Posts Tagged ‘science’

By Michael Marshall

Blobs of simple carbon-based compounds could have been the precursors to the first living cells. A new study suggests that such droplets could have formed quickly and easily on the young Earth.

“We were able to find these interesting microdroplet structures that could be synthesised from prebiotically available resources,” says Tony Jia of the Tokyo Institute of Technology in Japan. “Maybe they weren’t the direct precursors to modern cells, but perhaps they could have had some effect or had a role in the emergence of initial life.”

All modern cells are surrounded by an outer wall called a membrane, which is made of long chain-like molecules called lipids. Given the ubiquity of these membranes, many researchers studying how life began have made simple membrane-lined spheres, which they say could mimic the first simple cells.

The droplets Jia and his colleagues made are different. “They don’t have an outer layer,” says Jia. “In that sense they’re membrane-less.”

The first cells?
The team made them from simple chemicals called alpha-hydroxy acids. These are made by the same processes that create amino acids, suggesting they were present on the early Earth, says team member Kuhan Chandru of the National University of Malaysia. “You can find them in meteorites as well.” He showed in 2018 that alpha-hydroxy acids link up to form complex molecules at a wide range of temperatures.

In the new study, the team simply dissolved the acids in water, then left them to dry out at 80 °C for a week – mimicking the conditions near a hot volcanic pond.

The acids turned into a thick jelly, because they had again formed complex molecules. When the researchers added water, the jelly formed hundreds of droplets a few micrometres across. Further experiments showed that crucial biological molecules, including protein and RNA, could enter the droplets and still perform their functions.

Cells without walls
Membrane-less droplets were a key element of the first popular hypothesis for life’s origin, which was set out by Russian biologist Alexander Oparin in the 1920s. However, the idea fell out of favour when it emerged that all cells have membranes.

The idea is now being re-assessed, says Kate Adamala of the University of Minnesota in Minneapolis. She suspects that life went through a “membrane-less stage” and that membranes only arose later.

Both droplets and membrane-based cells are a container for life’s components. This is crucial, says Adamala, because it keeps all the parts together, creating an individual organism from what would otherwise be a mess of chemicals.

But membranes are such good barriers that the first cells would have struggled to get food in and waste out, Adamala argues. So at the very beginning, membrane-less droplets would be better. “You don’t have to be shut off from the environment, because those droplets are permeable and you can have things diffusing in and out of them.”

Journal reference: PNAS, DOI: 10.1073/pnas.1902336116

Read more: https://www.newscientist.com/article/2210671-early-life-on-earth-may-have-existed-as-miniature-droplets-of-jelly/#ixzz5uVl0RAI6

Advertisements


A mouse exploring one of the custom hologram generators used in the experiments at Stanford. By stimulating particular neurons, scientists were able to make engineered mice see visual patterns that weren’t there.

By Carl Zimmer

In a laboratory at the Stanford University School of Medicine, the mice are seeing things. And it’s not because they’ve been given drugs.

With new laser technology, scientists have triggered specific hallucinations in mice by switching on a few neurons with beams of light. The researchers reported the results on Thursday in the journal Science.

The technique promises to provide clues to how the billions of neurons in the brain make sense of the environment. Eventually the research also may lead to new treatments for psychological disorders, including uncontrollable hallucinations.

“This is spectacular — this is the dream,” said Lindsey Glickfeld, a neuroscientist at Duke University, who was not involved in the new study.

In the early 2000s, Dr. Karl Deisseroth, a psychiatrist and neuroscientist at Stanford, and other scientists engineered neurons in the brains of living mouse mice to switch on when exposed to a flash of light. The technique is known as optogenetics.

In the first wave of these experiments, researchers used light to learn how various types of neurons worked. But Dr. Deisseroth wanted to be able to pick out any individual cell in the brain and turn it on and off with light.

So he and his colleagues designed a new device: Instead of just bathing a mouse’s brain in light, it allowed the researchers to deliver tiny beams of red light that could strike dozens of individual brain neurons at once.

To try out this new system, Dr. Deisseroth and his colleagues focused on the brain’s perception of the visual world. When light enters the eyes — of a mouse or a human — it triggers nerve endings in the retina that send electrical impulses to the rear of the brain.

There, in a region called the visual cortex, neurons quickly detect edges and other patterns, which the brain then assembles into a picture of reality.

The scientists inserted two genes into neurons in the visual cortices of mice. One gene made the neurons sensitive to the red laser light. The other caused neurons to produce a green flash when turned on, letting the researchers track their activity in response to stimuli.

The engineered mice were shown pictures on a monitor. Some were of vertical stripes, others of horizontal stripes. Sometimes the stripes were bright, sometimes fuzzy. The researchers trained the mice to lick a pipe only if they saw vertical stripes. If they performed the test correctly, they were rewarded with a drop of water.

As the mice were shown images, thousands of neurons in their visual cortices flashed green. One population of cells switched on in response to vertical stripes; other neurons flipped on when the mice were shown horizontal ones.

The researchers picked a few dozen neurons from each group to target. They again showed the stripes to the mice, and this time they also fired light at the neurons from the corresponding group. Switching on the correct neurons helped the mice do better at recognizing stripes.

Then the researchers turned off the monitor, leaving the mice in darkness. Now the scientists switched on the neurons for horizontal and vertical stripes, without anything for the rodents to see. The mice responded by licking the pipe, as if they were actually seeing vertical stripes.

Anne Churchland, a neuroscientist at Cold Spring Harbor Laboratory who was not involved in the study, cautioned that this kind of experiment can’t reveal much about a mouse’s inner experience.

“It’s not like a creature can tell you, ‘Oh, wow, I saw a horizontal bar,’” she said.

Dr. Churchland said that it would take more research to better understand why the mice behaved as they did in response to the flashes of red light. Did they see the horizontal stripes more clearly, or were they less distracted by misleading signals?

One of the most remarkable results from the study came about when Dr. Deisseroth and his colleagues narrowed their beams of red light to fewer and fewer neurons. They kept getting the mice to lick the pipe as if they were seeing the vertical stripes.

In the end, the scientists found they could trigger the hallucinations by stimulating as few as two neurons. Thousands of other neurons in the visual cortex would follow the lead of those two cells, flashing green as they became active.

Clusters of neurons in the brain may be tuned so that they’re ready to fire at even a slight stimulus, Dr. Deisseroth and his colleagues concluded — like a snowbank poised to become an avalanche.

But it doesn’t take a fancy optogenetic device to make a few neurons fire. Even when they’re not receiving a stimulus, neurons sometimes just fire at random.

That raises a puzzle: If all it takes is two neurons, why are we not hallucinating all the time?

Maybe our brain wiring prevents it, Dr. Deisseroth said. When a neuron randomly fires, others may send signal it to quiet down.

Dr. Glickfeld speculated that attention may be crucial to triggering the avalanche of neuronal action only at the right times. “Attention allows you to ignore a lot of the background activity,” she said.

Dr. Deisseroth hopes to see what other hallucinations he can trigger with light. In other parts of the brain, he might be able to cause mice to perceive more complex images, such as the face of a cat. He might be able to coax neurons to create phantom sounds, or even phantom smells.

As a psychiatrist, Dr. Deisseroth has treated patients who have suffered from visual hallucinations. In his role as a neuroscientist, he’d like to find out more about how individual neurons give rise to these images — and how to stop them.

“Now we know where those cells are, what they look like, what their shape is,” he said. “In future work, we can get to know them in much more detail.”


Kumar Alagramam. PhD, Case Western Reserve University

The ability to hear depends on proteins to reach the outer membrane of sensory cells in the inner ear. But in certain types of hereditary hearing loss, mutations in the protein prevent it from reaching these membranes. Using a zebrafish model, researchers at Case Western Reserve University School of Medicine have found that an anti-malarial drug called artemisinin may help prevent hearing loss associated with this genetic disorder.

In a recent study, published in the Proceedings of the National Academy of Sciences (PNAS), researchers found the classic anti-malarial drug can help sensory cells of the inner ear recognize and transport an essential protein to specialized membranes using established pathways within the cell.

The sensory cells of the inner ear are marked by hair-like projections on the surface, earning them the nickname “hair cells.” Hair cells convert sound and movement-induced vibrations into electrical signals that are conveyed through nerves and translated in the brain as information used for hearing and balance.

The mutant form of the protein–clarin1–render hair cells unable to recognize and transport them to membranes essential for hearing using typical pathways within the cell. Instead, most mutant clarin1 proteins gets trapped inside hair cells, where they are ineffective and detrimental to cell survival. Faulty clarin1 secretion can occur in people with Usher syndrome, a common genetic cause of hearing and vision loss.

The study found artemisinin restores inner ear sensory cell function—and thus hearing and balance—in zebrafish genetically engineered to have human versions of an essential hearing protein.

Senior author on the study, Kumar N. Alagramam, the Anthony J. Maniglia Chair for Research and Education and associate professor at Case Western Reserve University School of Medicine Department of Otolaryngology at University Hospitals Cleveland Medical Center, has been studying ways to get mutant clarin1 protein to reach cell membranes to improve hearing in people with Usher syndrome.

“We knew mutant protein largely fails to reach the cell membrane, except patients with this mutation are born hearing,” Alagramam said. “This suggested to us that, somehow, at least a fraction of the mutant protein must get to cell membranes in the inner ear.”

Alagramam’s team searched for any unusual secretion pathways mutant clarin1 could take to get to hair cell membranes. “If we can understand how the human clarin1 mutant protein is transported to the membrane, then we can exploit that mechanism therapeutically,” Alagramam said.

For the PNAS study, Alagramam’s team created several new zebrafish models. They swapped the genes encoding zebrafish clarin1 with human versions—either normal clarin1, or clarin1 containing mutations found in humans with a type of Usher syndrome, which can lead to profound hearing loss.

“Using these ‘humanized’ fish models,” Alagramam said, “we were able to study the function of normal clarin1 and, more importantly, the functional consequences of its mutant counterpart. To our knowledge, this is the first time a human protein involved in hearing loss has been examined in this manner.”

Zebrafish offer several advantages to study hearing. Their larvae are transparent, making it easy to monitor inner ear cell shape and function. Their genes are also nearly identical to humans—particularly when it comes to genes that underlie hearing. Replacing zebrafish clarin1 with human clarin1 made an even more precise model.

The researchers found the unconventional cellular secretion pathway they were looking for by using florescent labels to track human clarin1 moving through zebrafish hair cells. The mutated clarin1 gets to the cell membrane using proteins and trafficking mechanisms within the cell, normally reserved for misfolded proteins “stuck” in certain cellular compartments.

“As far as we know, this is the first time a human mutant protein associated with hearing loss has been shown to be ‘escorted’ by the unconventional cellular secretion pathway,” Alagramam said. “This mechanism may shed light on the process underlying hearing loss associated with other mutant membrane proteins.”

The study showed the majority of mutant clarin1 gets trapped inside a network of tubules within the cell analogous to stairs and hallways helping proteins, including clarin1, get from place to place. Alagramam’s team surmised that liberating the mutant protein from this tubular network would be therapeutic and tested two drugs that target it: thapsigargin (an anti-cancer drug) and artemisinin (an anti-malarial drug).

The drugs did enable zebrafish larvae to liberate the trapped proteins and have higher clarin1 levels in the membrane; but artemisinin was the more effective of the two. Not only did the drug help mutant clarin1 to reach the membrane, hearing and balance functions were better preserved in zebrafish treated with the anti-malarial drug than untreated fish.

In zebrafish, survival depends on normal swim behavior, which in turn depends on balance and the ability to detect water movement, both of which are tied to hair cell function. Survival rates in zebrafish expressing the mutant clarin1 jumped from 5% to 45% after artemisinin treatment.

“Our report highlights the potential of artemisinin to mitigate both hearing and vision loss caused by clarin1 mutations,” Alagramam said. “This could be a re-purposable drug, with a safe profile, to treat Usher syndrome patients.”

Alagramam added that the unconventional secretion mechanism and the activation of that mechanism using artemisinin or similar drugs may also be relevant to other genetic disorders that involve mutant membrane proteins aggregating in the cell’s tubular network, including sensory and non-sensory disorders.

Gopal SR, et al. “Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.” PNAS.

Drug to treat malaria could mitigate hereditary hearing loss

By Knvul Sheikh

As our devices get smaller and more sophisticated, so do the materials we use to make them. That means we have to get up close to engineer new materials. Really close.

Different microscopy techniques allow scientists to see the nucleotide-by-nucleotide genetic sequences in cells down to the resolution of a couple atoms as seen in an atomic force microscopy image. But scientists at the IBM Almaden Research Center in San Jose, Calif., and the Institute for Basic Sciences in Seoul, have taken imaging a step further, developing a new magnetic resonance imaging technique that provides unprecedented detail, right down to the individual atoms of a sample.

The technique relies on the same basic physics behind the M.R.I. scans that are done in hospitals.

When doctors want to detect tumors, measure brain function or visualize the structure of joints, they employ huge M.R.I. machines, which apply a magnetic field across the human body. This temporarily disrupts the protons spinning in the nucleus of every atom in every cell. A subsequent, brief pulse of radio-frequency energy causes the protons to spin perpendicular to the pulse. Afterward, the protons return to their normal state, releasing energy that can be measured by sensors and made into an image.

But to gather enough diagnostic data, traditional hospital M.R.I.s must scan billions and billions of protons in a person’s body, said Christopher Lutz, a physicist at IBM. So he and his colleagues decided to pack the power of an M.R.I. machine into the tip of another specialized instrument known as a scanning tunneling microscope to see if they could image individual atoms.


Four M.R.I. scans, combined, of a single titanium atom, showing the magnetic field of the atom at different strengths.CreditWillke et al.

The tip of a scanning tunneling microscope is just a few atoms wide. And it moves along the surface of a sample, it picks up details about the size and conformation of molecules.

The researchers attached magnetized iron atoms to the tip, effectively combining scanning-tunneling microscope and M.R.I. technologies.

When the magnetized tip swept over a metal wafer of iron and titanium, it applied a magnetic field to the sample, disrupting the electrons (rather than the protons, as a typical M.R.I. would) within each atom. Then the researchers quickly turned a radio-frequency pulse on and off, so that the electrons would emit energy that could be visualized. The results were described Monday in the journal Nature Physics.

“It’s a really magnificent combination of imaging technologies,” said A. Duke Shereen, director of the M.R.I. Core Facility at the Advanced Science Research Center in New York. “Medical M.R.I.s can do great characterization of samples, but not at this small scale.”

The atomic M.R.I. provides subångström-level resolution, meaning it can distinguish neighboring atoms from one another, as well as reveal which types of atoms are visible based on their magnetic interactions.

“It is the ultimate way to miniaturization,” Dr. Lutz said. He hopes the new technology could one day be used to design atomic-scale methods of storing information, for quantum computers.

Current transistors are thousands of atoms wide and need to switch on and off to store a single bit of information in a computer. The ability to corral individual atoms could drastically increase computing power and enable researchers to tackle complex calculations such as predicting weather patterns or diagnosing illnesses with artificial intelligence.

Moving an atom from one location to another in a composite could also change and lead to the development of new ones.

The technique might also help scientists study how proteins fold and develop new drugs that bind to specific curves in a biological structure.

“We can now see something that we couldn’t see before,” Dr. Lutz said. “So our imagination can go to a whole bunch of new ideas that we can test out with this technology.”

Calgary student Nora Keegan has been studying decibel levels in hand dryers since she was 9 years old.

Children who say hand dryers “hurt my ears” are correct.

A new research paper by that very title has just been published in Paediatrics & Child Health, Canada’s premier peer-reviewed pediatric journal. And the researcher, 13-year-old Nora Keegan, has been studying the issue since she was nine years old.

“In Grade 4, I noticed that my ears kind of hurt after the hand dryer,” Keegan told the Calgary Eyeopener. “And then later, at the start of Grade 5, I also noticed that my ears were hurting after I used the hand dryer. So then I decided to test it to see if they were dangerous to hearing, and it turns out they are.”

Keegan used a decibel meter, and measured the noise at different heights and different distances from the wall.

“I thought it would be good to have a lot of children’s heights and also women’s height and men’s height, and then I measured 18 inches from the wall, which is the industry standard. And I also measured 12 inches from the wall since I thought the children might stand closer because their hands and arms are shorter.”

She discovered something even more alarming.

“And then one time I was testing on the decibel meter and my hand accidentally passed into the airstream flow, and the decibels shot up a lot,” she said. “So then I decided to make that another part of my testing method. So I also measured with hands in the air flow and without hands in the air.”

Keegan discovered that the sound was even louder with the hands in the airflow.

“And it was also really loud at children’s heights and manufacturers don’t measure for children’s height as much either.”

Eventually, Keegan determined that there are two models in particular that are harmful for children’s ears: the Dyson and XCelerator, which both operate at about 110 decibels. Health Canada has regulated that no toys operate at more than 100 decibels.

“So this is very loud, around the level of a rock concert,” Keegan said. “And this is also louder than Health Canada’s regulation for children’s toys, as they know that at this level it poses a danger to children’s hearing.”

Children have smaller ear canals and more sensitive follicles. And they tend to stand closer to the dryers because their bodies are smaller and their arms are shorter.

These are all things Keegan started documenting in a series of research projects.

“So it started out as a school science fair in Grade 5. And then I really enjoyed it, and I thought I could do more with it,” she said. “So then I continued working on it in Grade 6, and then Grade 7, I started writing the paper, and it just got published now in Paediatrics & Child Health.”

Keegan is a Grade 8 student at Branton Junior High School in Calgary. The full title of her paper is, “Children who say hand dryers ‘hurt my ears’ are correct: A real-world study examining the loudness of automated hand dryers in public places.”

But the young scientist, who says she hopes to have a career as a marine biologist, isn’t stopping with this personal success. She wants to do something about the problem.

By experimenting with different materials, she’s made a model that reduces the noise by 11 decibels.

Keegan’s synthetic air filter, which looks like a fuzzy handbag, absorbs the sound waves.

“The air comes down further so even though your hands still reach the airflow, then your ears are a greater distance from where the air comes out.”

Keegan conducted an informal test of the air filter at her school.

“I couldn’t really find a way to test it, but I installed it in my school’s washroom and I found that it didn’t (heat up). People seemed to enjoy it and it didn’t seem to have a problem.”

Keegan said she hasn’t tried to do anything official with the air filter — yet.

“I think I might go and talk to the manufacturers and also I might go and talk to Health Canada because even though this is a study, it’s still only one study. So it’d be better if they tested more hand dryers and found more about that loudness of hand dryers.”

Keegan assessed 44 different hand dryers, from places that kids would be using them all over Calgary — arenas, restaurants, schools, libraries and shopping malls.

https://www.cbc.ca/news/canada/calgary/calgary-student-nora-keegan-hand-dyer-research-decibel-1.5185853?utm_source=Nature+Briefing&utm_campaign=34225bcef1-briefing-dy-20190701&utm_medium=email&utm_term=0_c9dfd39373-34225bcef1-44039353

Doctors have newly outlined a type of dementia that could be more common than Alzheimer’s among the oldest adults, according to a report published Tuesday in the journal Brain.

The disease, called LATE, may often mirror the symptoms of Alzheimer’s disease, though it affects the brain differently and develops more slowly than Alzheimer’s. Doctors say the two are frequently found together, and in those cases may lead to a steeper cognitive decline than either by itself.

In developing its report, the international team of authors is hoping to spur research — and, perhaps one day, treatments — for a disease that tends to affect people over 80 and “has an expanding but under-recognized impact on public health,” according to the paper.

“We’re really overhauling the concept of what dementia is,” said lead author Dr. Peter Nelson, director of neuropathology at the University of Kentucky Medical Center.

Still, the disease itself didn’t come out of the blue. The evidence has been building for years, including reports of patients who didn’t quite fit the mold for known types of dementia such as Alzheimer’s.

“There isn’t going to be one single disease that is causing all forms of dementia,” said Sandra Weintraub, a professor of psychiatry, behavioral sciences and neurology at Northwestern University Feinberg School of Medicine. She was not involved in the new paper.

Weintraub said researchers have been well aware of the “heterogeneity of dementia,” but figuring out precisely why each type can look so different has been a challenge. Why do some people lose memory first, while others lose language or have personality changes? Why do some develop dementia earlier in life, while others develop it later?

Experts say this heterogeneity has complicated dementia research, including Alzheimer’s, because it hasn’t always been clear what the root cause was — and thus, if doctors were treating the right thing.

What is it?

The acronym LATE stands for limbic-predominant age-related TDP-43 encephalopathy. The full name refers to the area in the brain most likely to be affected, as well as the protein at the center of it all.

“These age-related dementia diseases are frequently associated with proteinaceous glop,” Nelson said. “But different proteins can contribute to the glop.”

In Alzheimer’s, you’ll find one set of glops. In Lewy body dementia, another glop.

And in LATE, the glop is a protein called TDP-43. Doctors aren’t sure why the protein is found in a modified, misfolded form in a disease like LATE.

“TDP-43 likes certain parts of the brain that the Alzheimer’s pathology is less enamored of,” explained Weintraub, who is also a member of Northwestern’s Mesulam Center for Cognitive Neurology and Alzheimer’s Disease.

“This is an area that’s going to be really huge in the future. What are the individual vulnerabilities that cause the proteins to go to particular regions of the brain?” she said. “It’s not just what the protein abnormality is, but where it is.”

More than a decade ago, doctors first linked the TDP protein to amyotrophic lateral sclerosis, otherwise known as ALS or Lou Gehrig’s disease. It was also linked to another type of dementia, called frontotemporal lobar degeneration.

LATE “is a disease that’s 100 times more common than either of those, and nobody knows about it,” said Nelson.

The new paper estimates, based on autopsy studies, that between 20 and 50% of people over 80 will have brain changes associated with LATE. And that prevalence increases with age.

Experts say nailing down these numbers — as well as finding better ways to detect and research the disease — is what they hope comes out of consensus statements like the new paper, which gives scientists a common language to discuss it, according to Nelson.

“People have, in their own separate bailiwicks, found different parts of the elephant,” he said. “But this is the first place where everybody gets together and says, ‘This is the whole elephant.’ ”

What this could mean for Alzheimer’s

The new guidelines could have an impact on Alzheimer’s research, as well. For one, experts say some high-profile drug trials may have suffered as a result of some patients having unidentified LATE — and thus not responding to treatment.

In fact, Nelson’s colleagues recently saw that firsthand: a patient, now deceased, who was part of an Alzheimer’s drug trial but developed dementia anyway.

“So, the clinical trial was a failure for Alzheimer’s disease,” Nelson said, “but it turns out he didn’t have Alzheimer’s disease. He had LATE.”

Nina Silverberg, director of the Alzheimer’s Disease Research Centers Program at the National Institute on Aging, said she suspects examples like this are not the majority — in part because people in clinical trials tend to be on the younger end of the spectrum.

“I’m sure it plays some part, but maybe not as much as one might think at first,” said Silverberg, who co-chaired the working group that led to the new paper.

Advances in testing had already shown that some patients in these trials lacked “the telltale signs of Alzheimer’s,” she said.

In some cases, perhaps it was LATE — “and it’s certainly possible that there are other, as yet undiscovered, pathologies that people may have,” she added.

“We could go back and screen all the people that had failed their Alzheimer’s disease therapies,” Nelson said. “But what we really need to do is go forward and try to get these people out of the Alzheimer’s clinical trials — and instead get them into their own clinical trials.”

Silverberg describes the new paper as “a roadmap” for research that could change as we come to discover more about the disease. And researchers can’t do it without a large, diverse group of patients, she added.

“It’s probably going to take years and research participants to help us understand all of that,” she said.

https://www.cnn.com/2019/04/30/health/dementia-late-alzheimers-study/index.html

ummary: Study identifies 104 high-risk genes for schizophrenia. One gene considered high-risk is also suspected in the development of autism.

Source: Vanderbilt University

Using a unique computational framework they developed, a team of scientist cyber-sleuths in the Vanderbilt University Department of Molecular Physiology and Biophysics and the Vanderbilt Genetics Institute (VGI) has identified 104 high-risk genes for schizophrenia.

Their discovery, which was reported April 15 in the journal Nature Neuroscience, supports the view that schizophrenia is a developmental disease, one which potentially can be detected and treated even before the onset of symptoms.

“This framework opens the door for several research directions,” said the paper’s senior author, Bingshan Li, PhD, associate professor of Molecular Physiology and Biophysics and an investigator in the VGI.

One direction is to determine whether drugs already approved for other, unrelated diseases could be repurposed to improve the treatment of schizophrenia. Another is to find in which cell types in the brain these genes are active along the development trajectory.

Ultimately, Li said, “I think we’ll have a better understanding of how prenatally these genes predispose risk, and that will give us a hint of how to potentially develop intervention strategies. It’s an ambitious goal … (but) by understanding the mechanism, drug development could be more targeted.”

Schizophrenia is a chronic, severe mental disorder characterized by hallucinations and delusions, “flat” emotional expression and cognitive difficulties.

Symptoms usually start between the ages of 16 and 30. Antipsychotic medications can relieve symptoms, but there is no cure for the disease.

Genetics plays a major role. While schizophrenia occurs in 1% of the population, the risk rises sharply to 50% for a person whose identical twin has the disease.

Recent genome-wide association studies (GWAS) have identified more than 100 loci, or fixed positions on different chromosomes, associated with schizophrenia. That may not be where high-risk genes are located, however. The loci could be regulating the activity of the genes at a distance — nearby or very far away.

To solve the problem, Li, with first authors Rui Chen, PhD, research instructor in Molecular Physiology and Biophysics, and postdoctoral research fellow Quan Wang, PhD, developed a computational framework they called the “Integrative Risk Genes Selector.”

The framework pulled the top genes from previously reported loci based on their cumulative supporting evidence from multi-dimensional genomics data as well as gene networks.

Which genes have high rates of mutation? Which are expressed prenatally? These are the kinds of questions a genetic “detective” might ask to identify and narrow the list of “suspects.”

The result was a list of 104 high-risk genes, some of which encode proteins targeted in other diseases by drugs already on the market. One gene is suspected in the development of autism spectrum disorder.

Much work remains to be done. But, said Chen, “Our framework can push GWAS a step forward … to further identify genes.” It also could be employed to help track down genetic suspects in other complex diseases.

Also contributing to the study were Li’s lab members Qiang Wei, PhD, Ying Ji and Hai Yang, PhD; VGI investigators Xue Zhong, PhD, Ran Tao, PhD, James Sutcliffe, PhD, and VGI Director Nancy Cox, PhD.

Chen also credits investigators in the Vanderbilt Center for Neuroscience Drug Discovery — Colleen Niswender, PhD, Branden Stansley, PhD, and center Director P. Jeffrey Conn, PhD — for their critical input.

Funding: The study was supported by the Vanderbilt Analysis Center for the Genome Sequencing Program and National Institutes of Health grant HG009086.

https://neurosciencenews.com/high-risk-schizophrenia-genes-12021/