that a younger generation might be more comfortable with the idea of mailing a vial of spit to a lab for DNA testing. During that first call, Cheryl was vague, saying simply that she was interested in genealogy and thought they had some connections. They eventually agreed to meet in person at Edward’s house. The night before the proposed meeting, Edie’s husband suggested that she look up this Cheryl lady online. She was a complete stranger, after all. So Edie Googled her, and found my article. Oops.

The next morning, Cheryl got in her yellow pick-up truck and made the pretty two-and-a-half-hour drive to Edward’s house. She knew, by this point, that there was no point in feeling anxious, nor in getting her hopes up. She had two new DNA kits in the back seat, just in case. “God gave me, in my spirit, the calm to know that everything was going to be OK,” she says.

When she arrived at Edward’s house he was at a doctor’s appointment. Edie answered the door and brought Cheryl into the kitchen for some coffee. “Are you still looking for your father?” she said. Cheryl, a bit taken aback, said she was. She took out some papers showing her cousin’s family tree, with Edward and his four brothers underlined.

Edward’s car pulled into the garage. He had picked up groceries, so Edie and Cheryl went out to help him unload. When he looked at Cheryl, his face went white and he dropped a bag of eggs on the ground. Cheryl went out to her truck for the DNA kits.

While she was out, Edie told her dad that Cheryl was looking for her father. “Edie, that’s Roy’s child,” he said, tears in his eyes. Roy was his older brother, Edie’s uncle, who had passed away in 1999. “Really?” Edie said, skeptical. “Look at her!” Edward said. But, he added, he wanted to hear more of Cheryl’s story before admitting to anything, to make sure he wasn’t grasping at straws.

Cheryl came back and sat down at the kitchen table. Edie then saw the resemblance to her uncle — especially in Cheryl’s eyes, nose and mouth. It seemed unmistakable. Edward, leaned against the sink, looked straight at her. “Well, Cheryl, tell me what you’re looking for.”

Cheryl told him the gist of her story, just as she’s told many times before. “What was your mother’s name?” he asked. Vivian Laverne Tipton, she said, from Richmond. “Did she have a sister with blonde hair named Virginia?” he asked. Yes, Virginia was her twin, Cheryl said. “Look no further,” Edward said. “You’re my brother Roy’s child.”

Over the next couple of hours the whole story came out. Virginia had been dating a Richmond bus driver named Perry who spent every weekend in a small town a couple of hours north. So Virginia started spending her weekends there, too. They stayed in a big, old house — “The Racer House” — which on the weekends was full of young people dancing and playing games. Soon Vivian was accompanying her sister on weekends, and that’s how she met Roy Barden, who was living there as a caretaker.

Edward remembers Vivian and Roy dating for about a year. At some point she told him she wanted to get married, but Roy wasn’t ready. When she told him that her doctor in Richmond said she was pregnant, he told her he wanted his doctor to verify it. After that, Roy told Edward, he never heard another word from her. She never came back to the Racer House, and never called.

Edward’s memories were vivid. There was no doubt in his mind that Cheryl was Roy’s daughter. But Cheryl, who’s been down these memory lanes before, needed DNA proof. Edie took one kit into another room for the spitting. Edward’s mouth was too dry, but he said he’d do it in the next few days.

Cheryl (right) with Edward (left) and Edie (middle)
Cheryl (right) with Edward (left) and Edie (middle)

Edie and Edward were excited by the news. There was a thorny issue to sort out, however. Years after Vivian left, Roy married another woman and they had four children, Cheryl’s presumed half-siblings. Roy’s widow was still alive, but sick, and Edward and Edie don’t get along well with that side of the family. So they didn’t know what to tell Cheryl about reaching out to her presumed siblings. “A search like this, it really could turn a lot of people’s lives upside-down,” Edie told me. “Things that they thought were the truth all of a sudden aren’t.”


About a month later, on August 15, Cheryl had Edie’s results: they were indeed first cousins. Nine days after that, the other test came back and confirmed that Edward was her uncle.

At that point, there was no reason not to believe Edward’s memories about Roy and Vivian. And yet, Cheryl couldn’t let her story end there. There was still a possibility that her father wasn’t Roy, but one of the other Barden brothers. It was a slim chance, sure, but it happens. (In fact, when I was reporting my original story I read a book by an adoptee whose family search was upended by one such fraternal mix-up.)

So once again Cheryl was faced with an ethical dilemma: Should she reach out to these possible half siblings? And if so, would they want to tell their ailing mother?

Ultimately, Cheryl did reach out to all four of her siblings, through Facebook, phone calls and handwritten letters. The first couple of weeks were pretty stressful for her, especially because one of her siblings asked for a bit of time to adjust. At one point, Cheryl told me via Facebook message, she had spent many days crying.

I asked her, as delicately as I could: Cheryl, do you really not believe your uncle’s story? Why do you need to keep testing your siblings?

“I feel I need to prove it, and yes even to me,” she responded. “I don’t trust well.”

“I just have so many mixed feelings right now. I don’t want to hurt anyone, most especially my newly found most precious Uncle, Edward.  Nor my cousin Edie!” she continued. Still, though, it wasn’t the end yet. “I want to be absolutely sure where I am in the family.”

Since then, I’m very happy to report, things have gotten much easier for Cheryl. In the past few weeks she’s had heartfelt meetings or phone calls with each of her siblings. One of them, Tim, took a DNA test for her, and on October 6, she got the results: half siblings. She sent me a message: “I am indeed the daughter of Roy Oscar Barden. And half sibling to Luther, Oscar, Tim, and Joyce Ann Barden. I am so excited! And relieved to finally have verified the truth.”

Her new siblings began sending her photographs of Roy over the years, which she naturally compared to pictures of herself.

Photos courtesy of Cheryl Whittle and the Barden family
Cheryl (left) and Roy (right). Photos courtesy of Cheryl Whittle and the Barden family

Cheryl’s siblings told their mother, Barbara, and she, too, has been remarkably welcoming. In fact, this past weekend, Cheryl stayed with Tim and his wife, Wanda, at their home. When she arrived, Tim gave her the trowel and hammer that their father had used as a brick mason. Then he took her to his mom’s house. Barbara gave Cheryl a tour, and showed her photos and the Family bible. Saturday Tim and Wanda organized a party so the rest of the family could meet Cheryl. They all told her she looks more like Roy than any of his other kids, and laughs like him, too. “Never in my wildest dreams would I have thought it would have gone so well,” Cheryl told me this morning.

I’m sincerely grateful for Cheryl and the many lessons she has taught me — not only about the real-life consequences of genetic genealogy, but about how rewarding it can be to keep up with sources long after you’ve written their story. (Or the first version of it, anyway.) I’m thrilled that my story now has a real, happy ending, and I wish Cheryl and her new family the happiest of beginnings.

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The Human Genome Is In Stalemate in the War Against Itself

A moth evolves ears that can hear the sonar of bats, and bats adapt by hushing their calls to whispers. A newt evolves powerful poisons that can kill would-be predators, and a snake evolves immunity to those poisons. A gazelle becomes faster to outrun its hunter, and a cheetah becomes faster still. The natural world is full of these evolutionary arms races—endless battles where one party’s adaptations are met by counter-adaptations from its opponent. Both sides move in and out of check, changing all the time but locked in a perpetual stalemate.

The human genome is engaged in a similar evolutionary arms race… against itself.

The opponents are jumping genes called retrotransposons that can hop around the genome. They increase in number by copying themselves and pasting the duplicates into new locations. This mobile lifestyle is so successful that retrotransposons make up more than 40 percent of the human genome. Some have settled down, and are now static shadows of their once-active selves. Others are still on the move.

If the copies land in the right place, they could act as clay for building new adaptations. If they land in the wrong place, which is perhaps more likely, they could cause diseases by disrupting important genes. So genomes have ways of keeping these wandering sequences under control. One involves a gene called KAP1. It’s a kind of tranquiliser—it sticks to retrotransposons and stops them from activating.

KAP1 works differently in different species, targeting those retrotransposons that are active in that owner’s genome. Our KAP1 won’t keep a mouse’s jumping genes in line, and vice versa. Some scientists believe that this specificity is caused by another group of genes called KZNFs. They tell KAP1 where to go by searching for, and sticking to, specific retrotransposons. They’re like beat cops that patrol a neighbourhood, look for crime, and radio for back-up. Each KZNF targets a different type of retrotransposon and different species have their own set.

At least, that’s what happens in theory. In reality, it has been hard to confirm this idea,  partly because these cops do such a good job that it’s hard to see jumping genes in action.

Frank Jacobs and David Greenberg from the University of California, Santa Cruz solved this problem by sticking the retrotransposons in mouse cells—a less policed environment. They filled the mouse stem cells with a single human chromosome. Mice are adapted to control their own retrotransposons, so they’re oblivious to ours. The jumping genes on the human chromosome, freed from their usual restraints, started spreading, much like an invasive species running amok on an island with no native predators. Now, the team could pit different human KZNFs against these restless genes to see if any could bring them to heel.

They found two that could—ZNF91 and ZNF93. Each of these represses a major class of retrotransposons—SVAs and L1s, respectively—that are still jumping about in the human genome today.

ZNF91 and ZNF93 are only found in primates, but they have changed a lot even without our narrow lineage. For example, the human version of ZNF91 has deluxe features that are shared by gorillas but not by monkeys. To understand the value of these changes, Ngan Nguyen and Benedict Paten took the modern genes and worked backwards, reconstructing their ancestral versions at different stages of their evolution.

They found that between 8 and 12 million years ago, ZNF91 gained features that dramatically improved its ability to keep retrotransposons in line. That’s the point in primate evolution before humans diverged from gorillas and chimps. ZNF93 went through similarly dramatic changes between 12 and 18 million years ago, before the we (and the other great apes) diverged from orang-utans.

These results suggest that ape KZNFs have rapidly evolved to keep jumping genes in check. Indeed, the KZNFs are one of the fastest growing families of primate genes. We have around 400 of them, and some 170 of these are primate-only innovations. This expanded police force reflects our ongoing genomic arms race.

And the jumping genes are starting to fight back. For example, the team found that ZNF93 represses L1 genes by recognising a short signature sequence that most of them have. But some L1s, especially the most recently evolved ones, have lost this signature entirely. They can jump unnoticed.

The missing sequence would normally makes the jumping genes better at jumping. But this booster rocket ended up as a wheel clamp, since ZNF93 evolved to recognise it. So some of the L1s lost the rocket. They jumped less effectively, but at least they could still jump.

anchorman-well-that-escalated-quicklyThis is a classic evolutionary arms race. The hosts thrusts, the parasite parries, and the duel continues. But unlike more familiar battles between snakes and toads, or hosts and viruses, this is a case where we’re waging war against our own DNA.

There’s a sense of futility about this. Much of our genome seems to be engaged in an ultimately pointless duel whether neither side can give or gain any ground. But these battles aren’t quite as fruitless as they might seem.

The team found that KZNFs partly suppress the genes around a retrotransposon too. When the cops finds their target, they tell all the bystanders to the lie on the ground too. This is important because it seriously affects the activity of many human genes, beyond retrotransposons. It means that KZNFs can eventually be used to control the activity of genes that jumping genes land next to. (“Excuse me, officer, but while you’re manhandling your suspect, would you mind also rescuing my cat?”) This arms race could have given rise to more complicated networks of genes, and perhaps more complicated bodies or behaviours.

Reference: Jacobs, Greenberg, Nguyen, Haeussler, Ewing, Katzman, Paten, Salama & Haussler. 2014. An evolutionary arms race betweenKRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature http://dx.doi.org/10.1038/nature13760

More on jumping genes

Humans Restrain Jumping DNA That Chimps Allow To Run Free

Under three layers of junk, the secret to a fatal brain disease

How a quarter of the cow genome came from snakes

Flesh-Eating Plant Cleaned Junk From Its Minimalist Genome


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How an Extreme Athlete Uncovered Her Own Genetic Flaw

When Kim Goodsell discovered that she had two extremely rare genetic diseases, she taught herself genetics to help find out why. This is a new story of mine, published concurrently in Mosaic, Pacific Standard, BBC Future, and more.

Kim Goodsell was running along a mountain trail when her left ankle began turning inward, unbidden. A few weeks later she started having trouble lifting her feet properly near the end of her runs, and her toes would scuff the ground. Her back started to ache, and then her joints too.

This was in 2002, and Kim, then 44 years old, was already an accomplished endurance athlete. She cycled, ran, climbed and skied through the Rockies for hours every day, and was a veteran of Ironman triathlons. She’d always been the strong one in her family. When she was four, she would let her teenage uncles stand on her stomach as a party trick. In high school, she was an accomplished gymnast and an ardent cyclist. By college, she was running the equivalent of a half marathon on most days. It wasn’t that she was much of a competitor, exactly – passing someone in a race felt more deflating than energising. Mostly Kim just wanted to be moving.

So when her limbs started glitching, she did what high-level athletes do, what she had always done: she pushed through. But in the summer of 2010, years of gradually worsening symptoms gave way to weeks of spectacular collapse. Kim was about to head to Lake Superior with her husband, CB. They planned to camp, kayak, and disappear from the world for as long as they could catch enough fish to eat. But in the days before their scheduled departure, she could not grip a pen or a fork, much less a paddle. Kim, a woman for whom extreme sports were everyday pursuits, could no longer cope with everyday pursuits. Instead of a lakeside tent, she found herself at the Mayo Clinic in Rochester, Minnesota.

After four days of tests, Kim’s neurologist told her that she had Charcot–Marie–Tooth disease, a genetic disorder that affects the peripheral neurons carrying signals between the spinal cord and the extremities. It’s rare and carries a varying suite of symptoms, but Kim’s are typical, starting at the feet and heading upward. The neurologist explained that as her neurons died, the surviving cells picked up the slack by sprouting new branches – a workaround that masked the underlying degeneration until the rate of cell death outpaced the rate of compensation. Hence Kim’s crash.

The neurologist told her to come back in a year so he could check how quickly the disease was progressing, but that it would certainly progress. Charcot–Marie–Tooth has no cure.

The Goodsells drove home and Kim, exhausted, slept for two days. When she woke up, she got to work. “My reaction to things that I have no control over is to find out as much as I can about them,” she says. She started by reviewing her clinic notes, and quickly noticed something odd: there was hardly any mention of her heart.

Years before she learned that she had Charcot–Marie–Tooth, Kim discovered that she had another genetic disorder – one that affects the heart, arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC gradually replaces the heart’s synchronised beating muscle with fat and scar tissue. It nearly killed her once; she still has an internal defibrillator to keep her heart beating. But even though it was there in her medical records, her neurologist hadn’t seen fit to mention it in his report. “It meant nothing to him,” says Kim. “I thought: Wow, that’s really funny.”

It wasn’t the omission per se that bothered her. It was the implicit suggestion that her two life-long diseases – one of the heart, one of the nervous system – were unrelated. That, in the genetic lottery, she was a double-loser. That lightning must have struck her twice.

Surely not, she thought. Surely there must be a connection.


I meet Kim at La Ventana in Baja California, Mexico. She spends winters here, mostly kitesurfing. The sand and water are postcard-quality, but La Ventana has barely any resorts or big hotels. So in the still air of the morning when kites won’t fly, the beach is empty. Kim likes it that way. She has been up since dawn, cycling among the cacti and swimming in the ocean with pelicans and frigatebirds for company. She hauls herself out of the water, dries off, and sits on a small terrace overlooking the ocean. Her face is tanned and wrinkled, and she manifests no obvious signs of her two conditions. That’s partly because she has developed workarounds to mask and control her symptoms. She brushes her teeth on one foot to offset her balance problems. She uses massage balls and spends hours stretching to stop her muscles and joints from seizing up.

“See how I’m sitting?” she says. She has pulled her legs up on the chair to her left, and her back is curving that way too.

“My spine curves this way” – she nods to the right – “so I sit curving to the opposite side. I consciously do the opposite.”

She has a history of that. In 1979 Kim was a mathematically gifted pre-med student at UC San Diego, her hometown college. Her path was clear: graduate, and follow her older brother into medical school. But on a trip to South America – her first time out of San Diego – she ended up hiking for three months instead of working at a clinic as she’d planned. When she returned home, her academic future seemed pale and uninspiring. And then CB – her future husband, at this point a fellow student and regular running partner – started taking her out on wilderness hikes. “He introduced me to the mountains and I thought: this is life,” Kim says.

Within months of graduating Kim dropped out. Her brother, who had been a father figure to her growing up, was furious. “We hardly spoke. CB was his friend and he couldn’t even look at him,” she says. “He said I was being completely irresponsible.” Kim and CB married in 1983, and aside from a brief stint as restaurant owners, they have never had 9-to-5 jobs. They mostly earned a living by buying and remodelling run-down houses and selling them at a profit, and then heading into the wilderness until their supplies ran out. In 1995 they found themselves in La Jolla, California, working on an especially stressful renovation that left Kim drained.

That was when her heart problems began. Kim started having episodes of ventricular tachycardia – the lower chambers of her heart contracted so quickly that they pumped out their contents before they had a chance to fill up, compromising the flow of blood (and therefore oxygen) to the rest of her body. One minute she would be racing down Highway 1 on her bike; the next she would feel like she had been “unplugged”, as if “there was nothing driving anymore”. A cardiologist at Scripps Memorial Hospital told her she’d need an internal defibrillator, but Kim said no – she was worried it’d get in the way of wearing a backpack on a run, and she had faith that she’d be able to deal with the ventricular tachycardia by slowing down and relaxing. “I didn’t want something implanted in me that would limit my opportunities of experiencing life,” she says.

The next week, the Goodsells finished their renovation, packed up and headed into the Sierra Nevada with no return date in sight. It was an unorthodox solution to a life-threatening heart condition: to vanish into the boondocks, far away from any medical care, to do even more exercise.

The thing is, it was the right one. The outdoors rejuvenated her. She was gone for one-and-a-half years, and her heart behaved the whole way through. That unbroken streak only broke when the Goodsells rejoined their old lives in 1997. Back in California, they were once again cycling down Highway 1 when her heart started to beat erratically again. This time, it did not stop.

By the time the paramedics arrived, Kim was slumped against a wall and her chest was shaking. Her tachycardia had lasted for almost an hour and progressed to ventricular fibrillation – that is, her heartbeat was erratic as well as fast. She blacked out in the ambulance, on the cusp of cardiac arrest.

She woke up at Scripps Memorial Hospital. The same cardiologist was there to greet her. Through further tests he discovered that the muscle of her right ventricle was marbled with fat and scar tissue and not contracting properly. These are classic signs of ARVC. It had only been properly described in 1982, back when Kim was regularly signing up for triathlons. ARVC is a major cause of fatal heart attacks in young people, and athletes are especially vulnerable as exercise can accelerate the disease’s progress. And since Kim wouldn’t stop exercising, she finally conceded to the defibrillator. They implanted it the next day.

Kim referred to the implant as her “internal terrorist”. Every shock was debilitating and led to months of anxiety. She had to learn to cope with the device, and it took several years to regain the joy she drew from hardcore exercise. That was when the other symptoms started.


These diseases are rare. In a crowd of a million adults, around 400 will have Charcot–Marie–Tooth and between 200 and 400 will have ARVC. But genetic diseases in general are actually quite common – 8 per cent of people have at least one. This paradoxical combination has fuelled the rise of many online communities where people with rare disorders can find each other. Heidi Rehm, a geneticist at Harvard Medical School, studies a condition called Norrie disease that mostly affects the eyes and ears. She developed a registry for Norrie disease patients to share their experiences, and learned that almost all the men with the disease had erectile dysfunction. “A patient goes to their doctor with blindness and deafness, and erectile dysfunction isn’t the first thing you ask about!” says Rehm. “Patients drove that discovery.” Through communities, families often make connections about their medical problems that their doctors miss.

But Kim was never one for relying on others. She tried a support group when she got her implant, but it did nothing for her. She dipped her toes in patient forums, but was always frustrated by the rampant misinformation. “People just weren’t interpreting things correctly,” Kim says. “I wanted more rigour.”

She started by diving into PubMed – an online search engine for biomedical papers – hunting down everything she could on Charcot–Marie–Tooth. She hoped that her brief fling with a scientific education would carry her through. But with pre-med knowledge that had been gathering dust for 30 years and no formal training in genetics, Kim quickly ran headfirst into a wall of unfamiliar concepts and impenetrable jargon. “It was like reading Chinese,” she says.

But she persisted. She scratched around in Google until she found uploaded PDFs of the articles she wanted. She would read an abstract and Google every word she didn’t understand. When those searches snowballed into even more jargon, she’d Google that too. The expanding tree of gibberish seemed infinite – apoptosis, phenotypic, desmosome – until, one day, it wasn’t. “You get a feeling for what’s being said,” Kim says. “Pretty soon you start to learn the language.”

“Kim has an incredible ability to understand the genetic literature,” says Martha Grogan, a cardiologist from the Mayo Clinic and an old friend of CB’s who now coordinates Kim’s care. “We have a lot of patients who ask great questions but with Kim, it’s like having another research fellow.”

At the time the Goodsells were staying at a friend’s house at Lake Michigan. Kim would sit on the balcony for eight hours a day, listening to the water and teaching herself genetics. Too weak to explore winding hillside trails, she channelled her perseverance and love of isolation towards scientific frontiers and the spiralling helices of her own DNA. “I spent hundreds of hours,” she says. “CB lost me during this process.”

Kim looked at every gene linked to Charcot–Marie–Tooth – there are more than 40 overall, each one imparting a slightly different character to the disease. One leapt out: LMNA, which codes for a group of rope-like proteins that mesh into a tangled network at the centre of our cells. This ‘nuclear lamina’ provides cells with structural support, and interacts with a bunch of other proteins to influence everything from the packaging and activation of genes to the suicide of damaged cells. Given this central role, it makes sense that mutations in LMNA are responsible for at least 15 different diseases, more than any other human gene. These laminopathies comprise a bafflingly diverse group – nerve disorders (like Charcot–Marie–Tooth), wasting diseases of fat and muscle, and even premature ageing.

As Kim read about these conditions and their symptoms, she saw her entire medical history reflected back at her – the contracted muscles in her neck and back, her slightly misaligned hips and the abnormal curve in her spine. She saw her Charcot–Marie–Tooth disease.

She also saw a heart disorder linked to the LMNA gene that wasn’t ARVC but which doctors sometimes mistake for it. “Everything was encapsulated,” she says. “It was like an umbrella over all of my phenotypes. I thought: This has to be the unifying principle.”


Kim was convinced that she had found the cause of her two diseases, but the only way to know for sure was to get the DNA of her LMNA gene sequenced to see if she had a mutation. First, she had to convince scientists that she was right. She started with Grogan, presenting her with the findings of her research. Grogan was impressed, but pragmatic. Even if Kim was right, it would not change her fate. Her implant was keeping her heart problems under control, and her Charcot–Marie–Tooth disease was incurable. He didn’t see a point. But Kim did. “I wanted to know,” she says. “Even if you have a terrible prognosis, the act of knowing assuages anxiety. There’s a sense of empowerment.”

In November 2010 Kim presented her case to Ralitza Gavrilova, a medical geneticist at the Mayo Clinic. She got a frosty reception. Gavrilova told Kim that her odds of being right were slim. “I got this sense that she thought I’d made an unfounded shot in the dark,” says Kim. “That I didn’t understand the complexity of the genome. That I had been reading the internet, and they come up with all sorts of things there.”

Gavrilova pushed Kim towards a different test, which would look at seven genes linked to ARVC. Her insurance would cover that, but if she insisted on sequencing the DNA of her LMNA gene, she would have to foot a $3,000 bill herself. Why waste the money, when it was such an unlikely call? But Kim was insistent. She knew that the known ARVC genes explain only a minority of cases and that none of them was linked to neural problems. In all her searching she had found only one that covered both her heart and nervous problem. Eventually, Gavrilova relented.

Kim, meanwhile, disappeared down to Baja in Mexico. Gavrilova’s scepticism had worn her down and she fully expected that the results would come back negative.

When she returned home in May, there was a letter waiting for her. It was from Gavrilova. She had been trying to call for months. The test had come back positive: on one of her two copies of LMNA Goodsell had a mutation, in a part of the gene that almost never changes. LMNA consists of 57,517 DNA ‘letters’, and in the vast majority of people (and most chimps, monkeys, mice and fish) the 1,044th position is filled by a G (guanine). Kim had a T (thymine). “All evidence suggests that the mutation found in this patient might be disease-causing,” Gavrilova wrote in her report.

In other words, Kim was right.

“I’m beyond impressed,” says Michael Ackerman, a geneticist at the Mayo Clinic. He specialises in inherited heart disorders like ARVC that can cause sudden death at any time. Such diseases make for people who do their homework, but Ackerman describes most as “Google-and-go” patients who check their diagnosis online, or read up about treatment options. Kim had written up her research as a white paper – 36 pages of research and analysis. “Kim’s the only one who handed me her own thesis,” he says. “Of all the 1,000-plus patients I’ve taken care of, none have done extensive detective work and told physicians which genetic test to order.”

He thinks she nailed it too. It is unlikely to be the whole story – Kim almost certainly has other mutations that are affecting the course of her disease – but LMNA “is certainly the leading contender for a unifying explanation, without there being a close second,” he says. “The evidence is pretty good for this being a smoking gun.”

The test had vindicated her hypothesis, but it also raised some confusing questions. Heart problems are a common feature of laminopathies, but those mutations had never been linked to ARVC, Kim’s specific heart malfunction. Had she been misdiagnosed? A few months later, Kim stumbled across a new paper by a team of British researchers who had studied 108 people with ARVC and found that four had LMNA mutations (and none of the standard ones). “To the best of our knowledge, this is the first report of ARVC caused by mutations in LMNA,” they wrote. They didn’t know about Kim’s work – they couldn’t have, of course. But she knew. Kim had beaten them to it. “I was so excited, I was running up and down the beach,” she says.


When patients get solutions to their own genetic puzzle, it’s always professional geneticists who do the solving. Take James Lupski. He has been studying Charcot–Marie–Tooth for decades, and discovered the first gene linked to the condition. He also has it himself. In 2010 he sequenced his own genome and discovered a previously unidentified mutation responsible for the disease. In other cases anxious parents have been instrumental in uncovering the causes of their kids’ mysterious genetic disorders after long diagnostic odysseys, but only by bringing their cases in front of the right scientists.

Kim, however, was an amateur. And to her, sequencing was not a Hail Mary pass that would – maybe, somehow – offer her answers; it was a way of confirming a carefully researched hypothesis.

“People have been talking about empowering consumers since there was an internet,” says Eric Topol, a geneticist at the Scripps Clinic. “But finally, we’ve reached a point where someone can delve into their condition beyond what the top physicians at the Mayo Clinic could. They couldn’t connect the dots. She did.”

Topol, a self-described “digital medicine aficionado”, argues that Kim is a harbinger of things to come. In his book The Creative Destruction of Medicine, Topol foretells a future where doctors are no longer the gatekeepers of medical information. Advances like personal genetic testing or sensors that measure molecules in the blood will give patients the power to better understand themselves and to exercise more control over their healthcare. Medicine is becoming more democratic.

Kim is a vanguard of that change. She lacked academic knowledge, but she had several advantages over her physicians and other researchers in the field. She had detailed first-hand knowledge of her own symptoms, allowing her to spot connections in the scientific literature that others had missed. She could devote hours to learning everything about her niche disorders – time and focus that no clinician could reasonably spend on a single case. And she had unparalleled motivation: “There’s nothing that engages your curiosity more than being confronted by your death,” she says.

It is also becoming ever easier for that curiosity to lead to discovery. In the past geneticists would try to diagnose patients by looking at their medical history and deciding which genes might be worth sequencing, as Gavrilova tried to do for Kim. The approach makes sense, but it only ever confirms known links between genes and diseases.

One way of finding new links is to sequence a patient’s exome – the 1 per cent of their genome that contains protein-coding genes. It’s cheaper than sequencing a full genome, but allows researchers to hunt for disease-related genes by interrogating every possible suspect simultaneously, without having to whittle down the list first. “Suddenly, we’re finding patients presenting with Disease X who have mutations in genes never previously associated with that disease,” says Daniel MacArthur, a geneticist at Massachusetts General Hospital. “That’s happening in nearly every disease field right now.”

Exome sequencing is now barely more expensive than sequencing much narrower gene panels. MacArthur says that the cost has already fallen below $1,000 and may halve again this year. And once patients have that information, they could use it to find others with the same mutations and check if they have the same symptoms.

Currently, the results from DNA sequencing studies are largely squirrelled away in boutique databases that collate mutations for specific diseases or genes. The ironically named Universal Mutation Database covers mutations in only 34 genes, including LMNA. Broader ones exist, but for decades they have been incomplete, rife with mistakes, or inaccessible, even to other researchers – a sad state of affairs that MacArthur laments as the “single greatest failure in human genetics”. Now, though, the National Institutes of Health are developing an open database called ClinVar that covers all disease mutations. “A lot of us are putting our hopes on this,” says MacArthur. “We need to come up with resources that empower people to make surprising links, which is hard to do if the data are broken up by disease or gene.”

But for every Kim, there are others who research their own conditions and come up with wrong answers. In one study four non-specialist volunteers tried to diagnose 26 cases from the New England Journal of Medicine by Googling the symptoms. They got less than a quarter right. Genetic diseases arguably lend themselves to confusion and misinformation. They are often both debilitating and enigmatic, and getting sequenced can offer little comfort beyond a diagnosis. If mainstream science has no easy answers to offer, many patients will follow any lead, no matter how weak. “There’s a tendency for people to spin very convoluted stories on tenuous threads of evidence. Even scientists do that,” says MacArthur. “I have heard of a lot of rare-disease patients who come up with hypotheses about their disease, and very few turn out to be correct.”

Even Kim’s tale could have taken a different turn. Last year, a team from the Baylor College of Medicine sequenced the exomes of 250 people with suspected genetic disorders, and found that four of them had two diseases caused by mutations in different genes. In other words, Kim’s hunch about her two diseases sharing a common root could well have been wrong. Lightning does occasionally strike twice.

“We almost always have to spend time with patients decoding and recoding the impression that they’ve acquired about their disease from their own homework,” says Ackerman. Kim was an exception, he says, and her other physicians echo that view. She is unique. She is one-of-a-kind. She is extraordinary. High praise, but it conceals the implicit suggestion that she is an outlier and will continue to be.


“Bullshit,” says Kim. “I hear this all the time: that I’m an exception. That the patient of the future is not going to do what I did.” She bristles at the very suggestion. “I almost take offence when I hear that what I’ve done is exceptional.”

We are talking over coffee at La Ventana. This is her fifth winter here, and she and CB have just celebrated their 30th wedding anniversary. CB leans back against a wall, quiet and contemplative. Kim sits forward, animated and effusive. She’s drinking decaf because of her heart, but it’s not like she needs the caffeine. “Take Rodney Mullen. He’s a real genius,” she says. Mullen is not a figure from science or medicine. He is, in fact, a legendary skateboarder, famous for inventing mind-blowing tricks that previously seemed impossible. One of them i actually called the ‘impossible’. “He executes these movements that defy reason, films them and publishes them on YouTube,” Kim says. “And inevitably, within a few weeks, someone will send him a clip saying: This kid can do it better than you. He gave that trick everything he had, he’s pulling from all of his experience, and here’s this kid who picks it up in a matter of weeks. Because he learned that it’s possible to do that. Rodney just acts as a conduit. He breaks barriers of disbelief.”

Her protestations aside, Kim is unique. Throughout her life she had built up a constellation of values and impulses – endurance, single-mindedness, self-reliance and opposition to authority – that all clicked in when she was confronted with her twin diagnoses. She was predisposed to win. Not everyone is. But as genetic information becomes cheaper, more accessible and more organised, that barrier may lower. People may not have to be like Kim to do what she did.

Kim isn’t cured. Her LMNA discovery offered her peace of mind but it did not suggest any obvious treatments. Still, she has made a suite of dietary changes, again based on her own research, which she feels have helped to bring her nervous symptoms under control. Some are generic, without much hard science behind them: she eats mostly organic fruit, vegetables, nuts and seeds, and avoids processed food. Others are more tailored. She drinks ginger tea because it thins the blood – she says that many people with laminopathies have problems with clots. Whether her choices are directly slowing the progress of her diseases or triggering a placebo effect, she is fit and happy. Her defibrillator hasn’t shocked her in months. And, of course, she still exercises constantly.

Up the hill from the beach we can see the little yellow house where she wrote the 36-page booklet that put together all her research. It convinced her doctors, yes, but it did even more. She showed it to her brother, now an anaesthesiologist, and it allowed them to reconcile. “It’s like I’ve finally done something worthy with my life,” Kim says. “He told me I’d done some really good research and that I’d missed my calling as a medical researcher. I told him I think I’ve been doing exactly what I needed to do.”

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From Ancient Genomes to Ancient Epigenomes

Late last year, scientists unveiled the complete genome of a female Neanderthal whose 130,000-year-old toe bone had been found in a cave in Siberia. As it turned out, her sequence of some 3 billion DNA letters was not all that much different from mine or yours. The researchers identified only about 35,000 places in the genome where all modern humans differ from our ancient hominid cousins. And only 3,000 of those were changes that could impact how genes are turned on and off.

But if our DNA is so similar to Neanderthals’, why were they so…different? They were brawnier than our ancestors, with short but muscular limbs, and big noses and eyebrows. They didn’t carry certain genetic variants that put modern humans at risk of autoimmune disease and celiac disease. And although they lived alongside our ancestors as the latter migrated into Europe, for some reason the Neanderthals didn’t survive.

Part of the answer undoubtedly lies in the way the Neanderthal genome actually worked — a complex process that depends not only on the underlying DNA code, but on the way genes get turned on and off. DNA molecules are constantly interacting with chemicals that control which genes can be activated. For example, a methyl group (one carbon and three hydrogen atoms) can latch on to the genome and help switch on or off the expression of nearby genes.

This dynamic layer of genome regulation, known as the ‘epigenome’, has received a ton of scientific attention in the last few decades. Researchers have claimed that epigenetics can explain (among many other things) how the placenta works, and why some people develop autism, and why enduring a famine in childhood might affect the health of one’s  future grandchildren. A commentary in last week’s issue of Science suggests that epigenetics may also hold the key to interpreting ancient genomes, including those of the Neanderthal, a 4,000-year-old Eskimo, and an 800-year-old plant.

It’s crazy, really, that scientists can glean anything from such old, old DNA. To put together the Neanderthal genome scientists had to combine many DNA fragments painstakingly extracted from bits of bones. But these DNA sequences also carried hints of the past epigenome.

DNA methylation usually happens on DNA bases called cytosines. As it turns out, cytosines decay differently depending on whether they are methylated. The cytosines that once carried methyl groups turned into a chemical called thymine, whereas those that were not methylated turned into a different chemical, called uracil. By measuring thymine, then, researchers can estimate the amount of DNA methylation in ancient samples.

In May a team of researchers did exactly that to the Neanderthal genome, comparing its thymine profile to that of present-day people. As they published in Science, the scientists found that the overall methylation map was very similar between the two species, showing that their thymine trick was indeed a good proxy of methylation. But they also found intriguing differences. Unlike modern humans, Neanderthals carried a lot of methylation on the HOXD9 and HOXD10 genes, which are both known to be involved in limb development. This might explain some of the anatomical differences between the species, the authors say. What’s more, the genes that were methylated differently in Neanderthals and modern humans are nearly twice as likely to be linked to diseases, and particularly brain disorders.

In another recent study, researchers used similar epigenetic sleuthing on a Paleo-Eskimo found in Greenland. There are certain places in the genome, called ‘clock CpG sites’, in which methylation levels correlate predictably with age. By looking at the Eskimo’s thymine profile at these sites (gleaned from a 4,000-year-old tuft of hair), the researchers discovered that the guy likely died in his 50s.

Most of the controversy swirling around modern epigenomes relates to the question of just how readily our genes respond to changes in the environment. Somewhat amazingly, that same question can be investigated with ancient epigenomes. In a study published last month, researchers estimated the methylation levels of barley samples — ranging from 500 to 2,500 years old — found in an archaeological site in southern Egypt. The samples showed steadily decreasing levels of methylation with age (which is a clear demonstration of the aforementioned cytosine decay process, not a sign of rapidly changing methylation patterns). But there was one exception: An 800-year-old sample, which had tested positive for a killer infection called the Barley Stripe Mosaic Virus, had far higher levels of DNA methylation than an uninfected sample of the same age. It’s a neat illustration of ancient epigenomes revealing ancient exposures.

I don’t want to make too much of this approach. Scientists still don’t really know how to interpret epigenetic changes in living people (whose diet, exposures and medical history can be tracked, however crudely). What epigenetic differences say about ancient species is even more mysterious. All the same, it’s pretty incredible to think of the long biological histories that scientists manage to dig out of ice and rock.

“Bigfoot” Unmasked

Bigfoot is an all-American monster. The mythical ape – a bastardized version of the Yeti – has supposedly been spotted in every state in the union except Hawaii (because that’d just be silly) and has been co-opted into a spokesape for jerky, pizza, and beer. Americans ripped off an existing tall tale, created hoaxes to bring the fiction to life, and ultimately tapped into Sasquatch’s pop culture appeal to make a quick buck. As far as cryptozoological legends go, Bigfoot is a great American mascot.

I’m sure Bigfoot believers are already bridling at this post. There is a very active community of Sasquatch devotees who are certain that there is an as-yet-unrecognized species of ape wandering through North America’s forests. They’d prefer that we forget the multiple hoaxes and turn our attention to personal anecdotes and what they claim as physical evidence for the critter. The most common tangible thread is hair. That would make some sense. A furry ape traipsing through the bushes and briars would have to leave some hairs behind. But are these mystery tufts truly indications of Bigfoot’s reality? Science says no.

Earlier this month, in Proceedings of the Royal Society B, Institute of Human Genetics researcher Bryan Sykes and colleagues published the identity of 30 hair samples said to have been shed by “anomalous primates”, including hairs believed to belong to Bigfoot. The team didn’t find any evidence of elusive apes.  Genetic analysis of 18 “Sasquatch” samples – collected from locations from Texas to Washington – turned out to be from much more familiar beasts. The “Bigfoot” hairs, Sykes and coauthors concluded, came from raccoons, sheep, black bears, porcupine, horses, canids, deer, and cows.

[Sasquatch isn’t real, but the creature’s pop-culture cred is good for selling jerky.]

Bigfoot isn’t the only legendary ape around, of course. Sykes and colleagues also tested hair samples purported to be from the original mythical hominoid, the Yeti of the Himalayas, as well as the lesser-known Almasty of Russia and Orang Pendek of Sumatra. There was no inexplicable “cryptid” evidence in any of the samples. The Orang Pendek hair came from a tapir, while the Almasty fur originated with bears, horses, cows, and raccoons.

But the researchers did find something unexpected. One of the Yeti hairs once grew on a goat-like ungulate called a serow, in line with a previous study, but two of the samples best matched genetic sequences from a polar bear that lived in the Himalayas over 40,000 years ago. This could be a sign that there is an unrecognized species of bear in the Himalayas, of recent polar bears in the area that have a darker hair color to make them look like brown bears, or of hybrids between polar bears and brown bears, Sykes and coauthors suggest. Then again, the mitochondrial genes the researchers zeroed in on weren’t informative enough to distinguish between dogs, coyotes, and wolves in other sampled hairs, meaning that launching a hunt for a new bear species on the genetic evidence along would be a tad premature. Perhaps the odd bear hairs are simply from Himalayan brown bears that have undoubted contributed to the legend of the Yeti.

As the Sykes paper and journal commentor Norman MacLeod both point out, the new study doesn’t absolutely disprove the existence of Bigfoot and company. But the paper does add to the crushing pile of non-evidence. With all the alleged sightings out across almost the whole of North America, you’d think there’d be so many populations of Bigfoot that you’d regularly find them raiding garbage in suburban neighborhoods or at least leaving behind some tangible sign of their existence in America’s woodlands. They haven’t. If Bigfoot lives anywhere, it’s in our imagination – a symbol of the wild, the unknown, and how our species is excellent at turning superstition into advertising.

For more commentary on Bigfoot and other cryptids, check out my 2012 op-ed in Slate and this interview with KUER’s Radio West.


MacLeod, N. 2014. Molecular analysis of “anomalous primate” hair samples. Proceedings of the Royal Society B. 20140843.

Sykes, B., Mullis, R., Hagenmuller, C., Melton, T., Sartori, M. 2014. Genetic analysis of hair samples attributed to yeti, bigfoot, and other anomalous primates. Proceedings of the Royal Society B. 281: 20140161

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Extinct Humans Passed High-Altitude Gene to Tibetans

Tibetan people can survive on the roof of the world—one of the most inhospitable places that anybody calls home—thanks to a version of a gene that they inherited from a group of extinct humans called Denisovans, who were only discovered four years ago thanks to 41,000-year-old DNA recovered from a couple of bones that would fit in your palm.  If any sentence can encapsulate why the study of human evolution has never been more exciting, it’s that one.

In 2010, Rasmus Nielsen from the University of California, Berkeley found that Tibetan people have a mutation in a gene called EPAS1, which helps them handle low levels of oxygen. Thanks to this mutation, they can cope with air that has 40 percent less oxygen than what most of us inhale, and they can live on a 4,000-metre-high plateau where most of us would fare poorly. To date, this is still “strongest instance of natural selection documented in a human population”—the EPAS1 mutation is found in 87 percent of Tibetans and just 9 percent of Han Chinese, even though the two groups have been separated for less than 3,000 years.

But when the team sequenced EPAS1 in 40 more Tibetans and 40 Han Chinese, they noticed that the Tibetan version is incredibly different to those in other people. It was so different that it couldn’t have gradually arisen in the Tibetan lineage. Instead, it looked like it was inherited from a different group of people.

By searching other complete genomes, the team finally found the source: the Denisovans! The Tibetan EPAS1 is almost identical to the Denisovan version. It’s now a Tibetan speciality, but it was a Denisovan innovation.

This discovery is all the more astonishing because we still have absolutely no idea what the Denisovans looked like. The only fossils that we have are a finger bone, a toe, and two teeth. Just by sequencing DNA from these fragments, scientists divined the existence of this previously unknown group of humans, deciphered their entire genome, and showed how their genes live on in modern people. Denisovan DNA makes up 5 to 7 percent of the genomes of people from the Pacific islands of Melanesia. Much tinier proportions live on in East Asians. And now, we know that some very useful Denisovan DNA lives on in Tibetans.

Svante Paabo, who sequenced the Denisovan genome, is delighted. “It’s very satisfying to see that gene flow from Denisovans, an extinct group of archaic humans which we discovered only four years ago, is now found to have had important consequences for people living today,” he says.

“It was a complete surprise,” says Nielsen. “It took years after the Denisovan genome was published for us to even try this, because we thought it was so far-fetched.”

The discovery also adds to a growing picture of human evolution—one involving a lot of cross-breeding. Humans evolved in Africa, and everyone outside that continent descends from a relatively small group of pioneers who left it at some point in our prehistory. These trailblazers were adapted to life on the tropical savannah. As they migrated, they experienced all the varied challenges that the world has to offer, such as extreme temperatures and new diseases.

At the time, the world was already populated by other groups of humans, like Neanderthals and Denisovans. As the African immigrants met up with these groups, they had sex. And through these liaisons, their genomes became infused with DNA from people who had long adapted to these new continents. “It’s a new way of thinking of human evolution—a network of exchange of genes between many lineages,” says Nielsen.

Nielsen suspects that modern humans had sex with Denisovans in Asia, somewhere between 30,000 and 40,000 years ago. They inherited the Denisovan version of EPAS1, which lingered in the populations at very low frequencies. The carriers fared better at higher altitudes, and their descendants colonised the Tibetan plateau. This explains why the team found the Denisovan EPAS1 in the vast majority of Tibetans, but also in a couple of Han Chinese people living outside of Tibet.

Denisova_TibetOther scientists have shown that sex with Neanderthals could also have imported useful genes into our genome, including those involved in skin, hair, and the immune system. “What we’re learning from ancient genomes is that while each of them may have contributed only a little to our ancestry, those genetic streams were full of tiny golden nuggets of useful genes,” says anthropologist John Hawks, who emailed me just before visiting Denisova Cave where the Denisovan fossils were found.

“What is a bit surprising is that Denisova is not at high altitude,” says Hawks. It’s in the Altai mountains of Siberia, but it’s not that high up. If Denisovans had the high-altitude version of EPAS1, this could imply that they also spread through the more mountainous parts of China and South Asia. “This gives a route by which Denisovans might have gotten into Southeast Asia where we know modern humans picked up their genes on the way to Australia,” says Hawks.

Nielsen adds that the Denisovans weren’t necessarily adapted to high altitudes. Their version of EPAS1 could have helped them in other ways, and coincidentally allowed the Tibetans to colonise the roof of the world.

If I travelled to the Tibetan plateau, my body would try to cope by making more red blood cells, which transport oxygen around my body. But I’d overcompensate and make too many of these cells. My blood would become thick and viscous, leaving me prone to high blood pressure and stroke. Tibetans don’t have this problem. Their EPAS1 stops them from overproducing red blood cells and helps them acclimatise to the altitude without doing themselves harm. But cold climates can also raise blood pressure by constricting blood vessels. So perhaps the Denisovan version of EPAS1 helped them to adapt to extreme cold, rather than a lack of oxygen.

“To give you a definitive answer, I’d need to find a Denisovan and do some physiological experiments,” he says. “And I can’t.”

Reference: Huerta-Sanchez, Jin, Asan, Bianba, Peter, Vinckenbosch, Liang, Yi, He, Somel, Ni, Wang, Ou, Huasang, Luosang, Cuo, Li, Gao, Yin, Wang, Zhang, Xu, Yang, Li, Wang, Wang & Nielsen. 2014. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. http://dx.doi.org/10.1038/nature13408

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My DNA Made Me Do It? How Behavioral Genetics Is Influencing the Justice System

On December 14, 2012, 20-year-old Adam Lanza killed 20 children at a Connecticut elementary school, as well as 6 school staffers, his mother, and himself. Within two weeks, the Connecticut Medical Examiner commissioned a group of geneticists to screen Lanza’s DNA.

And for what, exactly? Who knows. There are any number of genetic variants the scientists could zero in on — variants that have been linked to a propensity for violence, aggression, psychopathy, or psychiatric disorders. One thing I’d bet on: The screen will find something. Each of us carries genetic mutations somewhere along our 3-billion-letter DNA code. Some mutations are benign, some are not; some have huge effects, others tiny. But there’s no way to know how (or whether) any of them affects behavior.

Another thing I’d bet on: The media (and the public) will use the results of that genetic screen to explain what Lanza did. We all want answers, and a genetic test seemingly provides a long string of them. Answers from science, no less. But, as was pointed out by many scientists and commentators at the time, searching for answers in Lanza’s DNA is futile. “There is no one-to-one relationship between genetics and mental health or between mental health and violence,” read an editorial in Nature. “Something as simple as a DNA sequence cannot explain anything as complex as behaviour.”

The Connecticut Medical Examiner is apparently the first to ever request a genetic screen of a dead murderer. It’s an odd move, and perhaps one that can be blamed on intense public scrutiny in the wake of the tragedy. But using genetics to inform criminal cases is not new or even all that rare. As I learned in a fascinating commentary published in today’s issue of Neuron, behavioral genetics has a long history in the American justice system.

The “feeble minded” Carrie Buck, who was forcibly sterilized by the Commonwealth of Virginia. Photo from Wikipedia.

The author of the commentary, Paul Appelbaum of Columbia University, cites, for example, the Buck v. Bell Supreme Court case from 1927. The court upheld a Virginia law authorizing mandatory sterilization of people who are intellectually disabled, or “feeble minded”, because they threaten the gene pool. I’m not exaggerating. “It is better for all the world if, instead of waiting to execute degenerate offspring for crime or to let them starve for their imbecility, society can prevent those who are manifestly unfit from continuing their kind,” wrote Justice Oliver Wendell Holmes in the majority opinion. (If you want to be depressed all day, go read the Wikipedia entry about the case.)

Explicit genetic testing entered the courts in the late 1960s, but this time it was on behalf of the accused. Lawyers representing men carrying an extra Y chromosome — known today as ‘XYY syndrome’ — argued that because this genetic condition was overrepresented in prisons, it must drive violent behaviors. But most courts, according to Appelbaum, weren’t sympathetic to this logic, and refused to allow the genetic information into evidence.

Most cases calling on behavioral genetics, like the XYY example, do so in an attempt to lessen the culpability of a defendant who committed a crime. This isn’t usually relevant when deciding the verdict of the case (except for the very rare instances in which a defendant is found not guilty by reason of insanity). But mitigating factors — such as child abuse, drug use, abnormal brain activity, or genetic disposition — can matter a great deal during sentencing proceedings, particularly if the death penalty is on the table. “Judges tend to be fairly permissive at death penalty hearings,” Appelbaum writes.

In 2011 Deborah Denno, a law professor at Fordham University, reported 33 recorded* instances of neuropsychiatric genetic evidence in criminal courts between 2007 and 2011. She had previously reported 44 instances between 1994 and 2007, suggesting that it’s becoming slightly more common. In almost every instance, genetic evidence was used as a mitigating factor in a death penalty case.

The genetic evidence in Denno’s reports tended to be fairly crude: a family history of a condition. But specific genetic tests are beginning to seep into court, too. In 2007, several psychiatrists and geneticists described their experiences presenting evidence at criminal trials related to two gene variants: a variant of monoamine oxidase A, which when mixed with child maltreatment increases the risk of violent behavior, and a variant of the serotonin transporter gene, which when mixed with multiple stressful life events ups the risk of serious depression and suicide. A couple of cases used these scientific links to argue that defendants didn’t have the mental ability to plan their crime in advance. But most of the time genetic evidence was used to mitigate sentences. In 2011, for example, an Italian court reduced a female defendant’s sentence from life in prison to 20 years based on genetic evidence and brain scans that supposedly proved “partial mental illness.”

None of these examples trouble me too much. The U.S. court allows “any aspect of character or record” to be used as a mitigating factor during sentencing, including a defendant’s age, stress level, childhood experiences, criminal history, employment history, and even military service. So why not genetic predisposition, too? It also seems that, so far at least, judges and juries are showing an adequate level of skepticism about this kind of evidence. In 2010, I wrote a story about serial killer Brian Dugan, whose lawyers tried to use brain scans to show that he was a psychopath and didn’t deserve the death penalty. The jury wasn’t swayed.

Most shocking, to me, is how genetic evidence might be used in the civil court system, at least according to Appelbaum. Last year in Canada, a tenant sued her landlord for a fire that, she claimed, caused several injuries that will prevent her from ever working again. The plaintiff had a family history of Huntington’s disease, and the court ordered her to have a blood test to screen for the mutant gene to help determine whether her injuries were the result of the fire or her DNA. She didn’t want to take the test, but if she didn’t she’d have to drop the lawsuit. Appelbaum envisions other possible scenarios in future civil cases:

Employers contesting work-related mental disability claims might… want to compel claimants to undergo genetic testing to prove that an underlying disorder was not responsible for their impairment. Divorcing couples in child-custody disputes, in which court-ordered psychological evaluations are routine, may want to add genetic testing for behavioral traits or neuropsychiatric disorders to the list of procedures that their estranged spouses must undergo to assess their fitness to parent a child. Plaintiffs seeking to establish that a defendant acted recklessly (e.g., in precipitating an auto accident) might attempt to seek data regarding the defendant’s genetic predisposition to impulsive behavior. With increasing utilization of next-generation sequencing in medical settings, and arguments being made for sequencing newborns at birth, adverse parties in civil litigation may not need to compel genetic testing but merely to seek access to existing data.

In these civil cases, which are not usually matters of life and death, I would imagine that the bar for scientific scrutiny would be set lower than in criminal cases. That’s troubling, and all the more reason that we need to better educate the public about what genes can and cannot tell us. As genetic testing continues to infiltrate our medical system, and now our justice system, too, perhaps this education will happen naturally. One can hope.

The Nature editorial regarding the Lanza testing was titled “No easy answer”, and that’s really the crux of all of this. When a person does something awful, we want to know why. But it may be an impossible question.

*Most of Denno’s cases came from appellate courts because usually lower courts don’t have written opinions. So that means her numbers are almost certainly underestimates.