Tag: gene

Chinese scientists have put human brain genes in monkeys—and yes, they may be smarter

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by Antonio Regalado

Human intelligence is one of evolution’s most consequential inventions. It is the result of a sprint that started millions of years ago, leading to ever bigger brains and new abilities. Eventually, humans stood upright, took up the plow, and created civilization, while our primate cousins stayed in the trees.

Now scientists in southern China report that they’ve tried to narrow the evolutionary gap, creating several transgenic macaque monkeys with extra copies of a human gene suspected of playing a role in shaping human intelligence.

“This was the first attempt to understand the evolution of human cognition using a transgenic monkey model,” says Bing Su, the geneticist at the Kunming Institute of Zoology who led the effort.

According to their findings, the modified monkeys did better on a memory test involving colors and block pictures, and their brains also took longer to develop—as those of human children do. There wasn’t a difference in brain size.

The experiments, described on March 27 in a Beijing journal, National Science Review, and first reported by Chinese media, remain far from pinpointing the secrets of the human mind or leading to an uprising of brainy primates.

Instead, several Western scientists, including one who collaborated on the effort, called the experiments reckless and said they questioned the ethics of genetically modifying primates, an area where China has seized a technological edge.

“The use of transgenic monkeys to study human genes linked to brain evolution is a very risky road to take,” says James Sikela, a geneticist who carries out comparative studies among primates at the University of Colorado. He is concerned that the experiment shows disregard for the animals and will soon lead to more extreme modifications. “It is a classic slippery slope issue and one that we can expect to recur as this type of research is pursued,” he says.

Research using primates is increasingly difficult in Europe and the US, but China has rushed to apply the latest high-tech DNA tools to the animals. The country was first to create monkeys altered with the gene-editing tool CRISPR, and this January a Chinese institute announced it had produced a half-dozen clones of a monkey with a severe mental disturbance.

“It is troubling that the field is steamrolling along in this manner,” says Sikela.

Evolution story

Su, a researcher at the Kunming Institute of Zoology, specializes in searching for signs of “Darwinian selection”—that is, genes that have been spreading because they’re successful. His quest has spanned such topics as Himalayan yaks’ adaptation to high altitude and the evolution of human skin color in response to cold winters.

The biggest riddle of all, though, is intelligence. What we know is that our humanlike ancestors’ brains rapidly grew in size and power. To find the genes that caused the change, scientists have sought out differences between humans and chimpanzees, whose genes are about 98% similar to ours. The objective, says, Sikela, was to locate “the jewels of our genome”—that is, the DNA that makes us uniquely human.

For instance, one popular candidate gene called FOXP2—the “language gene” in press reports—became famous for its potential link to human speech. (A British family whose members inherited an abnormal version had trouble speaking.) Scientists from Tokyo to Berlin were soon mutating the gene in mice and listening with ultrasonic microphones to see if their squeaks changed.

Su was fascinated by a different gene, MCPH1, or microcephalin. Not only did the gene’s sequence differ between humans and apes, but babies with damage to microcephalin are born with tiny heads, providing a link to brain size. With his students, Su once used calipers and head spanners to the measure the heads of 867 Chinese men and women to see if the results could be explained by differences in the gene.

By 2010, though, Su saw a chance to carry out a potentially more definitive experiment—adding the human microcephalin gene to a monkey. China by then had begun pairing its sizeable breeding facilities for monkeys (the country exports more than 30,000 a year) with the newest genetic tools, an effort that has turned it into a mecca for foreign scientists who need monkeys to experiment on.

To create the animals, Su and collaborators at the Yunnan Key Laboratory of Primate Biomedical Research exposed monkey embryos to a virus carrying the human version of microcephalin. They generated 11 monkeys, five of which survived to take part in a battery of brain measurements. Those monkeys each have between two and nine copies of the human gene in their bodies.

Su’s monkeys raise some unusual questions about animal rights. In 2010, Sikela and three colleagues wrote a paper called “The ethics of using transgenic non-human primates to study what makes us human,” in which they concluded that human brain genes should never be added to apes, such as chimpanzees, because they are too similar to us. “You just go to the Planet of the Apes immediately in the popular imagination,” says Jacqueline Glover, a University of Colorado bioethicist who was one of the authors. “To humanize them is to cause harm. Where would they live and what would they do? Do not create a being that can’t have a meaningful life in any context.”

In an e-mail, Su says he agrees that apes are so close to humans that their brains shouldn’t be changed. But monkeys and humans last shared an ancestor 25 million years ago. To Su, that alleviates the ethical concerns. “Although their genome is close to ours, there are also tens of millions of differences,” he says. He doesn’t think the monkeys will become anything more than monkeys. “Impossible by introducing only a few human genes,” he says.

Smart monkey?

Judging by their experiments, the Chinese team did expect that their transgenic monkeys could end up with increased intelligence and brain size. That is why they put the creatures inside MRI machines to measure their white matter and gave them computerized memory tests. According to their report, the transgenic monkeys didn’t have larger brains, but they did better on a short-term memory quiz, a finding the team considers remarkable.

Several scientists think the Chinese experiment didn’t yield much new information. One of them is Martin Styner, a University of North Carolina computer scientist and specialist in MRI who is listed among the coauthors of the Chinese report. Styner says his role was limited to training Chinese students to extract brain volume data from MRI images, and that he considered removing his name from the paper, which he says was not able to find a publisher in the West.

“There are a bunch of aspects of this study that you could not do in the US,” says Styner. “It raised issues about the type of research and whether the animals were properly cared for.”

After what he’s seen, Styner says he’s not looking forward to more evolution research on transgenic monkeys. “I don’t think that is a good direction,” he says. “Now we have created this animal which is different than it is supposed to be. When we do experiments, we have to have a good understanding of what we are trying to learn, to help society, and that is not the case here.” One issue is that genetically modified monkeys are expensive to create and care for. With just five modified monkeys, it’s hard to reach firm conclusions about whether they really differ from normal monkeys in terms of brain size or memory skills. “They are trying to understand brain development. And I don’t think they are getting there,” says Styner.

In an e-mail, Su agreed that the small number of animals was a limitation. He says he has a solution, though. He is making more of the monkeys and is also testing new brain evolution genes. One that he has his eye on is SRGAP2C, a DNA variant that arose about two million years ago, just when Australopithecus was ceding the African savannah to early humans. That gene has been dubbed the “humanity switch” and the “missing genetic link” for its likely role in the emergence of human intelligence.

Su says he’s been adding it to monkeys, but that it’s too soon to say what the results are.

https://www.technologyreview.com/s/613277/chinese-scientists-have-put-human-brain-genes-in-monkeysand-yes-they-may-be-smarter/

Genetic technique for destroying mosquitoes

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by ASHLEY YEAGER

A gene drive has successfully caused the collapse of a malaria-carrying mosquito population in the lab, researches report today (September 24) in Nature Biotechnology. This is the first time a gene drive—a genetic element that ensures its own inheritance—has caused a population of mosquitoes to self-destruct, a result that holds promise for combating malaria.

“This breakthrough shows that gene drive can work, providing hope in the fight against a disease that has plagued mankind for centuries,” study coauthor Andrea Crisanti, a molecular parasitologist at Imperial College London, says in a university statement.

In the study, the team targeted a region of a gene called doublesex that is responsible for female development. Female Anopheles gambiae mosquitoes with two copies of the altered doublesex gene did not lay eggs. After eight generations, the drive had spread through the entire population, such that no eggs were laid.

“It’s a really stunning development,” Omar Akbari, an entomologist at the University of California, Irvine who was not involved to the study, tells Wired, noting that mosquitoes are under “huge evolutionary pressure” to resist gene drives that cause the population to collapse. However, Akbari tells Science News that this gene drive might not work well in the wild because resistance will probably pop up.

Crisanti, however, is more confident. “We are not saying this is 100 percent resistance-proof,” he tells The New York Times. “But it looks very promising.” Still, he adds in the university statement, “[i]t will still be at least 5-10 years before we consider testing any mosquitoes with gene drive in the wild.” First, his team will need to test the gene drive in larger containers, where the mosquitoes can act more naturally, Crisanti tells Wired—swarming to find a mate, for instance. Such details were difficult to mimic in the 20 cubic centimeter cages used in this study.

Despite the need for further testing, some researchers hailed the current study as a major success. “With this achievement,” Kevin Esfelt, who studies the evolution of gene drives at MIT, tells The New York Times, “the major barriers to saving [human] lives are arguably no longer mostly technical, but social and diplomatic.”

https://www.the-scientist.com/news-opinion/study–gene-drive-wipes-out-lab-mosquitoes-64849

Researchers have discovered a gene that has evolved through natural selection to impact both psychiatric disorders and personality, and may help to maintain human diversity.

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How and why human-unique characteristics such as highly social behavior, languages and complex culture have evolved is a long-standing question. A research team led by Tohoku University in Japan has revealed the evolution of a gene related to such human-unique psychiatric traits.

PhD candidate Daiki Sato and Professor Masakado Kawata have discovered SLC18A1 (VMAT1), which encodes vesicular monoamine transporter 1, as one of the genes evolved through natural selection in the human lineage. VMAT1 is mainly involved in the transport of neurochemicals, such as serotonin and dopamine in the body, and its malfunction leads to various psychiatric disorders. VMAT1 has variants consisting of two different amino acids, threonine (136Thr) and isoleucine (136Ile), at site 136.

Several studies have shown that these variants are associated with psychiatric disorders, including schizophrenia, bipolar disorder, anxiety, and neuroticism (a personality trait). It has been known that individuals with 136Thr tend to be more anxious and more depressed and have higher neuroticism scores. They showed that other mammals have 136Asn at this site but 136Thr had been favored over 136Asn during human evolution. Moreover, the 136Ile variant had originated nearly at the Out-of-Africa migration, and then, both 136Thr and 136Ile variants have been positively maintained by natural selection in non-African populations.

The study by Sato and Kawata indicates that natural selection has possibly shaped our psychiatric traits and maintained its diversity. The results provide two important implications for human psychiatric evolution. First, through positive selection, the evolution from Asn to Thr at site 136 on SLC18A1 was favored by natural selection during the evolution from ancestral primates to humans, although individuals with 136Thr are more anxious and have more depressed minds.

Second, they showed that the two variants of 136Thr and 136Ile have been maintained by natural selection using several population genetic methods. Any form of natural selection that maintains genetic diversity within populations is called “balancing selection”. Individual differences in psychiatric traits can be observed in any human population, and some personality traits are also found in non-human primates. This suggests the possibility that a part of genetic diversity associated with personality traits and/or psychiatric disorders are maintained by balancing selection, although such selective pressure is often weak and difficult to detect.

The Evolution of Psychiatric Disorders and Personality Traits

Heart disease risk is hidden in your genes. Scientists are getting better at finding it.

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In the United States, around 735,000 people each year have a heart attack. In all, heart disease (and its complications, including heart attacks) kills 610,000 a year here, making it the leading cause of death in America and worldwide.

Preventing heart disease is a huge public health challenge. And right now doctors have good, but limited, options for finding out who is at greatest risk for it.

Doctors know that about half the risk for heart disease comes from lifestyle choices: how much, and what, a person is eating, how much alcohol they drink, if they smoke.

The other half is related to genetics, and it’s much harder to assess. You can ask a person about their family history of heart disease and can check for high blood pressure and obesity, which are also related to genetics. But up until the recent explosion in genetic science, it was hard to probe the genes themselves.

Last week, in the journal Nature Genetics, researchers at Harvard University and the Broad Institute published evidence that they can check out 6 million spots in a person’s genome to assess their risk for developing coronary artery disease, when the main blood vessel supplying the heart with oxygen gets clogged with plaque. It’s a precursor to a heart attack, when a clot cuts off blood flow to the heart, starving it of oxygen.

In the study, people who carried the greatest number of genetic variants suggestive of heart attack risk were three or more times likely to develop coronary artery disease than controls. The researchers argue that with this test, about one in 12 people could be identified as having a higher risk of heart attack based on their genetics alone.

“If you told me there was a genetic score that could identify 8 percent of the population with more than a threefold risk, I’d say, that’s amazing,” Robert Yeh, a cardiologist at the Smith Center for Outcomes Research in Cardiology, who was not involved in the study, says. Currently, the best commonly available genetic test for heart disease risk — which looks for a single gene linked to high cholesterol — can only detect increased risk in 0.4 percent of people.

“The big takeaway is that we can now capture the inherited component to heart attack risk with a single number,” Sekar Kathiresan, the Massachusetts General Hospital cardiologist and geneticist who led the study, says. With this new tool, Kathiresan hopes doctors could put those people at higher risk on cholesterol-lowering medications (statins) at an earlier age, or more easily persuade them to make lifestyle changes to lower their risk.

The new tool here is called a polygenic risk score, which you can think of as a tally of the tiny changes in your genome that are correlated with risk of developing a disease.

In the coming years, you’re going to hear a lot more about them. These scores, while increasingly helpful in some areas of medicine, come with a lot of caveats. Indeed, when you dig a bit deeper into this latest Nature Genetics paper, you find there’s a lot more work to do to validate polygenic risk scores for heart disease, so they will be useful and relevant to people around the globe. For one: This study was exclusively conducted with subjects in the UK of white European background. The predictions derived from this group do not necessarily transfer over to another. For this and other reasons, scientists skeptical of polygenic risk scores say they are not yet ready for the clinic — and wonder if they will ever be.

At the same time, it seems likely these polygenic risk scores are going to change the way we think about our health and our medical decision-making.

What’s a polygenic risk score?
Over the past decade, medical researchers have realized that our risk for many common conditions like heart disease and diabetes are not influenced by just one gene, or even a small handful of them. Instead, studies analyzing huge numbers of sequenced human genomes have found that there are hundreds of genes that work in constellation influencing our risk for diseases.

DNA is the recipe for our biology. But it turns out that recipe looks something like an M.C. Escher drawing, with a huge number of genes influencing life outcomes in hard-to-understand, hard-to-follow, interconnected ways.

That is, there can be hundreds of interrelated spots in the genome that are correlated with a person’s risk for heart disease, or raising or lowering their height by a millimeter. Scientists are getting better at identifying these spots in the genome that confer risk and are now trying to figure out if tallying up these genetic changes — in what’s known as a “polygenic risk score” — is useful in trying to predict, and prevent, disease. (They are also calculating them for behavioral traits like educational attainment.)

In developing polygenic risk scores, in many cases, genetics researchers often don’t know what the underlying genes do. All they know is that these genes are correlated with — which does not mean cause — the disease. “It’s pretty mindless,” says Cecile Janssens, an epidemiologist at Emory University who is critical of the hype of polygenic risk scores.

Proponents of polygenic scoring, though, argue that you don’t need to know what the genes are doing to make predictions off them.

“It’s all about getting a predictor and then repeating it in other groups,” Kathiresan says. “At the end of the day, I could just call it a magic number generator. It doesn’t exactly matter how I’m getting there, as long as it works in other groups equally well.”

That’s what happened in this latest paper. A polygenic risk score derived from huge genome-wide association studies predicted heart attack risk in nearly 300,000 people in the UK. (Read more about how scientists come up with polygenic risk scores here.)

How good is the prediction?
Because each change in the genome — called single nucleotide polymorphisms, or SNPs (pronounced “snip”) — confers such a tiny change in risk, adding more and more of them to the risk score yields diminishing returns. “We see this trend already for years — every new SNP that we discover has a smaller effect than we knew already,” Janssens, says.

In the recent Nature Genetics study, she points out, when the researchers increased the number of SNPs in their risk model from 74 to 6 million, the predictive power of the test only increased by a smidgen. Most of those SNPs have a predictive power of approximately zero.

Here’s a chart showing where the polygenic risk score for coronary artery disease matters most. Polygenic scores, like so many human traits, are normally distributed, meaning they follow the pattern of the bell curve. But a person’s risk for coronary artery disease really only starts to increase if they have the very highest number of SNPs that are correlated with heart disease risk. The top 8 percent of the participants had a three times greater risk of heart disease. The top 0.5 percent had five times the risk.

There are many caveats to this risk prediction, which the authors of the study acknowledge. One is that it’s currently unclear if predicting heart attack risk in this manner provides an additional benefit to the risk models derived from asking people simple questions about their lifestyle and family history. The researchers suspect it does, but they didn’t set up their study to test this question.

Another is that this risk model was developed and tested solely on people who had donated their medical and genetic information to the UK Biobank, which contains only genetic data of people of white, European ancestry. The predictive power of these tests is expected to diminish in people of African ancestry, Asian ancestry, and so on. Genetics researchers will need to repeat polygenic risk studies with data from these populations if these predictions are truly going to be useful and equitable.

And yet one more: We shouldn’t take it for granted that intervening with early medication or lifestyle changes for the people at highest risk will make a difference in lowering their risk. Other studies have found that people with higher genetic risk scores for atherosclerosis tend to receive a stronger benefit from statins. But the question needs further testing.

All that said, Yeh, the research cardiologist, says there’s still a lot of optimism around these scores. Current risk factors for heart disease, like high blood pressure or family history, don’t always help single out who truly is most at risk.

“The majority of being who develop coronary artery disease are not people who have a multitude of cardiac risk factors,” Yeh says. “About half of people have just one risk factor, high blood pressure alone. People like that, although they only have one cardiac risk factor, sometimes none, they wouldn’t think of themselves of [having] a very high elevated risk for coronary artery disease.”

A genetic risk factor could help narrow it down.

We’re going to start seeing more and more polygenic tests for disease risk
Polygenic risk scores, says Eric Topol, a cardiologist and geneticist with Scripps Research, “are going to take hold in common medical practice. It’s a matter of when, not if.”

And they’ll be used for conditions outside of heart disease. Indeed, in the latest Nature Genetics study, the researchers also calculated risk scores for diabetes, atrial fibrillation (irregular heart rhythm), inflammatory bowel disease, and breast cancer. The genetic tests for these conditions found fewer people at elevated risk than the tests for heart disease. And not every test will be equally predictive.

Kathiresan points out that while only 8 percent of the study participants were singled out for elevated risk for coronary artery disease, about 20 percent of all the participants were flagged as having elevated risk for at least one of the diseases listed above.

And while these scores are now being generated for all kinds of health and behavioral issues, medicine isn’t really ready to implement them. Huge questions remain. For instance, while it’s possible to do a genetic risk assessment of an infant, or even an embryo, does it make sense or is it even ethical for new parents to learn their embryos or newborns are at a threefold risk for heart disease?

Doctors will also have to think long and hard about how they discuss these kinds of risks with their patients. Scoring in the 70th percentile of risk for coronary artery disease may sound scary, but it won’t increase a person’s chances of getting that disease by all that much.

There are also likely to be unintended consequences of giving patients a new health metric to fear. Consider what happened with cholesterol, a risk factor for heart disease that people began being commonly tested for in the 1980s. Fear of cholesterol came to inspire low-fat food trends. Those dietary trends made food companies money, but they didn’t necessarily make people healthier, especially as many of the foods marketed as low-fat were still loaded with sugar.

What happens when some huckster starts selling vitamins to complement a polygenic risk score, or some other forms of woo? (Currently, you can buy a customized diet guide based on a sequencing of your DNA.) There’s a lot of education that needs to happen here to prevent genetic risk prediction from becoming genetic astrology.

For now, aside from a polygenic risk score for breast cancer, these tests don’t yet exist in the clinic. But they’re going to get easier and easier to discover on your own. If you have your genetics data from a commercial company like 23andMe, you can upload it to a number of sites on the internet to see your risk scores for a slew of traits and diseases. Kathiresan’s team is hoping to build a free tool for people to assess their coronary artery disease risk in this manner.

Here’s a reasonable fear: It’s going to be hard for consumers, without much input from doctors, to know when the risk scores matter and when they do not. Heck, you can currently take a genetics test for intelligence that really won’t tell you anything valuable. It’s possible to develop polygenic risk score for loneliness, baldness, marital status, or really any human trait that is even vaguely influenced by genes. It takes more information — like odds ratios — to know whether those scores really matter in your life.

It will also be hard to know what to do to diminish risk. A high polygenic score for breast cancer might mean a woman wants to make more frequent mammogram appointments, Janssens says. But the current recommendations for people at higher risk of heart disease are things everyone should be doing: living a healthy lifestyle free of tobacco.

“I actually think there’s going to be a whole [medical] field that emerges, kind of like radiology emerged in 1900 with the invention of X-rays,” Kathiresan says, “where [doctors] are basically interpreting that genetic information for medical risk.”

That field needs to start up soon, because there’s a lot more coming.

https://www.vox.com/science-and-health/2018/8/24/17759772/genetics-polygenic-risk-heart-disease-nature

Elephants Revived a “Zombie” Gene that May Fend Off Cancer

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Elephants’ secret to their low rates of cancer might be explained in part by a so-called zombie gene—one that was revived during evolution from a defunct duplicate of another gene. In the face of DNA damage, elephant cells fire up the activity of the zombie gene LIF6 to kill cells, thereby destroying any cancer-causing genetic defects, researchers reported in Cell Reports.

“From an evolutionary biology perspective, it’s completely fascinating,” Joshua Schiffman, a pediatric oncologist at the University of Utah who was not involved in the work, tells National Geographic.

The better-known LIF gene has a number of functions in mammals, including as an extracellular cytokine. In elephants, LIF is duplicated numerous times as pseudogenes, which don’t have the proper sequence to produce functioning transcripts. For the latest study, the researchers wanted to see whether the duplications might have anything to do with elephant cells’ unusual response to DNA damage: indiscriminant destruction.

The team found that one of the pseudogenes, LIF6, evolved after LIF was duplicated in a way that produces a transcript, and that the gene product is controlled by TP53, a tumor suppressor. When the researchers overexpressed LIF6 in elephant cells, the cells underwent apoptosis. The same thing happened with they introduced the gene to Chinese hamster ovary cells, indicating that LIF6 has a role in elephants’ defense against DNA damage.

More work needs to be done to determine whether the LIF6 revival is responsible for elephants’ low cancer rates. There are likely to be other contributors, says coauthor Vincent Lynch, an evolutionary biologist at the University of Chicago, in an interview with The New York Times. “There are lots of stories like LIF6 in the elephant genome, and I want to know them all.”

https://www.the-scientist.com/news-opinion/elephants-revived-a-zombie-gene-that-perhaps-fends-off-cancer-64643

Scientist thinks he has developed a genetic test for heart attack risk and wants to give it away free.

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by Matthew Herper

A Harvard scientist thinks he’s reached a new milestone: a genetic test that helps identify people who are at high risk of having a heart attack. Can he convince doctors to use it?

“I think–in a few years, I think everybody will know this number, similar to the way we know our cholesterol right now,” muses Sekar Kathiresan, director of the Cardiovascular Disease Initiative at the Broad institute and a professor at Harvard Medical School.

Not everyone else is so sure. “I think it’s a brilliant approach,” says Harlan Krumholz, the Harold H. Hines Jr. professor of cardiology at Yale University and one of Kathiresan’s collaborators. But he worries about whether Kathiresan’s tests are ready to compete with the plethora of diagnostic tests, from AI-boosted CT scans to new types of “bad” cholesterol proteins, that are on offer. And he worries about cost. There is no commercial version of the gene test. But the very idea that such a test is not only available, but also near, is the result of a cresting wave of new genetic science, the result of large efforts to gather genetic information from millions of volunteers.

The number in question is what is called a polygenic risk score. Instead of looking for one miswritten gene that causes heart attacks, or, for that matter, other health problems, geneticists are increasingly looking at thousands of genetic alterations without even being sure what each does. In the case of Kathiresan’s polygenic score, the test looks for 6.6 million single-letter genetic changes that are more prevalent in people who have had early heart attacks.

Our genetic inheritances, the current thinking goes, are not so much a set of declarative orders as a cacophony of noise. There are big genetic changes that can have a big effect, but most diseases are the result of lots of tiny changes that add up. In Kathiresan’s words, it’s mostly a gemish (Yiddish for “a mixture”). And it’s not clear which changes are biologically important – Kathiresan says only 6,000 or so of the 6.6 million genetic changes are probably actually causing heart attacks. But finding those specific changes will take a long time. The risk score could be used now.

The effect of this genetic cacophony can be huge. The most common single mutation that increases the risk of heart disease is a gene that causes a disease called heterozygous familial hypercholesterolemia (literally: inherited high cholesterol) that occurs in one person in 250 and triple’s a person’s risk of having a heart attack. But today, in a paper in Nature Genetics, Kathiresan and his colleagues present data that 5% to 8% have a polygenic score that also at least triples their risk of having a heart attack. That’s about 20 times as many people, Kathiresan says.

“These patients are currently unaware of their risk because the polygenic patients don’t have higher levels of the usual risk factors,” Kathiresan says. “Their cholesterol is not high. Their blood pressure is not that high. They are hidden from the current risk assessment tools.”

In the Nature Genetics paper, Kathiresan’s team tested the 6-million-variant polygenic score in two groups of patients numbering, respectively, 120,280 and 288,978 people, from the U.K. BioBank, a government-backed effort in the United Kingdom to collect genetic data. For some patients, the risk was even higher, with the genetic changes predicting a fivefold increase in heart attack risk. The paper also argues that polygenic risk scores could be used to predict risk of conditions such as type 2 diabetes and breast cancer.

Another study, yet to be published, looked at the prevalence of both familial hypercholesterolemia and the polygenic score in a population of people who had heart attacks in their 40s and 50s, Katherisan says. Only 2% had familial hypercholesterolemia, but 20% had a high polygenic risk score. Knowing one’s polygenic risk score might matter. A 2016 paper in the New England Journal of Medicine showed that people with high polygenic scores had fewer heart attacks if they had healthier lifestyles, and a 2017 paper in the medical journal Circulation showed that patients with high polygenic risk scores got an outsize benefit from cholesterol-lowering statin drugs. Those papers, both by Kathiresan’s group, used a score that included only a few dozen gene variants.

Doctors should be skeptical of such a test. There’s a long history of tests in medicine that have done more harm than good by leading to people to take drugs they do not need. Cardiologists have gotten used to even higher standards for data. For instance, many might want to see if the test can show a benefit in a large study in which people are tested at random. Many will want more evidence that the test can identify people at high risk they’d otherwise miss, as Kathiresan says, and that it doesn’t lead to treatment in those who don’t need it. Kathiresan says he hopes to do a study in the highest-risk individuals to prove that statin drugs can lower their risk. If the test becomes a commercial prospect, more studies will drive up the eventual cost.

Kathiresan is hoping to follow a less expensive path. He notes that 17 million people have already used genotyping services like 23andMe and Ancestry. He hopes that people who use those services (23andMe costs $99, Ancestry $59) will submit their data to a portal he’ll build for free. He also says he’s in discussions with commercial providers, but he’s hoping that people will be able to get their polygenic scores for about as much as the cost of a cholesterol test. For the people at the highest risk, he argues, this is information that could be important. For others, he argues, why deny people information that has been scientifically validated?

Whether Kathiresan can really pull off a low-cost version in a medical system that is optimized to make money is as big a question as whether the test is ready for prime time. Krumholz worried about the cost of the test until a reporter told him of Kathiresan’s planned website. “If you say it’s free, I’m going, ‘Why not?'” Krumholz says. “It’s a better family history,” he says, comparing the test to asking whether a relative has had a heart attack. But that may be the biggest ‘if’. If anything is more puzzling than genetics, it is the economics of healthcare in the U.S.A.
https://www.forbes.com/sites/matthewherper/2018/08/13/a-harvard-scientist-thinks-he-has-a-gene-test-for-heart-attack-risk-he-wants-to-give-it-away-free/#557490e85959

Reducing NOVA1 gene helps prevent tumor growth in most common type of lung cancer

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Lung cancer seen on chest X ray.

Researchers have identified a gene that when inhibited or reduced, in turn, reduced or prevented human non-small cell lung cancer tumors from growing.

When mice were injected with non-small cell lung cancer cells that contained the gene NOVA1, three of four mice formed tumors. When the mice were injected with cancer cells without NOVA1, three of four mice remained tumor-free.

The fourth developed a tumor, but it was very small compared to the mice with the NOVA1 tumor cells, said Andrew Ludlow, first author on the study and assistant professor at the University of Michigan School of Kinesiology.

The research appears online today in Nature Communications. Ludlow did the work while a postdoctoral fellow at the University of Texas Southwestern Medical Center, in the shared lab of Woodring Wright, professor of cell biology and internal medicine, and Jerry Shay, professor of cell biology.

The study found that in cancer cells, the NOVA1 gene is thought to activate telomerase, the enzyme that maintains telomeres—the protective caps on the ends of chromosomes that preserve genetic information during cell division (think of the plastic aglets that prevent shoelace ends from fraying).

Telomerase isn’t active in healthy adult tissues, so telomeres degrade and shorten as we age. When they get too short, the body knows to remove those damaged or dead cells.

In most cancers, telomerase is reactivated and telomeres are maintained, thus preserving the genetic material, and these are the cells that mutate and become immortal.

Telomerase is present in most cancer types, and it’s an attractive therapeutic target for cancer. However, scientists haven’t had much luck inhibiting telomerase activity in cancer, Ludlow said.

Ludlow’s group wanted to try a new approach, so they screened lung cancer cell lines for splicing genes (genes that modify RNA) that might regulate telomerase in cancer, and identified NOVA1.

They found that reducing the NOVA1 gene reduced telomerase activity, which led to shorter telomeres, and cancer cells couldn’t survive and divide.

Researchers only looked at non-small cell lung cancers, and NOVA1 was present in about 70 percent of them.

“Non-small cell lung cancer is the most prevalent form of age-related cancer, and 80 to 85 percent of all lung cancers are non-small cell,” Ludlow said. “But there really aren’t that many treatments for it.”

According to the American Cancer Society, lung cancer causes the most cancer deaths among men and women, and is the second most common cancer, aside from skin cancer.

Before researchers can target NOVA1 or telomerase splicing as a serious potential therapy for non-small cell lung cancer, they must gain a much better understanding of how telomerase is regulated. This research is a step in that direction.

Ludlow’s group is also looking at ways to directly impact telomerase splicing, in addition to reducing NOVA1.

Explore further: Blocking two enzymes could make cancer cells mortal

More information: Andrew T. Ludlow et al, NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer, Nature Communications (2018). DOI: 10.1038/s41467-018-05582-x

https://medicalxpress.com/news/2018-08-nova1-gene-tumor-growth-common.html

Faulty Gene Leads to Alcohol-Induced Heart Failure

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Scientists have revealed a new link between alcohol, heart health and our genes.

The researchers investigated faulty versions of a gene called titin which are carried by one in 100 people or 600,000 people in the UK.

Titin is crucial for maintaining the elasticity of the heart muscle, and faulty versions are linked to a type of heart failure called dilated cardiomyopathy.

Now new research suggests the faulty gene may interact with alcohol to accelerate heart failure in some patients with the gene, even if they only drink moderate amounts of alcohol.

The research was carried out by scientists from Imperial College London, Royal Brompton Hospital, and MRC London Institute of Medical Sciences, and published this week in the latest edition of the Journal of the American College of Cardiology.

The study was supported by the Department of Health and Social Care and the Wellcome Trust through the Health Innovation Challenge Fund.

In the first part of the study, the team analysed 141 patients with a type of heart failure called alcoholic cardiomyopathy (ACM). This condition is triggered by drinking more than 70 units a week (roughly seven bottles of wine) for five years or more. In severe cases the condition can be fatal, or leave patients requiring a heart transplant.

The team found that the faulty titin gene may also play a role in the condition. In the study 13.5 per cent of patients were found to carry the mutation – much higher than the proportion of people who carry them in the general population.

These results suggest this condition is not simply the result of alcohol poisoning, but arises from a genetic predisposition – and that other family members may be at risk too, explained Dr James Ware, study author from the National Heart and Lung Institute at Imperial.

“Our research strongly suggests alcohol and genetics are interacting – and genetic predisposition and alcohol consumption can act together to lead to heart failure. At the moment this condition is assumed to be simply due to too much alcohol. But this research suggests these patients should also be checked for a genetic cause – by asking about a family history and considering testing for a faulty titin gene, as well as other genes linked to heart failure,” he said.

He added that relatives of patients with ACM should receive assessment and heart scans – and in some cases have genetic tests – to see if they unknowingly carry the faulty gene.

In a second part of the study, the researchers investigated whether alcohol may play a role in another type of heart failure called dilated cardiomyopathy (DCM). This condition causes the heart muscle to become stretched and thin, and has a number of causes including viral infections and certain medications. The condition can also be genetic, and around 12 per cent of cases of DCM are thought to be linked to a faulty titin gene.

In the study the team asked 716 patients with dilated cardiomyopathy how much alcohol they consumed.

None of the patients consumed the high-levels of alcohol needed to cause ACM. But the team found that in patients whose DCM was caused by the faulty titin gene, even moderately increased alcohol intake (defined as drinking above the weekly recommended limit of 14 units), affected the heart’s pumping power.

Compared to DCM patients who didn’t consume excess alcohol (and whose condition wasn’t caused by the faulty titin gene), excess alcohol was linked to reduction in heart output of 30 per cent.

More research is now needed to investigate how alcohol may affect people who carry the faulty titin gene, but do not have heart problems, added Dr Paul Barton, study co-author from the National Heart and Lung Institute at Imperial:

“Alcohol and the heart have a complicated relationship. While moderate levels may have benefits for heart health, too much can cause serious cardiac problems. This research suggests that in people with titin-related heart failure, alcohol may worsen the condition.

“An important wider question is also raised by the study: do mutations in titin predispose people to heart failure when exposed to other things that stress the heart, such as cancer drugs or certain viral infections? This is something we are actively seeking to address.”

The research was supported by the Department of Health and Social Care and Wellcome Trust through the Health Innovation Challenge Fund, the Medical Research Council, the NIHR Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust and the British Heart Foundation.

Reference: Ware, J. S., Amor-Salamanca, A., Tayal, U., Govind, R., Serrano, I., Salazar-Mendiguchía, J., … Garcia-Pavia, P. (2018). Genetic Etiology for Alcohol-Induced Cardiac Toxicity. Journal of the American College of Cardiology, 71(20), 2293–2302. https://doi.org/10.1016/j.jacc.2018.03.462

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Genetic basis of synethesia shown to relate to ability of neurons to form connections in the brain

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By Tereza Pultarova

About 4 percent of the people on Earth experience a mysterious phenomenon called synesthesia: They hear a sound and automatically see a color; or, they read a certain word, and a specific hue enters their mind’s eye. The condition has long puzzled scientists, but a small new study may offer some clues.

The study, published March 5 in the journal Proceedings of the National Academy of Sciences, offers insight into what might be happening in the brains of people with synesthesia.

Previous “studies of brain function using magnetic resonance imaging confirm that synesthesia is a real biological phenomenon,” said senior study author Simon Fisher, director of the Max Planck Institute for Psycholinguistics in the Netherlands. For example, when people with synesthesia “hear” color, brain scans show that there’s activity in the parts of the brain linked to both sight and sound, he said. (Not all people with the condition “hear” sights, however; the condition can also link other senses.)Indeed, the brains of people with synesthesia previously have been shown to be more connected across different regions than the brains of people whose senses are not cross-linked, Fisher told Live Science. The question, however, was what causes this different brain wiring, he said.

To answer that question, Fisher and his team looked to genetics.

Synesthesia frequently runs in families, so the researchers decided to look for genes that might be responsible for the development of the condition. They chose three families, in which multiple members across at least three generations had a specific type of synesthesia, the so-called sound-color synesthesia, meaning that hearing sounds evokes perceptions of colors. Typically, a specific sound or musical tone is consistently associated with a specific color for people who have this type of synesthesia. However, different members of a single family can see different colors when hearing the same sound, Fisher said.

The scientists used DNA sequencing to study the participants’ genes, Fisher said. Then, to identify genes that might be responsible for the condition, the scientists compared the genes of family members with synesthesia to the genes of family members without it, he said.

But the findings didn’t yield a straightforward result: “There was not a single gene that could explain synesthesia in all three families,” Fisher said. Instead, “there were 37 candidate variants,” or possible gene variations, he said.

Because the study included only a small number of people, there wasn’t enough data to single out the specific genes, of the 37 possibilities, that played a role in synesthesia. So, instead, the scientists looked at the biological functions of each gene to see how it could be related to the development of the condition. “There were just a few biological themes that were significantly enriched across the candidate genes identified,” Fisher said. “One of those was axonogenesis, a crucial process helping neurons get wired up to each other in the developing brain.” Axonogenesis refers to the development of neurons.

This is consistent with prior findings of altered connectivity in brain scans of people with synesthesia, Fisher said. In other words, the genes identified in the study play a role in how the brain is wired, offering a potential explanation for why the brains of people with synesthesia appear to be wired differently.

https://www.livescience.com/61930-synesthesia-hear-colors-genes.html

Identification of genes that are involved in age-related brain deterioration

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A group of genes and genetic switches involved in age-related brain deterioration have been identified by scientists at the Babraham Institute, Cambridge and Sapienza University, Rome. The research, published online today (5th March) in Aging Cell, found that changes to one of these genes, called Dbx2, could prematurely age brain stem cells, causing them to grow more slowly. The study was led jointly by Giuseppe Lupo and Emanuele Cacci in Italy and Peter Rugg-Gunn in the UK.

Cells in the brain are constantly dying and being replaced with new ones produced by brain stem cells. As we age, it becomes harder for these stem cells to produce new brain cells and so the brain slowly deteriorates. By comparing the genetic activity in brain cells from old and young mice, the scientists identified over 250 genes that changed their level of activity with age. Older cells turn some genes, including Dbx2, on and they turn other genes off.

By increasing the activity of Dbx2 in young brain stem cells, the team were able to make them behave more like older cells. Changes to the activity of this one gene slowed the growth of brain stem cells. These prematurely aged stem cells are not the same as old stem cells but have many key similarities. This means that many of the genes identified in this study are likely to have important roles in brain ageing.

The research also identified changes in several epigenetic marks – a type of genetic switch – in the older stem cells that might contribute to their deterioration with age. Epigenetic marks are chemical tags attached to the genome that affect the activity of certain genes. The placement of these marks in the genome change as we age and this alters how the cells behave. The researchers think that some of these changes that happen in the brain may alter causing brain stem cells to grow more slowly.

First author on the paper, Dr Giuseppe Lupo, Assistant Professor at Sapienza University said: “The genes and gene regulators that we identified are corrupted in neural stem cells from older mice. By studying the Dbx2 gene we have shown that these changes may contribute to ageing in the brain by slowing the growth of brain stem cells and by switching on the activity of other age-associated genes.”

Co-lead scientist Dr Peter Rugg-Gunn at the Babraham Institute said: “Ageing ultimately affects all of us and the societal and healthcare burden of neurodegenerative diseases is enormous. By understanding how ageing affects the brain, at least in mice, we hope to identify ways to spot neural stem cell decline. Eventually, we may find ways to slow or even reverse brain deterioration – potentially by resetting the epigenetic switches – helping more of us to stay mentally agile for longer into old age.”

Co-lead scientist Dr Emanuele Cacci at Sapienza University said: “We hope this research will lead to benefits for human health. We have succeeded in accelerating parts of the ageing process in neural stem cells. By studying these genes more closely, we now plan to try turning back the clock for older cells. If we can do this in mice, then the same thing could also be possible for humans.”

This article has been republished from materials provided by the Babraham Institute. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference: Lupo, G., Nisi, P. S., Esteve, P., Paul, Y.-L., Novo, C. L., Sidders, B., … Rugg-Gunn, P. J. (n.d.). Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. Aging Cell, n/a-n/a. https://doi.org/10.1111/acel.12745

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