GN/ Researchers propose new framework for regulating engineered crops
Genetics biweekly vol.36, 24th August — 7th September
TL;DR
- A new article calls for a new approach to regulating genetically engineered crops, arguing that current approaches for triggering safety testing vary dramatically among countries and generally lack scientific merit — particularly as advances in crop breeding have blurred the lines between conventional breeding and genetic engineering.
- An insulin-suppressing protein may be the fountain of youth for ants and provides clues about aging in other species, according to a new study.
- A team of scientists has designed a synthetic protein that quickly detects molecules of a deadly nerve agent that has been classified by the United Nations as a weapon of mass destruction and could be used in a chemical warfare attack.
- Mammals possess a novel gene that controls a novel structure in nerve cells, according to a new study.
- Researchers have discovered that the motion of chromatin, the material that DNA is made of, can help facilitate effective repair of DNA damage in the human nucleus — a finding that could lead to improved cancer diagnosis and treatment.
- The phenomenon of regeneration was discovered over 200 years ago in the freshwater polyp Hydra. Until now, however, it was largely unclear how the orderly regeneration of lost tissues or organs is activated after injury. In its investigations of Hydra, an interdisciplinary research team was able to show how wound healing signals released upon injury are converted into specific signals of pattern formation and cell differentiation.
- Adding an ingredient called an adjuvant can help vaccines elicit a more robust immune response, better training the body to fight a pathogen. Researchers report a substance that boosted the immune response to an experimental COVID-19 shot in mice by 25 times, compared to injection with the vaccine alone.
- Researchers have documented that corals can pass mutations acquired during their lifetimes to their offspring, providing increased genetic diversity for potential evolutionary adaptation.
- Changes known as epigenetic modifications play an important role in cancer development, among other things. Being able to analyze them quickly and reliably could, for example, contribute significantly to the further development of personalized therapy. A research team has now succeeded in characterizing the chemical changes in proteins that are typical for epigenetic modifications using nanopore analysis.
- The consumption of rice accounts for nearly half the total intake of cadmium, a toxic heavy metal, among humans. Now, scientists have found that the duplication of a cadmium transporter gene in the Pokkali rice cultivar reduces cadmium accumulation in the shoots and grain. They introduced this trait into a different rice cultivar and saw reduced cadmium accumulation with no effect on grain yield and quality, providing a useful target to breed low-cadmium-accumulating rice cultivars.
- And more!
Overview
Genetic technology is defined as the term which includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi and genetic modification. Only some gene technologies produce genetically modified organisms.
Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do and how DNA can be modified to add, remove or replace genes. You can find major genetic technologies development milestones via the link.
Gene Technology Market
- The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
- Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
- North America holds the largest share in the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.
- Another research provider, MarketsandMarkets, forecasts the genome editing, genome engineering market to grow from USD 3.19 billion in 2017 to USD 6.28 billion by 2022, at a compounded annual growth rate (CAGR) of 14.5% during the forecast period. The key factors propelling market growth are rising government funding and growth in the number of genomics projects, high prevalence of infectious diseases (like COVID-19) and cancer, technological advancements, increasing production of genetically modified (GM) crops, and growing application areas of genomics.
Latest News & Research
Toward product-based regulation of crops
by Fred Gould, Richard M. Amasino, Dominique Brossard, C. Robin Buell, Richard A. Dixon, Jose B. Falck-Zepeda, Michael A. Gallo, Ken E. Giller, Leland L. Glenna, Timothy Griffin, Daniel Magraw, Carol Mallory-Smith, Kevin V. Pixley, Elizabeth P. Ransom, David M. Stelly, C. Neal Stewart in Science
A new article calls for a new approach to regulating genetically engineered (GE) crops, arguing that current approaches for triggering safety testing vary dramatically among countries and generally lack scientific merit — particularly as advances in crop breeding have blurred the lines between conventional breeding and genetic engineering.
Rather than focusing on the methods and processes behind the creation of a GE crop to determine if testing is needed, a more effective framework would examine the specific new characteristics of the crop itself by using so-called “-omics” approaches, the article asserts. In the same way that biomedical sciences can use genomic approaches to scan human genomes for problematic mutations, genomics can be used to scan new crop varieties for unexpected DNA changes.
Additional “-omics” methods such as transcriptomics, proteomics, epigenomics and metabolomics test for other changes to the molecular composition of plants. These measurements of thousands of molecular traits can be used like a fingerprint to determine whether the product from a new variety is “substantially equivalent” to products already being produced by existing varieties — whether, for example, a new peach variety has molecular characteristics that are already found in one or more existing commercial peach varieties.
If the new product has either no differences or understood differences with no expected health or environmental effects when compared with products of existing varieties, no safety testing would be recommended, the article suggests. If, however, the product has new characteristics that have the potential for health or environmental effects, or if the product has differences that cannot be interpreted, safety testing would be recommended.
“The approaches used right now — which differ among governments — lack scientific rigor,” said Fred Gould, University Distinguished Professor at North Carolina State University, co-director of NC State’s Genetic Engineering and Society Center and the corresponding author of the article. “The size of the change made to a product and the origin of the DNA have little relationship with the results of that change; changing one base pair of DNA in a crop with 2.5 billion base pairs, like corn, can make a substantial difference.”
When dealing with varieties made using the powerful gene editing system known as CRISPR, for example, the European Union regulates all varieties while other governments base decisions on the size of the genetic change and the source of inserted genetic material. Meanwhile, in 2020 the U.S. Department of Agriculture established a rule that exempts from regulation conventionally bred crop varieties and GE crop varieties that could have been developed by methods other than genetic engineering.
The “-omics” approaches, if used appropriately, would not increase the cost of regulation, Gould said, adding that most new varieties would not trigger a need for regulation. “The most important question is, ‘Does the new variety have unfamiliar characteristics,’” Gould said. The paper estimates that technological advances could make the laboratory cost for a set of “-omics” tests decrease to about $5,000 within five to 10 years.
Insulin signaling in the long-lived reproductive caste of ants
by Hua Yan, Comzit Opachaloemphan, Francisco Carmona-Aldana, Giacomo Mancini, Jakub Mlejnek, Nicolas Descostes, Bogdan Sieriebriennikov, Alexandra Leibholz, Xiaofan Zhou, Long Ding, Maria Traficante, Claude Desplan, Danny Reinberg in Science
An insulin-suppressing protein may be the fountain of youth for ants and provides clues about aging in other species, according to a study led by New York University researchers.
The study shows that queen ants exhibit high metabolism for reproduction without undergoing aging by generating an anti-insulin protein that blocks only part of the insulin pathway that is responsible for aging.
In many animals, having many offspring is linked to a shorter lifespan. This trade-off between fertility and longevity in animals is thought to result from how nutritional and metabolic resources are allocated. Insulin — a hormone that helps convert food into energy — plays a major role in metabolism, but also in aging. Producing eggs is energy intensive and requires extra food, which raises insulin levels, but increased activity of the insulin pathway required for reproduction leads to shorter lifespan in most animals. In contrast, dietary restriction prolongs life by keeping insulin levels down; in fact, other researchers are exploring whether fasting improves longevity.
Ants are a notable exception to the trade-off between reproduction and longevity, as their queens — which are responsible for the whole colony’s reproduction — live much longer than worker ants while sharing the same genome. In a species such as the black garden ant, a queen can lay one million eggs and live for 30 years, while her sterile worker sisters only live for a year. In Harpegnathos saltator ants, a species of jumping ants native to India that was the focus of this study, queens typically live for five years while workers live for only seven months.When the Harpegnathos queen dies in a colony, a peculiar event occurs: female worker ants duel each other with their antennae, vying to become the next queen. The duel winners change “caste” in the ant society and become pseudoqueens, also known as gamergates, while still remaining in the (smaller) body of a worker. Pseudoqueens acquire queen-like behaviors, including laying eggs, and their life expectancy substantially increases from seven months to four years. But, if they are replaced by another queen, they revert to their worker status, stop laying eggs, and their lifespan is shortened back to seven months.
“By undergoing reversible ‘caste switching’ from workers to pseudoqueens that results in a dramatic increase in both their lifespan and ability to reproduce, Harpegnathos ants provide a unique opportunity to study how aging and reproduction can be disconnected,” said the study’s co-senior author Claude Desplan, Silver Professor of Biology and Neural Science at NYU.
Using bulk RNA-sequencing, the researchers studied tissue samples from both workers and pseudoqueens, focusing on parts of the ant involved in metabolism and reproduction including the brain, fat body (the liver of insects), and ovaries. They found that the ants that switched from worker to pseudoqueen produce more insulin in their brains in order to produce eggs. This increased insulin results in the activation of one of the two main branches of the insulin signaling pathway, MAPK, which controls metabolism and egg formation. The increased insulin in pseudoqueens induces ovary development, which then begins producing an insulin-suppressing protein called Imp-L2. Imp-L2 blocks signaling in the other main branch of the insulin signaling pathway, AKT, which controls aging and whose increased activity leads to shorter life span.
“The two main branches of the insulin signaling pathway appear to differentially regulate fertility and lifespan, with increased signaling in one aiding reproduction in pseudoqueens and decreased signaling in the other consistent with their extended longevity,” said the study’s co-senior author Danny Reinberg, the Terry and Mel Karmazin Professor of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and a Howard Hughes Medical Institute investigator.
“This interplay, which evolved in ants and perhaps in other insects, may contribute to the unusual longevity and many offspring in reproducing ants,” said Hua Yan, the study’s co-first author and a former postdoctoral researcher at NYU Grossman School of Medicine, who is now an assistant professor of biology at the University of Florida.
“Our work also illustrates the importance of using the appropriate model systems to ask questions about essential biological questions. For instance, most manipulations of longevity in animals like mice or flies usually extend their lifespans by 10 to 20 percent. Ants exhibit a remarkable 500 percent increase in longevity, which makes studying them much more powerful,” added Desplan.
Computational design of a sensitive, selective phase-changing sensor protein for the VX nerve agent
by James J. McCann, Douglas H. Pike, Mia C. Brown, David T. Crouse, Vikas Nanda, Ronald L. Koder in Science Advances
A team that includes Rutgers scientists has designed a synthetic protein that quickly detects molecules of a deadly nerve agent that has been classified by the United Nations as a weapon of mass destruction and could be used in a chemical warfare attack.
This development could pave the way for a new generation of tailor-made biosensors and treatments that could be deployed against the chemical warfare agent, VX, scientists said. The team created the protein through a special design on high-speed computers in Rutgers laboratories.
“We’ve made an artificial protein that binds a chemical target — in this case, the VX nerve agent,” said Vikas Nanda, an author on the study and a scientist at Rutgers’ Center for Advanced Biotechnology and Medicine (CABM). “We wanted to design it to generate a signal that could be coupled to a device, making a biosensor for chemical weapons. And we’ve been able to achieve that.”
VX is an odorless, tasteless, human-made chemical compound that is the most toxic and rapidly acting of any of the known chemical warfare agents. It works by attacking the nervous system, causing muscle paralysis and death via asphyxiation within minutes. Because VX is classified as a weapon of mass destruction, countries are banned from stockpiling it. However, nations are permitted to store small amounts for research. The Rutgers team designed the protein to have a cavity at its center that matched the precise shape and chemical composition of VX. Collaborators at the City College of New York took the Rutgers design and produced a real version of the protein, purified it and shipped the sample on ice overnight to an approved chemical weapon testing facility, MRIGlobal in Kansas City, Mo. There, the protein was tested against VX within 24 hours.
“The protein underwent a dramatic shape change, burying VX in the cavity we designed,” said Nanda, who also is a professor in the department of biochemistry and molecular biology at Rutgers Robert Wood Johnson Medical School. “This shape change is the signal which could be coupled to a sensor device.”
The protein, Nanda said, can detect VX at levels a thousand times more sensitive than current technologies. In addition, the protein doesn’t produce false positives that occur when present-day sensors accidentally detect non-nerve agent chemicals which are similar, like some pesticides. According to the website of the U.S. Centers for Disease Control and Prevention, VX or other nerve agents were possibly used in chemical warfare during the Iran-Iraq War in the 1980s. Chemical weapons experts have alleged it also has been used more recently in warfare and, in one case, an assassination. While antidotes are available for VX, they are most useful if given as soon as possible after exposure.
“The design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics,” Nanda said.
A novel gene controls a new structure: PiggyBac Transposable Element-derived 1, unique to mammals, controls mammal-specific neuronal paraspeckles
by Tamás Raskó, Amit Pande, Kathrin Radscheit, et al in Molecular Biology and Evolution
Evolution is often portrayed as a “tinkering” process, one that makes use of slight modifications to pre-existing capabilities. So how do organisms evolve brand new structures?
A new study by Dr. Zsuzsanna Izsvák from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) and Professor Laurence Hurst from the Milner Centre for Evolution at University of Bath (UK) found evidence that evolution of a new gene underpins the evolution of a new structure found in nerve cells. They describe this unusual gene called piggyBac Transposable Element-derived 1, or PGBD1.
PGBD1 is one of five related PGBD genes that shows a distinct resemblance to the piggyBac element first identified in insects — hence the name piggyBac Transposable Element-derived. The PiggyBac elements are “jumping genes,” also called transposons. They are able to copy themselves and to move from one location in the genome to another, sometimes introducing mutations or changing functions. PiggyBac transposons arrived into our species by horizontal transfer — similar to how some viruses can integrate their genome into our DNA. However, while the piggyBac transposons have lost their ability to jump around in our DNA over time, five piggyBac Transposable Element-derived genes (PGBD1–5) have been fixed in humans.
“We aimed at finding out what potentially useful function the PGBD genes might have,” says Zsuzsanna Izsvák. “For this study, we focused on PGBD1.”
Amongst the five PGBD genes PGBD1 is unique in that it has also incorporated parts of other genes, resulting in a protein that has extra parts that are able to bind other proteins and to bind DNA. PGBD1 is thus a novel gene that is part human gene fragment, part inactive jumping gene.
PGBD1 is found only in mammals. It is particularly active in cells that become neurons. The researchers first investigated, where PGBD1 protein binds to DNA, observing that it glues itself in and around genes associated with nerve development. They found PGBD1 controls nerve cell development by blocking genes expressed in mature nerve cells while keeping those genes associated with being pre-nerve cells activated. Reducing the level of PGBD1 in pre-nerve cells caused them to start developing as nerve cells. One of the genes that PGBD1 protein binds especially attracted their interest. NEAT1 is a strange gene that codes for an RNA which, unusually, doesn’t then go on to make a protein. Instead, this product, a non-coding RNA, makes the backbone of a physical structure, the paraspeckles. These are tiny structures in the nuclei of some of our cells that act like traps for some RNAs and proteins. The researchers found that in pre-nerve cells PGBD1 protein binds to the NEAT1 gene and stops it from working. However, when PGBD1 levels go down, NEAT1 RNA levels go up, paraspeckles form and cells become mature nerve cells. PGBD1 thus has evolved to be a key regulator of presence or absence of paraspeckles, and thus the regulator of nerve cell development.
What, however, is most intriguing is that paraspeckles are, like PGBD1, also mammal-specific. PGBD1 is then a rare example of a new gene that has evolved to regulate a new structure, albeit a rather small one. Zsuzsanna Izsvák, co-senior author from Max Delbrück Center, says: “This is a really unusual and serendipitous discovery. We have known that duplication of pre-existing genes can underpin the evolution of novelty, but this is a rare example of evolution doing more than just tinkering. This is a novel gene to control a novel structure.” The exciting question now is whether it also plays a role in adult neurons.
Co-senior author Professor Laurence Hurst of the Milner Centre for Evolution at the University of Bath adds: “We have worked out how paraspeckles are controlled, now we just need to work out how the paraspeckle itself evolved. This might be a much harder task as non-coding RNAs like NEAT1 tend to be fast evolving and therefore hard to trace over evolutionary time.”
This coupling between NEAT1 and PGBD1 may also be involved in schizophrenia. While NEAT1 has been previously associated with this neurological disease, the team identified some mutations in PGBD1 that they could show were also common in patients with schizophrenia — one of these mutations changes the protein of PGBD1 while others may control its level. First author Dr Tamas Raskó, at the time of the study a postdoctoral researcher in the group of Zsuzsanna Izsvák: “It is surely more than coincidence that both genes are involved in schizophrenia. It is very unusual to find a mutation that changes a protein that is coupled to this disease. The effects of this mutation must be a priority for further studies.”
DNA damage reduces heterogeneity and coherence of chromatin motions
by Maëlle Locatelli, Josh Lawrimore, Hua Lin, Sarvath Sanaullah, et al in Proceedings of the National Academy of Sciences
A multidisciplinary team of Indiana University researchers have discovered that the motion of chromatin, the material that DNA is made of, can help facilitate effective repair of DNA damage in the human nucleus — a finding that could lead to improved cancer diagnosis and treatment.
DNA damage happens naturally in human body and most of the damage can be repaired by the cell itself. However, unsuccessful repair could lead to cancer.
“DNA in the nucleus is always moving, not static. The motion of its high-order complex, chromatin, has a direct role in influencing DNA repair,” said Jing Liu, an assistant professor of physics in the School of Science at IUPUI. “In yeast, past research shows that DNA damage promotes chromatin motion, and the high mobility of it also facilitates the DNA repair. However, in human cells this relationship is more complicated.”
Liu and his colleagues found that chromatin on the site of DNA damage moves much faster than those away from the DNA damage. They also found that the chromatin in cell nuclei is not moving randomly. It’s a coherent movement, with the DNA moving as a group over a short distance. The researchers also found evidence that DNA damage may affect the DNA’s group movement by reducing the coherence. These findings indicate that chromatin motion is under tight control when DNA is damaged. This is important to prevent the damaged DNA from harmful contact and to improve the accuracy and efficacy of DNA repair, Liu said.
“Our findings reveal a fundamental role of the chromatin motion in DNA damage response and DNA repair,” Liu said. “These findings can help to understand the mechanism of DNA repair in human cells and cancer initiation in humans. Practically, we can use these findings as the metrics for the drug response of many different drugs used to treat cancer. We can test different drugs to see if the chromatin motion can be modified to enhance DNA repair.”
In order to conduct this research, Liu and his colleagues had to develop the computational tools necessary for analyzing massive amounts of data. With data sizes as large as a terabyte in some cases, Liu and his colleagues worked with IU’s University Information Technology Services to establish the Scalable Data Archive of highly dynamic cell images, which centralizes data storage, data transfer, and data processing.
In the future, the researchers hope to study single DNA molecules and how they are moving, and how individual and group dynamics differ and change in response to DNA damage. They’d also like to learn more about DNA movement in specific genes that are known to be more vulnerable to DNA damage.
Injury-induced MAPK activation triggers body axis formation in Hydra by default Wnt signaling
by Anja Tursch, Natascha Bartsch, Moritz Mercker, Jana Schlüter, Mark Lommel, Anna Marciniak-Czochra, Suat Özbek, Thomas W. Holstein in Proceedings of the National Academy of Sciences
The phenomenon of regeneration was discovered over 200 years ago in the freshwater polyp Hydra. Until now, however, it was largely unclear how the orderly regeneration of lost tissues or organs is activated after injury. In its investigations of Hydra, an interdisciplinary research team at Heidelberg University was able to show how wound healing signals released upon injury are converted into specific signals of pattern formation and cell differentiation. Essential components are the mitogen-activated protein kinases (MAPK) and the Wnt signalling pathway — molecular mechanisms that have remained relatively unchanged throughout evolution.
The ability to regenerate varies widely in animals. Most mammals and vertebrates have only limited regeneration capacity, while basal and simple animals that emerged early in evolution, like cnidarians and planarians, can regenerate their whole body. In all cases, the process of regeneration begins with wound healing. The cells at the site of injury proliferate and form an undifferentiated mass — a blastema — from which the missing structures are re-patterned. This activates genetic processes that also control embryonic development. To determine the molecular mechanisms involved, the research team led by Prof. Dr Thomas W. Holstein studied the freshwater polyp Hydra to understand the basic features of this activation of regeneration.
The core of their investigations is the doctoral thesis of Anja Tursch. She repeated the key experiment of Geneva naturalist Abraham Trembley (1710 to 1784) which led him to discover the regeneration phenomenon. The Hydra polyp is bisected, prompting the upper half to regenerate a new “head” and the lower half a new “foot” — hence totally different body parts can grow from the exact same tissue at the cut surface in the middle. Building on their previous work on Hydra regeneration, the researchers at the Centre for Organismal Studies (COS) of Heidelberg University have now shown how this is possible.
Regardless of where it occurs, any damage triggers nonspecific signals for an injury response, i.e. wound healing, via calcium ions and the production of reactive oxygen species. The signals are transmitted intracellularly by three mitogen-activated protein kinases — p38, JNKs, and ERK. Activation of these three molecules is required for both head and foot regeneration. Wnt signalling pathways are then activated that are important during embryonic development for the formation of rudimentary organs and the body axis. The generic signals of wound healing are thus transferred into position-specific signals of patterning and cell differentiation for regeneration.
“Our experiments show that the Wnt signalling pathway is a main component of the initially general injury response and, depending on signal strength, directs the tissue toward head or foot development,” explains Prof. Holstein. This is why, in the case of MAPK inhibition, the otherwise absent regeneration can be induced by artificially generated, recombinant Wnt proteins. “It was also surprising that in middle body parts that had both head and foot removed, heads can be induced at both ends in this way,” adds Dr Suat Özbek, a member of Prof. Holstein’s “Molecular Evolution and Genomics” research group at the COS.
Wnt/β-catenin, one piece of the Wnt signalling pathway, was already known to encode positional information for new head structure formation. In collaboration with mathematicians led by Prof. Dr Anna Marciniak-Czochra, the research team of Prof. Holstein and Dr Özbek developed a model that shows how basal positional information in the tissue transforms the initially undifferentiated injury response into a differential patterning process via the Wnt signalling pathway. “Because MAPKs and Wnts are highly evolutionarily conserved, this mechanism is likely deeply embedded in our genome, which is important for regenerative processes in vertebrates and mammals as well,” stresses Thomas Holstein.
Duplication of a manganese/cadmium transporter gene reduces cadmium accumulation in rice grain
by En Yu, Wenguang Wang, Naoki Yamaji, Shuichi Fukuoka, Jing Che, Daisei Ueno, Tsuyu Ando, Fenglin Deng, Kiyosumi Hori, Masahiro Yano, Ren Fang Shen, Jian Feng Ma in Nature Food
Rice is a staple food for nearly half the world’s population. However, it accumulates more cadmium from the soil than other cereals like barley and wheat. Reports estimate that 40–65% of our total intake of cadmium, a toxic heavy metal, is from rice. Eating cadmium-contaminated rice poses a serious health risk to humans, with conditions like Itai-itai disease being associated with high cadmium intake.
Efforts have been previously made to reduce the quantity of cadmium in rice through methods like importing clean soil, water management, and mixing contaminated soil with biochar and lime. However, these methods are time-consuming and expensive. To remedy this, scientists have turned to cross-breeding to cultivate rice that accumulate less cadmium.
“We have been working on the mechanisms of cadmium accumulation in rice and barley for a long time and have identified several key genes involved in its accumulation,” says Prof. Jian Feng Ma, who is affiliated to the Institute of Plant Sciences and Resources at Okayama University, Japan.
After examining 132 accessions of rice, Prof Ma and the members of his research group found that the gene, OsNramp5, when duplicated in tandem, reduced the accumulation of cadmium in Pokkali, a variety of rice that has been cultivated for 3000 years in Kerala, India. According to previous reports, OsNramp5 encodes a cadmium and manganese transporter protein in rice. The same gene, when duplicated in tandem, turns to increase the uptake of both the minerals into the root cells. Consequently, manganese competes with cadmium in the cells for translocation to the shoots, which in turn reduces the accumulation of cadmium in these parts.
The scientists found that out of the 132 accessions of rice, the tandem duplication of OsNramp5 was naturally found only in Pokkali, which can grow in salt-laden coastal soil. The researchers also noted that the spatial expression level of OsNramp5 was always around two-fold higher in the roots of Pokkali than that in the roots of Koshihikari.
As Pokkali stores extremely low cadmium in its shoots, the scientists introgressed (a term for the transfer of genetic information across species) the duplicated OsNramp5 gene in Koshihikari, a variety of rice that is very popular in Japan but accumulates relatively high levels of cadmium. Explaining how targeted breeding can help humans, Prof. Ma says, “We identified a gene responsible for differential accumulation of cadmium in rice grain based on natural variations in cadmium accumulation. Then, we applied this gene to successfully breed rice cultivars with low cadmium accumulation in the grain.”
The team found that the Koshihikari cultivar with the duplicated gene accumulated significantly lower amounts of cadmium without comprising on the grain quality or yield.
Recounting the benefits of a low cadmium-accumulating rice variety, Prof. Ma explains, “Cadmium is a toxic heavy metal and threatens our health through the food chain. Our study provided a useful material for breeding varieties of rice with low cadmium accumulation, which contributes to produce safe and healthy food. We hope that this gene will be widely used in breeding different rice cultivars with low cadmium accumulation. This will protect us from cadmium poisoning.”
Inheritance of somatic mutations by animal offspring
by Kate L. Vasquez Kuntz, Sheila A. Kitchen, Trinity L. Conn, Samuel A. Vohsen, Andrea N. Chan, Mark J. A. Vermeij, Christopher Page, Kristen L. Marhaver, Iliana B. Baums in Science Advances
In a discovery that challenges over a century of evolutionary conventional wisdom, corals have been shown to pass somatic mutations — changes to the DNA sequence that occur in non-reproductive cells — to their offspring. The finding, by an international team of scientists led by Penn State biologists, demonstrates a potential new route for the generation of genetic diversity, which is the raw material for evolutionary adaptation, and could be vital for allowing endangered corals to adapt to rapidly changing environmental conditions.
“For a trait, such as growth rate, to evolve, the genetic basis of that trait must be passed from generation to generation,” said Iliana Baums, professor of biology at Penn State and leader of the research team. “For most animals, a new genetic mutation can only contribute to evolutionary change if it occurs in a germline or reproductive cell, for example in an egg or sperm cell. Mutations that occur in the rest of the body, in the somatic cells, were thought to be evolutionarily irrelevant because they do not get passed on to offspring. However, corals appear to have a way around this barrier that seems to allow them to break this evolutionary rule.”
Since the time of Darwin, our understanding of evolution has become ever more detailed. We now know that an organism’s traits are heavily determined by the sequence of their DNA. Individuals in a population vary in their DNA sequence, and this genetic variation can lead to the variation in traits, such as body size, that could give an individual a reproductive advantage. Only rarely does a new genetic mutation occur that gives an individual such a reproductive advantage and evolution can only proceed further if — and this is the key — the individual can pass the change to its offspring.
“In most animals, reproductive cells are segregated from body cells early in development,” said Kate Vasquez Kuntz, a graduate student at Penn State and the co-lead author of the study. “So only genetic mutations that occur in the reproductive cells have the potential to contribute to the evolution of the species. This slow process of waiting for rare mutations in a particular set of cells can be particularly problematic given the rapid nature of climate change. However, for some organisms, like corals, the segregation of reproductive cells from all other cells may occur later in development or may never occur at all, allowing a path for genetic mutations to travel from a parent’s body to its offspring. This would increase genetic variation and potentially even serve as a ‘pre-screening’ system for advantageous mutations.”
Corals can reproduce both asexually (through budding and colony fragmentation) and sexually, by producing egg and sperm cells. For the Elkhorn corals studied here, which broadcast their egg and sperm cells into the water in spawning events, eggs from one coral colony are usually fertilized by sperm from a neighboring colony. However, the research team found that some Elkhorn coral eggs developed into viable offspring without a second coral being involved, a kind of single-parent sexual reproduction.
“This single-parent reproduction allowed us to more easily search for potential somatic mutations from the parent coral and track them into the offspring by simplifying the total number of genetic possibilities that could occur in the offspring,” said Sheila Kitchen, co-lead author of the study, a postdoctoral researcher at Penn State and the California Institute of Technology co-lead author of the study.
The research team genotyped samples — using a high-resolution molecular tool called a microarray to investigate DNA differences between the samples — from ten different locations on a large Elkhorn coral colony that had produced single-parent offspring, and samples from five neighboring colonies at nearly 20,000 genetic locations. The results showed that all six of the separate coral colonies belonged to the same original coral genotype (known as a “genet”), meaning essentially that they were clones derived from a single original colony through asexual reproduction and colony fragmentation. Thus, any genetic variation found in these corals would have been the result of somatic mutation. The team found a total of 268 somatic mutations in the samples, with each coral sample harboring between 2 and 149 somatic mutations.
The team then looked at the single-parent offspring from the parent Elkhorn coral colony and found that 50% of the somatic mutations had been inherited. The exact mechanism of how the somatic mutations make their way into germline cells in the corals is still unknown, but the researchers suspect that the segregation between body and germline cells in corals may be incomplete and some body cells may retain the capacity to form germ cells, allowing somatic mutations to make their way into offspring. They also found evidence for the inheritance of somatic mutations in some offspring from the mating of two separate coral parents but will need additional studies to confirm this.
“Because corals grow as colonies of genetically-identical polyps, somatic mutations that arise in one coral polyp can be exposed to the environment and screened for their utility without necessarily affecting the entire colony,” said Baums. “Therefore, cells with potentially harmful mutations may die off and cells with potentially advantages mutations could thrive and spread as the coral colony continues to grow. If these mutations can then be passed on to offspring — as we have now demonstrated — it means that corals have an additional tool that might be able to speed up their adaptation to climate change.”
A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses
by Ya-Qian Li, Cheng Yan, Xi-Feng Wang, Mao-Ying Xian, Guo-Qing Zou, Xiao-Fei Gao, Rui Luo, Zheng Liu in ACS Infectious Diseases
Ironically, some vaccines need their own “boosters.” Adding an ingredient called an adjuvant can help vaccines elicit a more robust immune response, better training the body to fight a pathogen. In a new study, researchers report a substance that boosted the immune response to an experimental COVID-19 shot in mice by 25 times, compared to injection with the vaccine alone.
Although the first COVID-19 shots authorized in the U.S. apply cutting-edge genetic technology, the tried-and-true strategy of using proteins from the pathogen can produce vaccines that are less expensive to make and easier to store. So far, the U.S. Food and Drug Administration has authorized only one protein-based vaccine, made by Novavax, against SARS-CoV-2. However, many currently available inoculations against other diseases rely on proteins or pieces of them, and these shots contain adjuvants to enhance their effect. Researchers have found that molecules derived from α-galactosylceramide (αGC), a compound from marine sponges, can act as adjuvants by stimulating a small population of immune cells important for defending the body against viral infections. Rui Luo, Zheng Liu and their colleagues wanted to see if they could devise a version of αGC to significantly boost the immune response elicited by a protein-based COVID-19 vaccine.
The team made four analogs of αGC and added each to an experimental vaccine containing a piece of SARS-CoV-2’s spike protein, which the virus uses to infect cells. The researchers gave mice three injections over 29 days and tracked their immune response out to 35 days. To measure the effects of the adjuvants, they looked at various aspects of immune function, including two ways the immune system eliminates pathogens: through antibodies, which are immune proteins that latch onto an invader, and T cells, which kill diseased cells. None of the four meaningfully enhanced the T cell response, but all of them produced antibodies with a much greater capacity for interfering with the virus. The analog called αGC-CPOEt led to the production of antibodies with the greatest neutralizing capacity — 25 times greater than what the vaccine could elicit without an adjuvant. These results suggest αGC-CPOEt merits further investigation as a potential adjuvant to fight COVID-19 and other infectious diseases, the researchers say.
Resolving Isomeric Posttranslational Modifications Using a Biological Nanopore as a Sensor of Molecular Shape
by Tobias Ensslen, Kumar Sarthak, Aleksei Aksimentiev, Jan C. Behrends in Journal of the American Chemical Society
Changes known as epigenetic modifications play an important role in cancer development, among other things. Being able to analyze them quickly and reliably could, for example, contribute significantly to the further development of personalized therapy. A research team from the Institute of Physiology at the University of Freiburg has now succeeded in characterizing the chemical changes in proteins that are typical for epigenetic modifications using nanopore analysis.
In recent years, nanopores have become a widely applicable tool for the analysis of molecules. Due to their special properties, they allow the structure of molecules to be analyzed within fractions of a second: As cylindrically arranged proteins, nanopores form tiny channels only a few millionths of a millimeter (nanometer) in diameter that can be embedded in biomembranes. “For the experiments, we apply a constant voltage across the membrane so that ions from the surrounding medium flow through the pore. This creates a constant, precisely measurable electric current” explains Prof. Dr. Jan C. Behrends from the Faculty of Medicine at the University of Freiburg, in whose laboratory the now-published experiments took place. However, when a molecule migrates into the pore, the current is blocked: the larger the molecule, the more strongly it is blocked too.
In the context of the experiments now published, the Freiburg scientists devoted themselves to the investigation of the so-called histone protein H4. This protein is firmly associated with DNA in all cells with a nucleus and is one of the best-researched targets of epigenetic modifications. A region at the N-terminal end of the protein is particularly affected by these modifications.
“The protein sequence there contains the amino acid lysine several times,” Behrends explains. Acetyl or methyl groups, for example, can be attached to these lysines, which are designated K8, K12 and K16 according to their position in the protein chain, as part of epigenetic modifications. Which chemical modification takes place at which lysine position is definitely of medical importance, as the Freiburg physiologist points out. “Acetylation at K16, for example, is important for human development, while methylation at K12 plays a role in the development of some prostate and lung tumors, according to the latest results from Medical Center — University of Freiburg.”
In their experiments, Behrends and his team were now able to clearly distinguish H4 fragments with or without acetylation, as well as fragments with one, two or three acetylations. Moreover, they succeeded in demonstrating that the nanopore they used was also sensitive to the site of acetylation: histone fragments with an acetyl group at K8 blocked current through the pore more strongly than those acetylated at K12, and these in turn more strongly than those with a K16 acetylation. “This kind of sensitivity is surprising in that these fragments are identical in terms of their mass and total volume,” Behrends says. Thus, the pore current appears to be sensitive not only to the size, but also to the shape of the molecule. It was equally easy to distinguish between the different variants of doubly acetylated histone fragments — K8 and K12, K8 and K16, and K12 and K16 — again, despite the identical mass. H4 fragments methylated to different extents and at different positions also blocked the current through the pore to different degrees, although not as clearly as the acetylated variants.
“We have been able to show for the first time through our experiments that nanopore analytics allows us to distinguish molecules not only by their size, but also by their shape,” summarizes study leader Behrends. Molecular dynamics simulations conducted by the research group led by Aleksei Aksimentiev from the University of Illinois in the US — also involved in the study- and show that a highly inhomogeneous electric field inside the pore plays a key role for this effect.
While the sequencing of DNA using nanopores is already established and commercialized, the development of nanopore-based analysis of proteins is just beginning, Behrends emphasizes. “The difficulty with sequencing proteins is that these are molecules with very non-uniform charge patterns.” While DNA, which is negatively charged, migrates directionally in the electric field and can thus be pulled through the pore base by base, proteins consist of building blocks made of the amino acids with different charges. As a result, directed movement in the electric field and “scanning” amino acid by amino acid is not possible. The Freiburg scientists therefore relied on a different approach for their experiments. Instead of a pore with a short constriction, as used in DNA sequencing, they used a tailor-made pore with a kind of molecular trap. “This allowed the entire protein fragment to be captured at once,” says Behrends.
It is not yet clear up to which fragment size this type of analysis can be used. However, additional experiments show that the method will also be suitable for the analysis of the H4 fragments previously used in epigenetic research. These contain 14 amino acids instead of the ten used here, and are currently investigated for epigenetic modifications with tandem mass spectrometry, a highly elaborate technique. The researchers hope that the nanopores will make the analysis much simpler, faster and more cost-effective, and that it can be carried out close to the patient.
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