Deutsche Forschungsgemeinschaft

Tiny organisms such as bacteria and fungi help to promote the health and function of plant roots. It is commonly assumed that the composition of these microbes is dependent on the properties of the soil. However, researchers have now discovered when studying different local varieties of maize that the genetic makeup of the plants also helps to influence which microorganisms cluster around the roots. Tiny organisms such as bacteria and fungi help to promote the health and function of plant roots. It is commonly assumed that the composition of these microbes is dependent on the properties of the soil. However, an international team of researchers led by the University of Bonn has now discovered when studying different local varieties of maize that the genetic makeup of the plants also helps to influence which microorganisms cluster around the roots. The results, which have now been published in the journal Nature Plants, could help to breed future varieties of maize that are better suited to drought and limited nutrients. In order to grow properly, plants take in water and nutrients through their roots. But they have the assistance of some tiny helpers: A layer of bacteria and fungi, just a few millimeters thick, can be found directly around the roots. "These microorganisms are essential for the health and fitness of the plants," says Dr. Peng Yu, head of the junior research group "Root Functional Biology" at the Institute of Crop Science and Resource Conservation (INRES) at the University of Bonn. The microbes help with the absorption of water and nutrients and protect the plants against harmful organisms -- similar to how the "microbiome" in the intestines of humans helps to determine whether we become ill or stay healthy. The traditional view is that the composition of the microbiome -- the totality of all microorganisms -- is mainly determined by the properties of the soil. This includes things such as the type of soil and whether it is more acidic or alkaline. However, an international team of researchers led by the University of Bonn has now demonstrated in maize plants that the genetic makeup of the host plants has a significant influence on the composition of the root microbes. "Our study also showed that the microbiome around the roots has a crucial influence on how resilient the maize plants are when faced with stressful conditions such as a nutrient deficits or lack of water," says Prof. Dr. Frank Hochholdinger from the Crop Functional Genomics department in INRES at the University of Bonn. In view of global climate change and the limited supply of the nutrient phosphorus, resilience of these plants to drought and a lack of nutrients could play an even greater role in the future. Adapting regional varieties of maize to environmental conditions The various varieties of maize have very different genetic composition. Regional varieties have adapted themselves to very different environmental conditions depending on whether they are cultivated, for example, in cooler highland or the warmer lowland areas of South America. "The fact that farmers have continued to select those varieties of maize suited to the local climate over many centuries has led to very different genotypes that we were able to utilize for our study," says Dr. Yu, who is head of an Emmy Noether junior research group funded by the German Research Foundation and also a member of the PhenoRob Cluster of Excellence and the transdisciplinary research area "Sustainable Futures" at the University of Bonn. In cooperation with scientists from Southwest University in Chongqing (China), the researchers studied a total of 129 different varieties of maize. Some of these were cultivated under "normal" conditions while others experienced deficiencies in phosphorus, nitrogen, or water. Additionally, the team sequenced the DNA of the microbes from 3168 samples taken from the layer found directly around the roots that is just a few millimeters thick. The role played by the genetic makeup of the roots became apparent in those plants grown under stressful conditions. Interestingly, the lack of nutrients and water had a significant influence on the composition of the microbes. Furthermore, the team discovered important characteristic differences in the microbiome between different varieties of maize under the same stressful conditions. "We were able to prove that certain maize genes are able to interact with certain bacteria," says Dr. Yu to explain on the most important results. Using data on the growth conditions at the place of origin of a certain variety of maize and on its genetic composition, the researchers were even able to predict which key organisms would be found in the microbiome around the roots. The bacterium Massilia promotes the growth of lateral roots The results for bacteria of the genus Massilia especially stood out: "It was very noticeable that very few specimens of this microbe were found when there was a sufficient supply of nitrogen," says Prof. Dr. Gabriel Schaaf from the Ecophysiology of Plant Nutrition department at INRES and member of the PhenoRob Cluster of Excellence. If there was a lack of nitrogen, however, lots of Massilia could be found clustering around the roots. The team then inoculated maize roots with this bacterium. The plants grew a lot more lateral roots as a result and were therefore able to significantly improve their uptake of nutrients and water. But how do maize plants manage to harness the tiny Massilia bacterium for this type of root growth? Following further studies, the researchers discovered that the roots actually attracted the Massilia bacteria using flavones. This substance is one of many secondary metabolites in the plant and stimulates the growth of lateral roots with the aid of the bacteria. "However, this was dependent on whether the maize plant had a microtubule-binding gene," says Dr. Peng Yu. If this gene was missing, the plant did not produce more lateral roots. The varieties of maize with the missing gene come from a huge database of maize mutations that has been set up by the researchers headed by Dr. Caroline Marcon at INRES. This database helps researchers explain the functions of maize genes. Maize varieties better adapted to drought and a lack of nutrients The international team of researchers hopes that they will also be able to predict yield in the medium term. "We are carrying out basic research," says Hochholdinger. "However, these results could act as the basis for cultivation of maize varieties better suited to drought and a lack of phosphorus by using genome and microbiome data."

Researchers report the results of the first ever genome-wide association study (GWAS) of a biosafety level 4 (BSL-4) virus. The team found two key human genetic factors that could help explain why some people develop severe Lassa fever, and a set of LARGE1 variants linked to a reduced chance of getting Lassa fever. The work could lay the foundation for better treatments for Lassa fever and other similar diseases. The scientists are already working on a similar genetics study of Ebola susceptibility. While combing through the human genome in 2007, computational geneticist Pardis Sabeti made a discovery that would transform her research career. As a then postdoctoral fellow at the Broad Institute of MIT and Harvard, Sabeti discovered potential evidence that some unknown mutation in a gene called LARGE1 had a beneficial effect in the Nigerian population. Other scientists had discovered that this gene was critical for the Lassa virus to enter cells. Sabeti wondered whether a mutation in LARGE1 might prevent Lassa fever -- an infection that is caused by the Lassa virus, is endemic in West Africa, and can be deadly in some people while only mild in others. To find out, Sabeti decided later in 2007, as a new faculty member at Harvard University, that one of the first projects her new lab at the Broad would take on would be a genome-wide association study (GWAS) of Lassa susceptibility. She reached out to her collaborator Christian Happi, now the Director of the African Center of Excellence for Genomics of Infectious Diseases (ACEGID) at Redeemer's University in Nigeria, and together they launched the study. Now, their groups and collaborators report the results of that study in Nature Microbiology -- the first ever GWAS of a biosafety level 4 (BSL-4) virus. The team found two key human genetic factors that could help explain why some people develop severe Lassa fever, and a set of LARGE1 variants linked to a reduced chance of getting Lassa fever. The work could lay the foundation for better treatments for Lassa fever and other similar diseases. The scientists are already working on a similar genetics study of Ebola susceptibility. The paper also describes the many challenges the team had to overcome during their 16-year collaborative effort, such as studying a dangerous virus and recruiting patients with a disease that is not well documented in West Africa. Dozens of scientists contributed to the work and spent seven years recruiting patients in Nigeria and Sierra Leone and many additional years establishing the research program and analyzing the results. "It truly took a village to get this done," said Happi, a co-senior author along with Sabeti. "Generations of people in our labs, across different institutions and countries, spent significant parts of their careers bringing this to fruition," added Sabeti, an institute member at the Broad, a Howard Hughes Medical Institute investigator, a professor at the Center for Systems Biology and the Department of Organismic and Evolutionary Biology at Harvard University, and a professor in the Department of Immunology and Infectious Disease at the Harvard T. H. Chan School of Public Health. The co-first authors of the study are Dylan Kotliar, an internal medicine resident at Brigham and Women's Hospital and an MD/PhD student in Sabeti's lab while the project was ongoing; Siddharth Raju, a graduate student in Sabeti's lab; Shervin Tabrizi, a postdoctoral researcher at the Broad; and Ikponmwosa Odia, a researcher at Irrua Specialist Teaching Hospital in Nigeria. Lassa learnings Sabeti recalls the team's early discussions when launching the project. They knew they had to be cautious at every step: To work with a BSL-4 virus, scientists must wear pressurized suits connected to HEPA-filtered air in a special containment lab. The virus causes fever, sore throat, coughing, and vomiting, but can quickly progress to organ failure in some people. "This was an extremely challenging study to get off the ground," said Kotliar, who worked on the project throughout his entire PhD in the Sabeti lab. "I think the battle scars, the things we've learned along the way about how to get a project like this done, are going to be important for future research into viruses in developing countries." Finding participants for the study would be challenging too. There are currently no FDA-approved diagnostics for Lassa, and Lassa virus cases are typically not documented. There are fewer than 1,000 cases reported each year in Nigeria, the most populous country where the virus is endemic, and cases are often in rural areas far from diagnostic centers, many of which don't have the technology to detect the virus. Infections with other viruses, and genomic complexity among different strains of the same Lassa virus can complicate analysis. Moreover, African populations have been historically underrepresented in past genetic studies, which reduces statistical power in data analyses and can make it difficult to identify key genetic variants. When Sabeti began thinking about how to start the project, she reached out to Happi, whom she knew through their mutual work on the malaria-causing pathogen, Plasmodium falciparum. With the help of collaborators including Peter Okokhere, a doctor treating Lassa patients at the Irrua Specialist Teaching Hospital, they began recruiting patients from both Nigeria and Sierra Leone. Then, they compared the genomes of about 500 people who'd had Lassa fever and nearly 2,000 who hadn't. In the Nigerian cohort, the team found that people with a set of variants in the LARGE1 gene -- which modifies a cell receptor that binds to certain viruses -- were less likely to get Lassa fever. Sabeti, Happi, and their colleagues also found genomic regions associated with Lassa fatality: in the LIF1 gene, which encodes an immune-signaling molecule, and, in the Nigerian cohort, the GRM7 gene, which is involved in the central nervous system. The team then used a large-scale screen called a massively parallel reporter assay to home in on which variants within these genomic regions might be functional and could be targets of new treatments. Better detection The researchers say that to improve detection and treatment of Lassa fever, more diagnostic centers and diagnostics that work in the field are needed, along with better health infrastructure to connect remote locations with major hospitals. "This really highlights the need for continued investment in understanding African population genetics," added Raju. "Even with a relatively limited sample set, we've increased our understanding of some African populations, specifically in immune-related genes -- and that shows how much more there is to do going forward." Sixteen years after they first started thinking about the genetics of Lassa fever, Sabeti and Happi are excited about the study's findings, which could explain the biological differences between mild and severe illness. They said the work also shows that, as thoughtful collaborations between countries, genome-wide association studies of BSL-4 viruses are possible. The researchers have already begun conducting a similar study of Ebola in Sierra Leone and Liberia, and other scientists are calling for increased pathogen surveillance and scientific training in Africa. "We're standing at a moment where we can actually start developing point-of-need diagnostics for Lassa virus and testing much more broadly," Happi said. "We need better infrastructure, but I think we've shown that this kind of study is a worthwhile pursuit." This work was supported in part by the National Institute of Health, the German Research Foundation, and the Howard Hughes Medical Institute.

What does the inside of a carbon atom's nucleus look like? A new study provides a comprehensive answer to this question. In the study, the researchers simulated all known energy states of the nucleus. These include the puzzling Hoyle state. If it did not exist, carbon and oxygen would only be present in the universe in tiny traces. Ultimately, we therefore also owe it our own existence. What does the inside of a carbon atom's nucleus look like? A new study by Forschungszentrum Jülich, Michigan State University (USA) and the University of Bonn provides the first comprehensive answer to this question. In the study, the researchers simulated all known energy states of the nucleus. These include the puzzling Hoyle state. If it did not exist, carbon and oxygen would only be present in the universe in tiny traces. Ultimately, we therefore also owe it our own existence. The study has now been published in the journal Nature Communications. The nucleus of a carbon atom normally consists of six protons and six neutrons. But how exactly are they arranged? And how does their configuration change when the nucleus is bombarded with high-energy radiation? For decades, science has been searching for answers to these questions. Not least because they could provide the key to a mystery that has long puzzled physicists: Why is there a significant amount of carbon in space at all -- an atom without which there would be no life on Earth? After all, shortly after the Big Bang, there was only hydrogen and helium. The hydrogen nucleus consists of a single proton, that of helium of two protons and two neutrons. All heavier elements were only created many billions of years later by aging stars. In them, helium nuclei fused into carbon nuclei at immense pressure and extremely high temperatures. This requires three helium nuclei to fuse together. "But it's actually very unlikely for this to happen," explains Prof. Dr. Ulf Meißner of the Helmholtz Institute of Radiation and Nuclear Physics at the University of Bonn and the Institute for Advanced Simulation at Forschungszentrum Jülich. The reason: The helium nuclei together have a much higher energy than a carbon nucleus. However, this does not mean that they fuse particularly readily -- on the contrary: It is as if three people wanted to jump onto a merry-go-round. But since they run much faster than the merry-go-round turns, they do not succeed. Simulation on the supercomputer As early as the 1950s, the British astronomer Fred Hoyle therefore postulated that the three helium nuclei first come together to form a kind of transition state. This "Hoyle state" has a very similar energy to the helium nuclei. To stay in the picture: It is a faster-spinning version of the merry-go-round, which the three passengers can therefore easily jump onto. When that happens, the carousel slows down to its normal speed. "Only by taking a detour via the Hoyle state can stars create carbon at all in any appreciable quantity," says Meißner, who is also a member of the Transdisciplinary Research Areas "Modeling" and "Matter" of the University of Bonn. About ten years ago, together with colleagues from the USA, Forschungszentrum Jülich and Ruhr-Universität Bochum, he succeeded in simulating this Hoyle state for the first time. "We already had an idea then of how the protons and neutrons of the carbon nucleus are arranged in this state," he explains. "However, we were not able to prove with certainty that this assumption was true." With the help of an advanced method, the researchers have now succeeded. This is essentially based on confinement: In reality, the protons and neutrons -- the nucleons -- can be located anywhere in space. For their calculations, however, the team restricted this freedom: "We arranged our nuclear particles on the nodes of a three-dimensional lattice," Meißner explains. "So we allowed them only certain strictly defined positions." Computing time: five million processor hours Thanks to this restriction, it was possible to calculate the motion of nucleons. Since nuclear particles affect each other differently depending on their distance from each other, this task is very complex. The researchers also ran their simulation several million times with slightly different starting conditions. This allowed them to see where the protons and neutrons were most likely to be. "We performed these calculations for all known energy states of the carbon nucleus," Meißner says. The calculations were performed on the JEWELS supercomputer at Forschungszentrum Jülich. They required a total of about five million processor hours, with many thousands of processors working simultaneously. The results effectively provide images from the carbon nucleus. They prove that the nuclear particles do not exist independently of each other. "Instead, they are clustered into groups of two neutrons and two protons each," the physicist explains. This means that the three helium nuclei can still be detected after they have fused to form the carbon nucleus. Depending on the energy state, they are present in different spatial formations -- either arranged into an isosceles triangle or like a slightly bent arm, with the shoulder, elbow joint and wrist each occupied by a cluster. The study not only allows researchers to better understand the physics of the carbon nucleus. Meißner: "The methods we have developed can easily be used to simulate other nuclei and will certainly lead to entirely new insights." Participating institutions and funding: Forschungszentrum Jülich, Michigan State University (USA), the China Academy of Engineering Physics and the University of Bonn were involved in the study. The work was made possible by funding from the German Research Foundation, the National Natural Science Foundation of China, the Chinese Academy of Sciences (CAS), the Volkswagen Foundation, the European Research Council (ERC), the U.S. Department of Energy, the Nuclear Computational Low-Energy Initiative (NUCLEI), and the Gauss Center for Supercomputing e.V.