Friday, November 01, 2024

Identifying the genes that viruses ‘steal’ from ocean microbes

Study suggests viruses reprogram at least 1/3 of metabolic processes

Ohio State University

COLUMBUS, Ohio – The microbes that cycle nutrients in the ocean don’t do the work on their own – the viruses that infect them also influence the process. It’s a vital job for the rest of the planet, enabling oceans to absorb half of the human-generated carbon in the atmosphere and produce half of the oxygen we breathe.

A new study gets scientists closer to more fully understanding where viruses fit into the global ocean picture of cycling nutrients such as nitrogen, phosphorous and, of particular interest, carbon. The research broadly expands on a 20-year-old finding that genes can be exchanged between viruses and the photosynthetic cells they infect and consolidates data resulting from more than 100 papers on viruses and metabolism that followed.

The research team, led by The Ohio State University, reports in the journal Microbiome on its creation of a catalog of genes that viruses “stole” from the marine microbes they infected across all of the world’s oceans. Scientists identified and organized almost 23,000 genes known as auxiliary metabolic genes (AMGs), including over 7,000 never previously documented. The analysis suggests that about 1 in 5 ocean virus populations carries at least one AMG.

Adding even more context to the viruses’ role, the researchers mapped 340 metabolic pathways attributed to microbes in the oceans – changes to the nutrient balance resulting from organisms consuming and generating molecules based on their survival needs. Of those, the scientists found that viral AMGs mapped to 128 pathways – meaning viruses affected over 37% of those processes.

“We still don’t know the extent of viruses’ impact. But now that we know the pathways that viruses target via AMGs, we could use metabolic modeling approaches to quantitatively estimate the viral impact on the host communities and ocean functioning,” said first study author Funing Tian, who completed the work as a PhD student in microbiology at Ohio State.

“Future modeling work could involve increasing or decreasing metabolic fluxes occurring through these pathways and seeing how the impact of viruses would change.”

Tian and her co-lead author, former Ohio State microbiology postdoctoral scholar James Wainaina, focused on DNA viruses that infect prokaryotes: bacteria and other single-celled organisms floating throughout the world’s oceans.

Wainaina and Tian were members of the lab led by the study’s senior author, Matthew Sullivan, professor of microbiology and founding director of the Center of Microbiome Science at Ohio State.

Sullivan was the virus coordinator for the Tara Oceans Consortium, a three-year global study of the impact of climate change on the world’s oceans. As part of that international collaboration, he has led previous work to catalog close to 200,000 DNA and 5,500 RNA virus species in the oceans, and to ascertain viruses’ potential to mitigate climate change.

Tian and Wainaina analyzed 7.6 terabytes of Tara Oceans metagenomic sequence data for this study, increasing the known ocean DNA virus populations to 579,904. From these populations, the team took many computational steps to identify the auxiliary metabolic genes located in virus genomes.

They conservatively identified a total of 86,913 AMGs that grouped into 22,779 sequence-based gene clusters. Of those, 7,248 were identified for the first time. Viruses lift these genes from the microbial cells they infect and incorporate the genes into their own genome – giving them the power to reprogram a host cell’s function in a way that ensures viral survival.

“The challenge with auxiliary metabolic genes is that people know they’re there, but the gene is similar to the cellular copy – that makes it important to differentiate between the viral copy and the microbial copy,” Wainaina said.

“To minimize false positives, we undertook curation steps to make sure we focused only on AMGs that were on viral genome segments,” Tian said.

They then further analyzed the genomic data to determine metabolic pathways – each one a series of related actions that alter a cell’s function – that could be traced to specific microbial species, revealing 340 such pathways. With their new catalog of “stolen” genes, the researchers found that 128 of these pathways were targeted by viral AMGs.

“That’s our big finding,” Tian said. “Before this paper, it was unknown how many metabolic pathways were encoded in microbes throughout the global oceans, and even less understood among those how many were targeted by viruses via AMGs.”

Added Wainaina, “It’s not only about the number, but also which specific pathways viruses are involved in – that informs the biogeochemical cycles viruses are reprogramming and manipulating in the ocean.”

The AMG catalog and metabolic pathway mapping provide a foundation for microbiome engineering experimentation and modeling that will help researchers make more accurate predictions about viruses’ roles in ocean biogeochemical processes, Sullivan said.

“Most current models don’t include viruses at all, and only some include microbes,” he said. “It’s exciting that we’ve generated these data that are critical for bringing viruses and their impacts into new predictive models.”

This work was supported by the National Science Foundation, the Gordon and Betty Moore Foundation, the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, the G. Unger Vetlese and Ambrose Monell Foundations, and the Ohio Supercomputer Center.

Tian is now a bioinformatician at the University of Chicago, and Wainaina is an assistant scientist in the Biology Department at Woods Hole Oceanographic Institution. Additional co-authors include Cristina Howard-Varona, Guillermo Domínguez-Huerta, Benjamin Bolduc, Garrett Smith, Marissa Gittrich, Olivier Zablocki and Dylan Cronin of Ohio State; Maria Consuelo Gazitúa of Viromica Consulting; Damien Eveillard of Nantes Université; and Steven Hallam of the University of British Columbia.

Contacts:

Funing Tian, funing.tian@bsd.uchicago.edu
James Wainaina, james.wainaina@whoi.edu
Matthew Sullivan, Sullivan.948@osu.edu

Written by Emily Caldwell, Caldwell.151@osu.edu

Journal

Microbiome

DOI

10.1186/s40168-024-01876-z

Article Title

Prokaryotic-virus-encoded auxiliary metabolic genes throughout the global oceans

Harnessing vibrations: RPI-engineered material generates electricity from unexpected source

The material has the potential for use in machines and infrastructure to produce renewable energy

Rensselaer Polytechnic Institute

A polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed. The device could be used in consumer goods, such as a shoe that lights up when the user walks — image:
The RPI team developed a polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed. The device could be used in consumer goods, such as a shoe that lights up when the user walks, though it has potential applications in transportation and infrastructure.
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Credit: Rensselaer Polytechnic Institute

Imagine tires that charge a vehicle as it drives, streetlights powered by the rumble of traffic, or skyscrapers that generate electricity as the buildings naturally sway and shudder.

These energy innovations could be possible thanks to researchers at Rensselaer Polytechnic Institute developing environmentally friendly materials that produce electricity when compressed or exposed to vibrations.

In a recent study published in the journal Nature Communications, the team developed a polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed, a phenomenon known as the piezoelectric effect. While other piezoelectric materials currently exist, this is one of the few high-performing ones that does not contain lead, making it an excellent candidate for use in machines, infrastructure as well as bio-medical applications.

“We are excited and encouraged by our findings and their potential to support the transition to green energy,” said Nikhil Koratkar, Ph.D., corresponding author of the study and the John A. Clark and Edward T. Crossan Professor in the Department of Mechanical, Aerospace, and Nuclear Engineering. “Lead is toxic and increasing being restricted and phased out of materials and devices. Our goal was to create a material that was lead-free and could be made inexpensively using elements commonly found in nature.”

The energy harvesting film, which is only 0.3 millimeters thick, could be integrated into a wide variety of devices, machines, and structures, Koratkar explained.

“Essentially, the material converts mechanical energy into electrical energy — the greater the applied pressure load and the greater the surface area over which the pressure is applied, the greater the effect,” Koratkar said. “For example, it could be used beneath highways to generate electricity when cars drive over them. It could also be used in building materials, making electricity when buildings vibrate.”

The piezoelectric effect occurs in materials that lack structural symmetry. Under stress, piezoelectric materials deform in such a way that causes positive and negative ions within the material to separate. This “dipole moment,” as it is known scientifically, can be harnessed and turned into an electric current. In the chalcogenide perovskite material discovered by the RPI team, structural symmetry can be easily broken under stress leading to a pronounced piezoelectric response.

Once they synthesized their new material, which contains barium, zirconium and sulfur, the researchers tested its ability to produce electricity by subjecting it to various bodily movements, such as walking, running, clapping, and tapping fingers.

The researchers found that the material generated electricity during these experiments, enough to even power banks of LED’s that spelled out RPI.

“These tests show this technology could be useful, for example, in a device worn by runners or bikers that lights up their shoes or helmets and makes them more visible. However, this is just a proof of concept, as we’d like to eventually see this kind of material implemented at scale, where it can really make a difference in energy production,” Koratkar said.

Moving forward, Koratkar’s lab will explore the entire family of chalcogenide perovskite compounds in the search for those that exhibit an even stronger piezoelectric effect. Artificial intelligence and machine learning could prove useful tools in this pursuit, Koratkar said.

“Sustainable energy production is vital to our future,” said Shekhar Garde, Ph.D., dean of the RPI School of Engineering. “Professor Koratkar’s work is a great example of how innovating approaches to materials discovery can help address a global problem.”

A polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed. The device could be used in consumer goods, such as a shoe that lights up when the user walks

The RPI team developed a polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed. The device could be used in consumer goods, such as a shoe that lights up when the user walks, though it has potential applications in transportation and infrastructure.

A polymer film infused with a special chalcogenide perovskite compound that produces electricity when squeezed or stressed

Journal

Nature Communications

DOI

10.1038/s41467-024-50130-5

Method of Research

Experimental study

Subject of Research

Not applicable

Article Title

Piezoelectricity in chalcogenide perovskites

Grant unites humanities and health sciences for infectious disease coursework

Virginia Tech

image:
Cora Olson (at left) and Thomas Ewing discuss the ways the humanities and health sciences can work together during a workshop.
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Credit: Photo by Kelsey Bartlett for Virginia Tech.

The key to better understanding the spread of infectious diseases may lie where the humanities and the health sciences meet.

It’s a theme that a group of Virginia Tech faculty is exploring to develop new undergraduate courses that will likely be offered next fall across departments.

Professors in the College of Liberal Arts and Human Sciences are teaming up with colleagues in the College of Science and the Virginia-Maryland College of Veterinary Medicine for the project, titled Human Dimensions of Infectious Disease.

Their work is funded by a $50,000 Human Connections Grant from the National Endowment of the Humanities, which seeks to expand the role of the humanities through interdisciplinary partnerships. Collectively, their areas of expertise include topics such as health communication, health and medicine rhetoric, biomedical ethics, history of medicine, global-international health issues, biology, and infectious disease modeling.

The group held workshops over the summer to discuss how different disciplines can work together on a range of infectious-disease related issues. During one of the workshops, professors pointed out mistakes made — both by the media and the scientific community — as researchers and the public grasped for a better understanding of the coronavirus. Many of the issues stemmed from a lack of proper communication.

Lessons learned from a pandemic

“One of the most important things that emerged from the pandemic is the importance of narrative,” said Nick Ruktanonchai, assistant professor in the Department of Population Health Sciences. “How are things being portrayed? How are people taking them? Are they able to take in the narrative?”

During the early stages of the pandemic, research preprints, which are preliminary, non-peer reviewed versions of research articles, were shared hastily because researchers needed to learn about the disease in “days and weeks rather than months,” he said.

“Modeling any emerging pandemic is really difficult,” Ruktanonchai said. “There's a million different things you evaluate, and it's especially hard.”

But it soon became an issue because fewer than half of the news outlets that reported on research preprints included that the science was not peer reviewed — potentially contributing to a cycle of misinformation. He said incentives to publish the research created “some good” and “some bad” science. He stressed the importance of learning from past mistakes and making sure students understand how to interact with news and literature.

Rebecca Hester, associate professor in the Department of Science, Technology, and Society, shared similar sentiments. She said stories told about science have real-world impact on people’s lives because they shape the work scientists do in the lab and the policies that govern everyone.

She said while students are often taught “how to do the science and apply it,” they aren’t always taught “what kind of science should be applied."

“One of the things that is really relevant for this group and with regard to infectious diseases is that there’s a huge connection between helping people understand what story is being told and what the actual policy and scientific solutions are that get proposed based on that story,” she said. “I think that's another way that the humanities can really help scientific students as well as humanistic students.”

Thomas Ewing, professor in the Department of History and the College of Liberal Arts and Human Sciences’ associate dean for graduate studies and research, is leading the project. As a historian, Ewing knows the importance of learning from the past, which he said can help people understand “what’s different and unique about what they’re going through” as well as similarities to other events.

“You can go back and look at how people have responded to something like a vaccine mandate, which Americans have had in various forms for decades, but they’ve tended to be more for children’s vaccines,” he said.

(From left) Yuba Gautam, Adrienne Holz, Cora Olson, and Thomas Ewing share ideas with colleagues over Zoom. Photo by Kelsey Bartlett for Virginia Tech.

A new approach

The group will continue to meet monthly throughout the academic year to develop three new courses that explore human dimensions of infectious diseases, the history of infectious diseases, and health disparities and infectious diseases. In the meantime, professors are updating their current course curriculums and teaching approaches to include aspects of the group’s discussions.

Ewing said the initiative is consistent with Virginia Tech and the College of Liberal Arts and Human Science priorities to emphasize interdisciplinary approaches to important social and educational issues.

The grants are competitive, Ewing said, with a 21 percent funding rate over the past five years. Along with funding faculty workshops, the grant will help bring speakers to Virginia Tech to share their expertise in connecting humanities and public health approaches to infectious diseases.

Who’s involved

Julie Gerdes, assistant professor of technical and professional writing and rhetoric
Edward Polanco, assistant professor of history
Patrick Ridge, associate professor of Spanish
Adrienne Holz, associate professor in the school of communication
Jeremy Draghi, assistant professor of biological sciences
Department of Science, Technology, and Society Assistant Professors Cora Olson and John Aggrey and Associate Professor Rebecca Hester
Department of Population Health Sciences Assistant Professors Alasdair Cohen, Cori W. Ruktanonchai and Nick Ruktanonchai and Associate Professor Yuba Gautam

Plankton balloon to six times their size in newly discovered mode of oceanic travel

Cell Press

image:
This photograph shows two big and two little *Pyrocystis noctiluca*.
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Credit: Prakash lab / Stanford University

Many plankton journey from the cold, dark depths of our oceans to the surface, only to eventually drift down again into the darkness in a perpetual rhythm. Yet, how single-celled phytoplankton, most of which have no appendages to help them swim, make this pilgrimage has remained a mystery. In a paper publishing October 17 in the Cell Press journal Current Biology, researchers describe a species of bioluminescent phytoplankton, called Pyrocystis noctiluca, that balloons to six times their original size of a few hundred microns. This massive inflation allows the plankton to journey up to 200 meters toward the ocean’s surface to capture sunlight, then sink back showcasing a unique strategy for long-distance ocean travel.

Phytoplankton are, on average, 5%–10% heavier than seawater, meaning that if they want to remain at the surface to photosynthesize, they have to find a way to best gravity. “We decided to work on things that seemingly have no appendages to swim,” says senior author Manu Prakash, a marine biologist and bioengineer at Stanford University. “What we have discovered in this paper is that these P. noctiluca cells are like little submarines that can control their density so precisely that they can choose where they want to be in the water column.”

On a research vessel off the coast of Hawaii, Prakash and a postdoctoral fellow at Stanford University, Adam Larson (@Planktonico), one of the first authors on the study, stumbled upon a bloom of P. noctiluca and surprisingly found two very different sizes in their nets. “It took a while to piece together why until we recorded the videos where we saw the cells doing this massive inflation,” says Larson. “It can happen quite suddenly, so if you sleep by the microscope for 10 minutes, you might miss it.”

To test what effects this rapid growth might have on the plankton, the research team utilized their novel “gravity machine.” “The gravity machine allows us to see a single cell at subcellular resolution in an infinite water column,” says Prakash. “It’s a little bit like a Ferris wheel for gerbils or mice but for a single cell. It’s the size of a dinner plate and rotates, so the cell doesn’t know that it’s not climbing or sinking in its own frame of reference.” By altering water pressure and density within the gravity machine, the team can create a virtual reality environment mimicking the ocean’s depths. With the machine, the team discovered that inflated cells were less dense than the surrounding seawater, letting them escape the downward pull of gravity and float toward the virtual surface.

Further investigation showed this expansion happens as a natural part of the plankton’s cell cycle. Once a single-celled plankton divides into two, an internal structure called a vacuole, a kind of flexible water tank, filters in fresh water, causing the two new cells to massively grow in size. These two daughter cells, now swelled with the lighter freshwater, sail upward. “What we realized is that this is a very clever way to essentially slingshot in the ocean during cell division,” Prakash says. “So, what happens during normal time? You’re making a lot of proteins, you have tons of sunlight, and you make a lot of biomass until you get heavier and you sink. Then, you do cell division in the deeper waters and use inflation to get back to the size of the mother.”

The entire cell cycle takes roughly 7 days, coinciding with the plankton’s vertical pursuit of light and nutrients. “You can then see how this cell cycle could have evolved,” says Prakash. “I think this is the first time we have clear evidence that the cell cycle, which is such a fundamental mechanism of controlling a cell and cell division, is possibly controlled by an ecological parameter.”

With these insights in mind, using a theoretical framework, the team discovered the ecological parameter acting as a fundamental limit driving this evolution. “All cells experience a gravitational pull downward, and unless they or subsequent progeny fight back, they will sink forever to the bottom of the ocean in a gravitational trap,” says postdoctoral fellow Rahul Chajwa, the other first author of the study, also at Stanford University. Now, using the results from the gravity machine, as well as their ecological and physiological observations, the research team has developed a mathematical framework that could be generalized and applied to all plankton in the ocean.

For future projects, Prakash’s lab is looking to uncover hidden mysteries of a vast number of plankton who may use the new biochemistry to regulate density and move up and down the water column. “We have roughly around 600 species in our Behavioral Atlas right now, and we are systematically measuring all kinds of mechanisms. It’s turning out that there are four or five different tricks all co-evolving for this function. I think one of the threads that’s really fun is that we have a long list of organisms to study; because there are millions of species that live in the ocean, this is the tip of the iceberg.”

Hongquan Li, a graduate student in the Prakash lab, is also an author on the study.

###

The research was primarily supported by the Simons Foundation and the International Human Frontier Science Program Organization. The team acknowleges further financial support from the Schmidt Futures Innovation Fellowship, the Moore Foundation, Dalio Philanthropies, the NSF Center for Cellular Construction, a NSF GCR Convergence Grant, and the Woods Institute for the Environment.

Current Biology, Larson et al.: “Inflation induced motility for long-distance vertical migration” https://www.cell.com/current-biology/fulltext/S0960-9822(24)01287-9

Current Biology (@CurrentBiology), published by Cell Press, is a bimonthly journal that features papers across all areas of biology. Current Biology strives to foster communication across fields of biology, both by publishing important findings of general interest and through highly accessible front matter for non-specialists. Visit: http://www.cell.com/current-biology. To receive Cell Press media alerts, contact press@cell.com.

Dividing Pyrocystis noctiluca [VIDEO] |

Pyrocystis cell cycle [VIDEO] |

Journal

Current Biology

DOI

10.1016/j.cub.2024.09.046

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Inflation induced motility for long-distance vertical migration

Two 2024 Nobel laureates are affiliates of the Marine Biological Laboratory, Woods Hole

The MBL now counts 63 Nobel laureates since 1929 among its scientists, course faculty, and alumni.

Marine Biological Laboratory

image:
Gary Ruvkun of Harvard Medical School/Mass General Hospital, former co-director of the MBL Biology of Aging course. Credit:Joshua Touster
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Credit: Joshua Touster

The Marine Biological Laboratory (MBL) in Woods Hole, Mass., has long been a magnet for scientific talent, as partly evidenced by the long list of Nobel laureates affiliated with the lab since 1929. Last week, the MBL was proud to add two new scientists to this list, which now includes 63 names:

* Gary Ruvkin, former co-director of the MBL Biology of Aging course, was co-recipient with Victor Ambros of the Nobel Prize in Physiology or Medicine (for the discovery of microRNA and its role in gene regulation). Read more here.

* John Hopfield, former faculty in the MBL Methods in Computational Neuroscience Course, was co-recipient with Geoffrey Hinton of the Nobel Prize in Physics (for foundational discoveries in the development of artificial neural networks). Read more here.

Ruvkun's and Hopfield's research accomplishments are "an example of the cutting-edge content and groundbreaking discoveries that students in the MBL's Advanced Research Training Courses are exposed to," said Linda Hyman, Burroughs-Wellcome Director of Education at MBL.

Almost all of the MBL-affiliated Nobel laureates have received the prize in Physiology or Medicine or in Chemistry. Other than Hopfield, one other MBL affiliate has received a Nobel Prize in Physics: Donald Glaser in 1960, an alumnus of the MBL Physiology course, for his development of the bubble chamber.

John Hopfield of Princeton University, former faculty in the MBL Methods in Computational Neuroscience course.

Credit

Denise Applewhite, Princeton University

—###—

The Marine Biological Laboratory (MBL) is dedicated to scientific discovery – exploring fundamental biology, understanding marine biodiversity and the environment, and informing the human condition through research and education. Founded in Woods Hole, Massachusetts in 1888, the MBL is a private, nonprofit institution and an affiliate of the University of Chicago.

Center for Genomic Diagnostics receives first USDA grant

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign

Researcher Image — image:
Brian Cunningham, Intel Alumni Endowed Chair of Electrical and Computer Engineering, and Ying Fang, professor of pathobiology in the College of Veterinary Medicine (center) and lab members to develop portable point-of-use biosensor for detection of African swine fever virus in farm environments.
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Credit: Isaac Mitchell

Foreign animal diseases are a global threat to swine production with the potential for detrimental economic implications. Recently, researchers at the University of Illinois Urbana-Champaign received a three-year grant of $650,000 from the U.S. Department of Agriculture to develop sensitive, rapid, low-cost, and portable point-of-use biosensors to improve on-farm detection and surveillance of African swine fever virus.

ASFV is a large DNA virus that infects swine and can result in a lethal hemorrhagic fever, spread rapidly to neighboring pigs, and cause excessive morbidity and mortality in swine populations. There currently is no effective vaccine or treatment for ASFV to help prevent infection and transmission. Further, detection of the virus is challenging because it relies on expensive offsite laboratory-based methods which often take too long for successful disease mitigation.

“ASFV is very important right now because it is already a deadly disease in other countries, and it can kill pigs quickly, usually within 7 to 10 days,” said Ying Fang (CGD/MMG), a professor of pathobiology in the College of Veterinary Medicine. “For field surveillance, if we have a portable device, we can take it to the field, and quickly detect ASFV-infected pigs. In this way, we can immediately apply the control and prevention measures.”

With her expertise in animal diseases, Fang teamed up with Brian Cunningham (CGD leader), the Intel Alumni Endowed Chair of Electrical and Computer Engineering, to develop a biosensor for ASFV. Cunningham’s research focuses on developing nanotechnology-based biosensors for cancer and infectious diseases.

“We have been working on these technology approaches for about ten years, continuously refining and improving the biosensors, but mainly for cancer and infectious human diseases. So, when this USDA grant funding opportunity came up, Professor Fang encouraged us to try for it,” Cunningham said.

The project funding began on September 1 of this year, with the grant support coming from the USDA National Institute of Food and Agriculture’s Nanotechnology for Agriculture and Food Systems program. Over the next three years, the team will work on using genomics and proteomics to determine the diagnostic targets, specific viral nucleic acid sequences and proteins, for ASFV detection. Then, Fang’s research group will use their expert knowledge to develop and test laboratory-based methods for ASFV detection using this target. These methods will then be incorporated into Cunningham’s portable cartridge devices that use novel physics principles and nanotechnology methods to detect the target molecules from the virus.

The work done at Illinois will focus on gene and protein level detection because research with live ASFV requires specialized facilities to eliminate exposure and transmission. To test their novel biosensor with active ASFV, Fang and Cunningham will collaborate with Jishu Shi, a professor of vaccine immunology at Kansas State University which houses the necessary biosafety level 3 facilities.

Overall, this grant represents a new portfolio of research for the Center for Genomic Diagnostics theme at the Carl R. Woese Institute for Genomic Biology. “We have been focused exclusively on human health and diseases and the underlying engineering science for sensing them. This represents how we have really strong pathobiology and veterinary medicine, combined with innovative engineering, here at Illinois. I think alone, neither of us would be able to do this project, but together, we make an excellent team,” Cunningham said.

“I hope this collaboration sends signals out university-wide that veterinary medicine is also important and an area that needs to be emphasized. So, I'm hoping to have more of this kind of collaboration and to continue developing new technologies to apply to livestock animals and veterinary medicine,” Fang said.

WashU researchers use genetics to find psychopathology risks

GREAT CESARE LOMBROSO'S GHOST

A multitude of genetic, behavioral and environmental factors come together to create mental health problems in teens, study finds.

Washington University in St. Louis

When trying to understand how genetic influences factor into youth behavior, researchers at Washington University in St. Louis have taken the “big trawl” approach, casting their net wide to pull in all the measured traits, behaviors and environments that make up who we are and examine associations with the genetic building blocks comprising risk for mental health problems.

This cutting-edge methodology has turned up valuable new insights into factors related to psychopathological genetic risk, such as stressful life events and screen time. Although the results, published in Nature Mental Health, are unable to say if one causes the other, the findings provide promising leads to understand the nature of psychiatric disorders emerging during adolescence.

“We’re catching all the little fish here,” said Nicole Karcher, assistant professor of psychiatry at WashU Medicine, likening their genetic screening tools to trawling the ocean.

“But now we get to wade through the fish that we caught, and future steps include understanding the extent to which these are meaningful in terms of their ability to reduce risk for mental health concerns.”

An innovative approach to “catching” risk factors

Much of what we know about links between the genome and behavior come from Genome-wide Associations Studies (GWAS), which identify links between specific genetic variants across the genome and a feature of interest, also known as a phenotype. Phenotypes can range from physical characteristics to psychiatric disorders (e.g., depression, anxiety).

Many behavioral disorders are correlated at the genetic level. Results from a GWAS scanning for genetic links to depression, therefore, may also reflect genetic associations with frequently co-occurring conditions such as anxiety.

“We know that one behavioral variable is not going to be the only association with genetic risk, so we were interested in taking a more agnostic, data-driven approach to the wealth of information that is available in large datasets,” said Karcher.

Doing so would hopefully identify not only expected associations between genetic risk and psychiatric symptoms, but also potential novel associations that could improve insight into how psychiatric disorder risk may unfold.

So senior author Karcher and first author Sarah Paul, a graduate student in Ryan Bogdan's Behavioral Research and Imaging Neurogenetics Laboratory at Art & Sciences, ran what’s called a phenome-wide association study (PheWAS) that inverts the GWAS.

Rather than starting with the psychiatric condition and looking for associated genetic variants, their PheWAS started with genetic variants known to be linked with mental health disorders and examined their relationship to hundreds of measured variables reflecting behavior, symptoms, environments, health problems and other phenotypes. They included approximately 1,300 to 1,700 phenotypes in total from the Adolescent Brain Cognitive Development (ABCD) Study.

“We took a pretty broad approach,” said Paul, describing different phenotypes as “anything from impulse control problems and problematic behavior or psychotic-like experiences to screen time, to how much caffeine they consumed.”

Think of it as fishing with a big net.

That means they want to identify associations between genetic predisposition and potentially modifiable risk factors that can be potentially addressed before the onset of psychopathology, Bogdan, the Dean’s Distinguished Professor of Psychological & Brain Sciences in Arts & Sciences, said.

What they caught

The results of the PheWAS show some surprises and confirm some of what they already know about genetic risks and behaviors that are associated with mental health disorders in youth.

The WashU researchers took 11 GWAS and created four broad genetic risk factors, or polygenic scores: neurodevelopmental, internalizing (e.g., depression, anxiety), compulsive and psychotic. Below are some of the associations they found in those categories:

*Genetic risk for neurodevelopmental psychopathology (predominantly ADHD and Autism Spectrum Disorder, as well as Major Depressive Disorder and problematic alcohol use) was associated with some 190 phenotypes including inattention and impulsivity issues, as well as total screen time, sleep problems and psychotic-like experiences. Even environmental conditions like neighborhood crime rates and lower parental monitoring are associated with neurodevelopmental genetic risk.

*Genetic risk for internalizing behavior (Major Depressive Disorder, Generalized Anxiety Disorder, PTSD, as well as problematic alcohol use) were broadly associated with some 120 phenotypes such as depression, stressful life events, psychotic-like experiences and screen time.

*Psychotic risk (predominantly Schizophrenia and Bipolar Disorder) had few phenotype associations aside from lower school involvement and more consumption of energy drinks.

Karcher said it was somewhat surprising that “genetic liability” for mental health concerns may manifest through potentially modifiable behaviors in childhood and early adolescence.

The research sorted hundreds and hundreds of variables potentially associated with genetic risk, and the results highlighted several associations, including the association between neurodevelopmental genetic risk and screentime, she added.

“The PheWAS was able to point out these pockets of associations that may not have been found otherwise,” she said.

One such pocket was the association between psychotic disorder genetic risk and energy drink consumption. These studies are looking at correlation, not causation, so they cannot conclude that energy drink consumption causes psychotic disorders. It could be that there are genetic components that make these individuals more at risk for psychotic disorders and those same components might make these individuals more likely to consume caffeinated beverages.

A similar phenomenon could be a play with the strong association between screen time and neurodevelopmental risk.

The point of the PheWAS is not to sort those details of causation but get pointed in the right direction with “a 20,000-foot view of the associations,” Karcher said.

Time will tell as the ABCD kids get older and genomic databases get more diverse.

“Following these youth into early adulthood will help better inform how genetic risk is associated with things like screen time, psychopathology, symptoms, and sleep over the course of adolescence into early adulthood,” Paul said. “That will help paint a clearer picture of how these links between your overall genetic risk and your behavior and traits change or don’t change over time.”

Overall, the present work illustrates how the PheWAS technique can be used to identify potential targets for future prevention and early intervention strategies, with this study identifying several potentially modifiable targets, such as screen time and caffeinated beverage consumption, that could represent early “catches” for reducing risk for developing mental health concerns.

Previous genome-wide studies of psychiatric diagnoses/phenotypes make use of data from individuals most genetically similar to European reference populations, with limited well-powered GWAS available for other populations in the world. So, one major limitation of this study was that because the GWAS predominantly used data from European reference populations, only ABCD data from individuals with European ancestry could be used in the PheWAS.

“That really limits the generalizability of these findings,” Paul said, “but as more GWAS become available in individuals genetically similar to other reference populations, and as more sophisticated polygenic score approaches are developed, we should be able to expand the study population to be more inclusive.”

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Paul SE, Colbert SMC, Gorelik AJ, Hansen IS, Nagella I, Blaydon L, Hornstein A, Johnson EC, Hatoum AS, Baranger DAA, Elsayed NM, Barch DM, Bogdan R, Karcher NR. Phenome-wide Investigation of Behavioral, Environmental, and Neural Associations with Cross-Disorder Genetic Liability in Youth of European Ancestry. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00313-2

Data for this study were provided by the Adolescent Brain Cognitive Development (ABCD) study , which was funded by awards U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147 from the NIH and additional federal partners (https://abcdstudy.org/federal-partners.html). This study was supported by R01 DA054750. Authors received funding support from NIH: SEP was supported by F31AA029934. NRK was supported by K23MH12179201. AJG was supported by NSF DGE-213989. ECJ was supported by K01DA051759. ASH was supported by K01AA030083. DMB (R01-MH113883; R01-MH066031; U01-MH109589; U01-A005020803; R01-MH090786), RB (R01-DA054750, R01-AG045231, R01-AG061162, R21-AA027827, R01-DA046224, U01-DA055367). NME was supported by NSF DGE-1745038.

Journal

Nature Mental Health