CRISPR-Cas9 technique targeting epigenetics reverses disease in mice

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Much of the enthusiasm around gene-editing techniques, particularly the CRISPR-Cas9 technology, centers on the ability to insert or remove genes or to repair disease-causing mutations. A major concern of the CRISPR-Cas9 approach, in which the double-stranded DNA molecule is cut, is how the cell responds to that cut and how it is repaired. With some frequency, this technique leaves new mutations in its wake with uncertain side effects.

In a paper appearing in the journal Cell on December 7, scientists at the Salk Institute report a modified CRISPR-Cas9 technique that alters the activity, rather than the underlying sequence, of disease-associated genes. The researchers demonstrate that this technique can be used in mice to treat several different diseases.

“Cutting DNA opens the door to introducing new mutations,” says senior author Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Studies whose laboratory developed the new technique. “That is something that is going to stay with us with CRISPR or any other tool we develop that cuts DNA. It is a major bottleneck in the field of genetics — the possibility that the cell, after the DNA is cut, may introduce harmful mistakes.”

That fact guided every experiment in the Belmonte lab as they developed the technique using a modified CRISPR-Cas9 system that does not cut the DNA. Their findings are the first to provide evidence that one can alter the phenotype of an animal with a epigenetic editing technology, preserving DNA integrity.

The principal idea behind the Salk technique is the use of two adeno-associated viruses (AAVs) as the machinery to introduce their genetic manipulation machinery to cells in post-natal mice. The researchers inserted the gene for the Cas9 enzyme into one AAV virus. They used another AAV virus to introduce a short single guide RNA (sgRNA), which specifies the precise location in the mouse genome where Cas9 will bind, and a transcriptional activator. The shorter sgRNA is only 14 or 15 nucleotides compared with the standard 20 nucleotides used in most CRISPR-Cas9 techniques, and this prevents Cas9 from cutting the DNA.

“Basically, we used the modified guide RNA to bring a transcriptional activator to work together with the Cas9 and delivered that complex to the region of the genome we were interested in,” says co-first author Hsin-Kai Liao of the Belmonte laboratory.

The complex sits in the region of DNA of interest and promotes expression of a gene of interest. Similar techniques could be used to activate virtually any gene or genetic pathway without the risk of introducing potentially harmful mutations.

“We wanted to change the cell fate with therapeutic efficiency without a DNA cut,” co-first author Fumiyuki Hatanaka explains.

Strikingly, the team demonstrated disease reversal in several disease models in mice. In a mouse model of acute kidney disease, they showed that the technique activated previously damaged or silenced genes to restore normal kidney function. They were also able to induce some liver cells to differentiate into pancreatic ?-like cells, which produce insulin, to partially rescue a mouse model of type 1 diabetes.

The team also showed that they could recover muscle growth and function in mouse models of muscular dystrophy, a disease with a known gene mutation. Instead of trying to correct the mutated gene, the researchers increased the expression of genes in the same pathway as the mutated gene, over-riding the effect of the damaged gene. “We are not fixing the gene; the mutation is still there,” says Belmonte, “Instead, we are working on the epigenome and the mice recover the expression of other genes in the same pathway. That is enough to recover the muscle function of these mutant mice.”

Preliminary data suggest that the technique is safe and does not produce unwanted genetic mutations. However, the researchers are pursuing further studies to ensure safety, practicality, and efficiency before considering bringing it to a clinical environment.

Belmonte sees this technology as a way of potentially treating neurological disorders such as Alzheimer’s and Parkinson’s diseases. Just as the technique restored kidney, muscle, and insulin-producing function in the mouse models, he sees a future for rejuvenating neuronal populations.

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Black holes’ magnetism surprisingly wimpy

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Black holes are famous for their muscle: an intense gravitational pull known to gobble up entire stars and launch streams of matter into space at almost the speed of light.

It turns out the reality may not live up to the hype.

In a paper published today in the journal Science, University of Florida scientists have discovered these tears in the fabric of the universe have significantly weaker magnetic fields than previously thought.

A 40-mile-wide black hole 8,000 light years from Earth named V404 Cygni yielded the first precise measurements of the magnetic field that surrounds the deepest wells of gravity in the universe.

The measurements bring scientists closer to understanding how black holes’ magnetism works, deepening our knowledge of how matter behaves under the most extreme conditions — knowledge that could broaden the limits of nuclear fusion power and GPS systems.

The measurements also will help scientists solve the half-century-old mystery of how “jets” of particles traveling at nearly the speed of light shoot out of black holes’ magnetic fields, while everything else is sucked into their abysses, said study co-author Stephen Eikenberry, a professor of astronomy in UF’s College of Liberal Arts and Sciences.

“The question is, how do you do that?” Eikenberry said. “Our surprisingly low measurements will force new constraints on theoretical models that previously focused on strong magnetic fields accelerating and directing the jet flows. We weren’t expecting this, so it changes much of what we thought we knew.”

Study authors developed the measurements from data collected in 2015 during a black hole’s rare outburst of jets. The event was observed through the lens mirror of the 34-foot Gran Telescopio Canarias, the world’s largest telescope, co-owned by UF and located in Spain’s Canary Islands, with the help of its UF-built infrared camera named CIRCE (Canarias InfraRed Camera Experiment).

Smaller jet-producing black holes, like the one observed for the study, are the rock stars of galaxies. Their outbursts occur suddenly and are short-lived, said study lead author Yigit Dalilar and co-author Alan Garner, doctoral students in UF’s astronomy department. The 2015 outbursts of V404 Cygni lasted only a couple of weeks. The previous time the same black hole had a similar episode was in 1989.

“To observe it was something that happens once or twice in one’s career,” Dalilar said. “This discovery puts us one step closer to understanding how the universe works.”

The world’s smallest Mona Lisa

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In 2006, Caltech’s Paul Rothemund (BS ’94)  now research professor of bioengineering, computing and mathematical sciences, and computation and neural systems — developed a method to fold a long strand of DNA into a prescribed shape. The technique, dubbed DNA origami, enabled scientists to create self-assembling DNA structures that could carry any specified pattern, such as a 100-nanometer-wide smiley face.

DNA origami revolutionized the field of nanotechnology, opening up possibilities of building tiny molecular devices or “smart” programmable materials. However, some of these applications require much larger DNA origami structures.

Now, scientists in the laboratory of Lulu Qian, assistant professor of bioengineering at Caltech, have developed an inexpensive method by which DNA origami self-assembles into large arrays with entirely customizable patterns, creating a sort of canvas that can display any image. To demonstrate this, the team created the world’s smallest recreation of Leonardo da Vinci’s Mona Lisa — out of DNA.

The work is described in a paper appearing in the December 7 issue of the journal Nature.

While DNA is perhaps best known for encoding the genetic information of living things, the molecule is also an excellent chemical building block. A single-stranded DNA molecule is composed of smaller molecules called nucleotides — abbreviated A, T, C, and G — arranged in a string, or sequence. The nucleotides in a single-stranded DNA molecule can bond with those of another single strand to form double-stranded DNA, but the nucleotides bind only in very specific ways: an A nucleotide with a T or a C nucleotide with a G. These strict base-pairing “rules” make it possible to design DNA origami.

To make a single square of DNA origami, one just needs a long single strand of DNA and many shorter single strands — called staples — designed to bind to multiple designated places on the long strand. When the short staples and the long strand are combined in a test tube, the staples pull regions of the long strand together, causing it to fold over itself into the desired shape. A large DNA canvas is assembled out of many smaller square origami tiles, like putting together a puzzle. Molecules can be selectively attached to the staples in order to create a raised pattern that can be seen using atomic force microscopy.

The Caltech team developed software that can take an image such as the Mona Lisa, divide it up into small square sections, and determine the DNA sequences needed to make up those squares. Next, their challenge was to get those sections to self-assemble into a superstructure that recreates the Mona Lisa.

“We could make each tile with unique edge staples so that they could only bind to certain other tiles and self-assemble into a unique position in the superstructure,” explains Grigory Tikhomirov, senior postdoctoral scholar and the paper’s lead author, “but then we would have to have hundreds of unique edges, which would be not only very difficult to design but also extremely expensive to synthesize. We wanted to only use a small number of different edge staples but still get all the tiles in the right places.”

The key to doing this was to assemble the tiles in stages, like assembling small regions of a puzzle and then assembling those to make larger regions before finally putting the larger regions together to make the completed puzzle. Each mini puzzle utilizes the same four edges, but because these puzzles are assembled separately, there is no risk, for example, of a corner tile attaching in the wrong corner. The team has called the method “fractal assembly” because the same set of assembly rules is applied at different scales.

“Once we have synthesized each individual tile, we place each one into its own test tube for a total of 64 tubes,” says Philip Petersen, a graduate student and co-first author on the paper. “We know exactly which tiles are in which tubes, so we know how to combine them to assemble the final product. First, we combine the contents of four particular tubes together until we get 16 two-by-two squares. Then those are combined in a certain way to get four tubes each with a four-by-four square. And then the final four tubes are combined to create one large, eight-by-eight square composed of 64 tiles. We design the edges of each tile so that we know exactly how they will combine.”

The Qian team’s final structure was 64 times larger than the original DNA origami structure designed by Rothemund in 2006. Remarkably, thanks to the recycling of the same edge interactions, the number of different DNA strands required for the assembly of this DNA superstructure was about the same as for Rothemund’s original origami. This should make the new method similarly affordable, according to Qian.

“The hierarchical nature of our approach allows using only a small and constant set of unique building blocks, in this case DNA strands with unique sequences, to build structures with increasing sizes and, in principle, an unlimited number of different paintings,” says Tikhomirov. “This economical approach of building more with less is similar to how our bodies are built. All our cells have the same genome and are built using the same set of building blocks, such as amino acids, carbohydrates, and lipids. However, via varying gene expression, each cell uses the same building blocks to build different machinery, for example, muscle cells and cells in the retina.”

The team also created software to enable scientists everywhere to create DNA nanostructures using fractal assembly.

“To make our technique readily accessible to other researchers who are interested in exploring applications using micrometer-scale flat DNA nanostructures, we developed an online software tool that converts the user’s desired image to DNA strands and wet-lab protocols,” says Qian. “The protocol can be directly read by a liquid-handling robot to automatically mix the DNA strands together. The DNA nanostructure can be assembled effortlessly.”

Using this online software tool and automatic liquid-handling techniques, several other patterns were designed and assembled from DNA strands, including a life-sized portrait of a bacterium and a bacterium-sized portrait of a rooster.

“Other researchers have previously worked on attaching diverse molecules such as polymers, proteins, and nanoparticles to much smaller DNA canvases for the purpose of building electronic circuits with tiny features, fabricating advanced materials, or studying the interactions between chemicals or biomolecules,” says Petersen. “Our work gives them an even larger canvas to draw upon.”

The paper is titled “Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns.” The work was funded by the Burroughs Wellcome Fund, the National Institutes of Health’s National Research Service Award, and the National Science Foundation.

Synchrotron sheds light on the amphibious lifestyle of a new raptorial dinosaur

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An exceptionally well-preserved dinosaur skeleton from Mongolia unites an unexpected combination of features that defines a new group of semi-aquatic predators related to Velociraptor. Detailed 3D synchrotron analysis allowed an international team of researchers to present the bizarre 75 million-year-old predator, named Halszkaraptor escuilliei, in Nature. The study not only describes a new genus and species of bird-like dinosaur that lived during the Campanian stage of the Cretaceous in Mongolia but also sheds light on an unexpected amphibious lifestyle for raptorial dinosaurs.

Theropods encompass all carnivorous dinosaurs, including the largest land-living predators in the history of life on Earth, such as Tyrannosaurus, and iconic agile hunters like Velociraptor. During 160 million years of the Mesozoic Era, theropods became the dominant predators on all continents, yet never conquered aquatic environments. Although some theropods reportedly incorporated fish in their diet, proposed indications for aquatic locomotion associated with exclusively aquatic lifestyles remain controversial.

A swan-necked and flipper-forelimbed new dinosaur species that combines an unexpected mix of features now demonstrates that some bird-like dinosaurs did adopt a semi-aquatic lifestyle. The fossil, nicknamed “Halszka” for Halszkaraptor escuilliei, was found at Ukhaa Tolgod. This locality in southern Mongolia has been known by palaeontologists for decades and is often targeted by poachers. “Illicit fossil trade presents a great challenge to modern palaeontology and accounts for a dramatic loss of Mongolian scientific heritage,” says Pascal Godefroit of the Royal Belgian Institute of Natural Sciences in Brussels. “Illegally exported from Mongolia, Halszka resided in private collections around the world before it was acquired in 2015 and offered to palaeontologists for study and to prepare its return to Mongolia.”

Although several important groups of predatory dinosaurs have been discovered in Mongolia, Halszka does not belong to any of them, having a number of strange features that are mostly absent among dinosaurs, but are shared by reptilian and avian groups with aquatic or semiaquatic ecologies. “The first time I examined the specimen, I even questioned whether it was a genuine fossil” says Andrea Cau of the Geological Museum Capellini in Bologna. Although Halszka is unique in many ways, certain parts of the skeleton, including the sickle-shaped “killer claws” on its feet, are shared with well-known dinosaurs such as Velociraptor. “This unexpected mix of traits makes it difficult to place Halszka within traditional classifications,” Cau remarks.

In order to ascertain the integrity of the fossil, the specimen was visualised and reconstructed in three dimensions using synchrotron multi-resolution X-ray microtomography. “This technique is currently the most powerful and sensitive method to image internal details without damaging invaluable fossils. The ESRF has become the worldwide leader for high quality X-ray imaging of such precious specimens,” notes Paul Tafforeau of the ESRF. “We had to mobilise an ESRF team of palaeontologists to study the complete anatomy of Halzka. So far, it’s the specimen for which the greatest number of experiments were made on a single fossil,” adds Tafforeau.

“Our first goal was to demonstrate that this bizarre and unexpected fossil is indeed a genuine animal: multi-resolution scanning confirmed that the skeleton is not a composite assembled from parts of different dinosaurs,” explains Dennis Voeten of the ESRF. “We implemented new methods for the acquisition and optimisation of tomographic scan data, which not only confirmed the integrity of the specimen, but also revealed additional palaeontological information,” Vincent Fernandez of the ESRF clarifies.

The synchrotron was even able to reveal, in astonishing detail, those parts of the skeleton that have remained deep within the rock ever since the dinosaur got buried. “Our analysis demonstrated that numerous teeth, which are not visible externally, are still preserved inside the mouth,” says Vincent Beyrand of the ESRF. “We also identified a neurovascular mesh inside its snout that resembles those of modern crocodiles to a remarkable degree. These aspects suggest that Halszka was an aquatic predator.”

The ESRF data revealed that the fossil represents a new genus and species of amphibious dinosaur that walked on two legs on land, with postural adaptations similar to short-tailed birds (like ducks), but used its flipper-like forelimbs to manoeuvre in water (like penguins and other aquatic birds), relying on its long neck for foraging and ambush hunting.

This new species was named Halszkaraptor escuilliei. Its generic name honours the late palaeontologist Halszka Osmólska. “This important genus is named in recognition of Halszka’s contribution to the study of Mongolian dinosaurs from the Gobi,” comments Rinchen Barsbold of the Mongolian Academy of Sciences. “The specific name refers to François Escuillié and thereby acknowledges his role in the first recognition and in the return of this specimen to Mongolia,” adds Khishigjav Tsogtbaatar of the Institute of Paleontology and Geology in Ulaanbaatar.

Halszkaraptor is not the only strange dinosaur recovered from the Gobi. Several previously described enigmatic Mongolian theropods were closely related to the new species, the study found. United in a new group, named Halszkaraptorinae, “is an unexpected subfamily of dromaeosaurs — the group colloquially known as raptors. This bizarre subfamily appears to have evolved a lifestyle different from all other predatory dinosaurs,” says Philip Currie of the University of Alberta.

“When we look beyond fossil dinosaurs, we find most of Halszkaraptor’s unusual features among aquatic reptiles and swimming birds,” concludes lead author Andrea Cau. “The peculiar morphology of Halszkaraptor fits best with that of an amphibious predator that was adapted to a combined terrestrial and aquatic ecology: a peculiar lifestyle that was previously unreported in these dinosaurs. Thanks to synchrotron tomography, we now demonstrate that raptorial dinosaurs not only ran and flew, but also swam!”

Harmful effects of being overweight underestimated

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The harmful effects of being overweight have been underestimated, according to a new study that analysed body mass index (BMI), health and mortality data in around 60,000 parents and their children, to establish how obesity actually influences risk of death.

Previous studies have suggested that the optimum BMI, at which the risk of death is minimised, appears to be above the range normally recommended by doctors, leading to claims it is good for health to be mildly overweight. However, scientists suspect these studies do not reflect the true effect of BMI on health, because early stages of illness, health-damaging behaviours, such as cigarette smoking, and other factors can lead to both lower BMI and increased risk of death. This makes it difficult to estimate how BMI actually influences risk of death (the causal effect), as opposed to the observed association between BMI and risk of death. This aim of this study was to assess the causal link between BMI and risk of death.

Using HUNT, a Norwegian population-based health cohort study based in a rural county with 130,000 residents, the Bristol Medical School team, with co-workers from the Norwegian University of Science and Technology, were able to see how mortality in the parents related to both their own BMI (the conventional approach) and to the BMI of their adult children. Because BMI of parents and their offspring is related, due to genetic factors, offspring BMI is an indicator of the BMI of the parents. The BMI of adult children is not influenced by illness among the parents, therefore using offspring BMI avoids the problems inherent in simply relating the BMI of the parents to their risk of death.

The health records of around 30,000 mother and child pairs and 30,000 father and child pairs were assessed to examine the extent to which BMI may influence mortality risk in a situation that is not biased by “reverse causation”illness leading to low BMI rather than BMI influencing illness.

The team found that when offspring BMI was used instead of the parent’s own BMI, the apparent harmful effects of low BMI were reduced and the harmful effects of high BMI were greater than those found in the conventional analyses. Importantly, the results suggest that previous studies have underestimated the harmful effects of being overweight.

The current advice from doctors to maintain a BMI of between 18.5 and 25 is supported by this study, and the widely reported suggestion that being overweight may be healthy is shown to be incorrect.

Dr David Carslake, the study’s lead author and Senior Research Associate from the MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, said: “An alarming increase in obesity levels across the world which have risen from 105 million in 1975 to 641 million in 2014, according to a recent Lancet study, create concern about the implications for public health.

“This study demonstrates that correlation is not causation and that when it comes to public health recommendations we need to be cautious interpreting data based on associations alone. We found that previous studies have underestimated the impact of being overweight on mortality and our findings support current advice to maintain a BMI of between 18.5 and 25.”

Professor George Davey Smith, Director of the MRC IEU and Professor of Clinical Epidemiology at the University of Bristol, added: “We are used to seeing conflicting studies purporting to show that something is either good or bad for our health. These generally come from naïve observational studies, which can produce seriously misleading findings. More robust approaches for identifying the causal effects of factors influencing health, such as the methods applied in this study, are required if we are to make recommendations for public health based on reliable evidence.”

Holding infants or not can leave traces on their genes

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The amount of close and comforting contact between infants and their caregivers can affect children at the molecular level, an effect detectable four years later, according to new research from the University of British Columbia and BC Children’s Hospital Research Institute.

The study showed that children who had been more distressed as infants and had received less physical contact had a molecular profile in their cells that was underdeveloped for their age — pointing to the possibility that they were lagging biologically.

“In children, we think slower epigenetic aging might indicate an inability to thrive,” said Michael Kobor, a Professor in the UBC Department of Medical Genetics who leads the “Healthy Starts” theme at BC Children’s Hospital Research Institute.

Although the implications for childhood development and adult health have yet to be understood, this finding builds on similar work in rodents. This is the first study to show in humans that the simple act of touching, early in life, has deeply-rooted and potentially lifelong consequences on genetic expression.

The study, published last month in Development and Psychopathology, involved 94 healthy children in British Columbia. Researchers from UBC and BC Children’s Hospital asked parents of 5-week-old babies to keep a diary of their infants’ behavior (such as sleeping, fussing, crying or feeding) as well as the duration of caregiving that involved bodily contact. When the children were about 4 1/2 years old, their DNA was sampled by swabbing the inside of their cheeks.

The team examined a biochemical modification called DNA methylation, in which some parts of the chromosome are tagged with small molecules made of carbon and hydrogen. These molecules act as “dimmer switches” that help to control how active each gene is, and thus affect how cells function.

The extent of methylation, and where on the DNA it specifically happens, can be influenced by external conditions, especially in childhood. These epigenetic patterns also change in predictable ways as we age.

Scientists found consistent methylation differences between high-contact and low-contact children at five specific DNA sites. Two of these sites fall within genes: one plays a role in the immune system, and the other is involved in metabolism. However, the downstream effects of these epigenetic changes on child development and health aren’t known yet.

The children who experienced higher distress and received relatively little contact had an “epigenetic age” that was lower than would be expected, given their actual age. Such a discrepancy has been linked to poor health in several recent studies.

“We plan on following up to see whether the ‘biological immaturity’ we saw in these children carries broad implications for their health, especially their psychological development,” says lead author Sarah Moore, a postdoctoral fellow. “If further research confirms this initial finding, it will underscore the importance of providing physical contact, especially for distressed infants.”

How height happens: Hundreds of genetic ‘switches’ that affect height

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It’s been understood for decades that a host of factors — everything from pre- and post-natal health, nutrition, and genetics — play a role in determining height, but efforts to untangle the complex web of factors that contribute to height have long been stymied.

That picture, however, is becoming clearer, thanks to the work of Harvard scientists.

Led by Associate Professor of Human Evolutionary Biology Terence D. Capellini, a team of researchers discovered hundreds of genetic “switches” that have an influence on height and performed functional tests that demonstrated precisely how one such switch alters the function of a key gene involved in height differences. The study is described in a December 5 paper published in eLife.

“Large genome-wide association studies on upwards of 250,000 people found about 700 genetic regions associated with height,” Capellini said. “But within each region there could be many single DNA variants linked together, so there are potentially tens of thousands of variants spanning those regions. The question is how do you whittle that number down to those specific variants that influence height?”

The first step, Capellini said, was to filter the list of more than 60,000 genetic variants to those that are likely functional in the cartilage growth plates of bones. To do this they identified in the femurs of developing mice regions of the DNA that act as regulatory “switches” — that is, sequences of DNA that cause nearby genes to turn on or off. As part of that search, Capellini and colleagues focused on areas where the genome was “open,” or available for transcription using a technique called ATAC-seq.

The problem, however, is that process identifies every switch in the growth plate cartilage cell, many of which may not be involved in bone growth but rather basic cellular processes. To separate those “general” switches from those related to bone growth and thus likely height, the team performed the same test again, but on a different cell type, and identified sequences that were open in both. “If we find a common sequence that’s open in a brain cell and in a cartilage cell, we can say it likely turns on some gene that may be important for cells to live,” Capellini said. “So we filtered those out, but we didn’t ignore them completely, because they may actually be important. While we first concentrated on the bone-specific switches, we know there are a lot of inputs to height — it’s about the length of our bones, but we also know hormones trigger height, malnutrition can impact height, among other inputs so there may be general genetic factors that influence height.”

As part of that work, Capellini said, researchers also performed a number of “quality control” tests to ensure the unique switches they identified were actually involved in bone and cartilage development as well as height.

After performing those tests and filters, Michael Guo, an author on the study, was next able to determine how many of the 60,000 variants associated with height actually reside in on/off switches for bone. This resulted in a list of about 900 genetic variants.

To make sure that this process generated unique height signals, Capellini and colleagues performed additional analyses. “We took genome-wide analyses from other studies that had nothing to do with height and looked to see if we saw the same signal, and we didn’t, which makes sense,” he said. “We also looked at switches from other cell types to see if these genetic variants appeared, and they didn’t. That really suggests to us that the signals we’re seeing are very strong, it’s not just a property of the genome or a property of identifying these switches.”

The team then chose one on/off switch, associated with a gene known as Chondroitin Sulfate Synthase 1, or CHSY1, which plays a key role in how cartilage cells create the extra-cellular matrix that hardens into bone. In turn, the gene influences femur length in mice and humans.

“We did some tests to find out how this switch effects CHSY1 activity, and found that both versions — for taller height and shorter height — act as repressors on the gene,” Capellini said. “But surprisingly the height-increasing variant isn’t as strong.”

To verify that the switch indeed acts in a repressive manner, using CRISPR tools, researchers removed the switch or the variant altogether from human cartilage cells, and saw a very strong increase in the expression of the gene.

Going forward, Capellini and colleagues hope to use high-throughput functional methods to understand the role each variant plays in human height, and to develop other methods to test all 60,000-plus variants in order to study height in a more unbiased manner.

In addition to providing a new understanding of a complex human trait, the study may ultimately demonstrate how genetic tools might be used to understand other conditions — like macular degeneration, diabetes or even heart disease — that are tied to both environmental and genetic factors.

“For any disease or trait, being able to say here is a switch that turns a gene on or off, and here is the mutation in that switch that can effect it dramatically…that’s pretty powerful,” Capellini said. “That will allow us figure out what are the biological pathways that are worth targeting. The future of personalized medicine will rely on knowing what specific pieces of DNA are doing in the body, and this is one way to do that.”