TL;DR
- A new study suggests that unrepaired DNA damage can increase the speed of aging.
- Researchers discovered that the enzyme RNA polymerase II recognizes and transcribes artificially added base pairs in genetic code, a new insight that could help advance the development of new vaccines and medicines.
- Nanodecoys made from human lung spheroid cells (LSCs) can bind to and neutralize SARS-CoV-2, promoting viral clearance and reducing lung injury in a macaque model of COVID-19. By mimicking the receptor that the virus binds to rather than targeting the virus itself, nanodecoy therapy could remain effective against emerging variants of the virus.
- Researchers announced the development of a new method to increase the utility and equity of large genetic databases.
- Fruit flies have found at least two solutions to the problem of sorting their sex chromosomes: a matter of life and death.
- Researchers now have a better understanding of the mechanism underlying how certain bacteria can transfer genetic material across taxonomic kingdoms, including to fungi and protists. Their work could have applications in changing how bacteria perform certain functions or react to changes in their environment.
- Sour taste does not have the nearly universal appeal that sweet taste does. Slightly sour foods or drinks such as yogurt and lemon juice are yummy to many, but such highly sour foods as spoiled milk are yucky, even dangerous. Like humans, many other animals, including insects, prefer slightly acidic over very acidic foods.
- Researchers develop technology to introduce genes into single cells in a targeted manner.
- Biologists have discovered 71 new ‘imprinted’ genes in the mouse genome, a finding that takes them a step closer to unravelling some of the mysteries of epigenetics — an area of science that describes how genes are switched on (and off) in different cells, at different stages in development and adulthood.
- In a discovery that challenges long-held dogma in biology, researchers show that mammalian cells can convert RNA sequences back into DNA, a feat more common in viruses than eukaryotic cells.
- Like the movie version of Spider-Man who shoots spider webs from holes in his wrists, a little alpine plant has been found to eject cobweb-like threads from tiny holes in specialized cells on its leaves. It’s these tiny holes that have taken plant scientists by surprise because puncturing the surface of a plant cell would normally cause it to explode like a water balloon.
- 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
An aged immune system drives senescence and ageing of solid organs
by Matthew J. Yousefzadeh, Rafael R. Flores, Yi Zhu, Zoe C. Schmiechen, Robert W. Brooks, Christy E. Trussoni, Yuxiang Cui, Luise Angelini, Kyoo-A Lee, Sara J. McGowan, Adam L. Burrack, Dong Wang, Qing Dong, Aiping Lu, Tokio Sano, Ryan D. O’Kelly, Collin A. McGuckian, Jonathan I. Kato, Michael P. Bank, Erin A. Wade, Smitha P. S. Pillai, Jenna Klug, Warren C. Ladiges, Christin E. Burd, Sara E. Lewis, Nicholas F. LaRusso, Nam V. Vo, Yinsheng Wang, Eric E. Kelley, Johnny Huard, Ingunn M. Stromnes, Paul D. Robbins, Laura J. Niedernhofer in Nature
Every day, our bodies face a bombardment of UV rays, ozone, cigarette smoke, industrial chemicals and other hazards. This exposure can lead to free-radical production in our bodies, which damages our DNA and tissues.
A new study from West Virginia University researcher Eric E. Kelley — in collaboration with the University of Minnesota — suggests that unrepaired DNA damage can increase the speed of aging.
Kelley and his team created genetically-modified mice with a crucial DNA-repair protein missing from their hematopoietic stem cells, immature immune cells that develop into white blood cells. Without this repair protein, the mice were unable to fix damaged DNA accrued in their immune cells.
“By the time the genetically-modified mouse is 5 months old, it’s like a 2-year-old mouse,” said Kelley, associate professor and associate chair of research in the School of Medicine’s Department of Physiology and Pharmacology. “It has all the symptoms and physical characteristics. It has hearing loss, osteoporosis, renal dysfunction, visual impairment, hypertension, as well as other age-related issues. It’s prematurely aged just because it has lost its ability to repair its DNA.”
According to Kelley, a normal 2-year-old mouse is about equivalent in age to a human in their late 70s to early 80s.
Kelley and his colleagues found that markers for cell aging, or senescence, as well as for cell damage and oxidation were significantly greater in the immune cells of genetically-modified mice compared to normal, wild-type mice. But the damage was not limited to the immune system; the modified mice also demonstrated aged, damaged cells in organs such as the liver and kidney.
These results suggest that unrepaired DNA damage may cause the entire body to age prematurely.
When we are exposed to a pollutant, such as radiation for cancer treatment, energy is transferred to the water in our body, breaking the water apart. This creates highly reactive molecules — free radicals — that will quickly interact with another molecule in order to gain electrons. When these free radicals interact with important biomolecules, such as a protein or DNA, it causes damage that can keep that biomolecule from working properly.
Some exposure to pollutants is unavoidable, but there are several lifestyle choices that increase exposure to pollution and thus increase free radicals in the body. Smoking, drinking and exposure to pesticides and other chemicals through occupational hazards all significantly increase free radicals.
“A cigarette has over 10 to the 16th free radicals per puff, just from combusted carbon materials,” Kelley said.
In addition to free radicals produced by pollutant exposure, the human body is constantly producing free radicals during a process used to turn food into energy, called oxidative phosphorylation.
“We have mechanisms in the mitochondria that mop free radicals up for us, but if they become overwhelmed — if we have over-nutrition, if we eat too much junk, if we smoke — the defense mechanism absolutely cannot keep up,” Kelley said.
As bodies age, the amount of damage caused by free-radical formation becomes greater than the antioxidant defenses. Eventually, the balance between the two tips over to the oxidant side, and damage starts to win out over repair. If we are exposed to a greater amount of pollutants and accumulate more free radicals, this balance will be disrupted even sooner, causing premature aging.
The issue of premature aging due to free-radical damage is especially important in West Virginia. The state has the greatest percentage of obese citizens in the nation and a high rate of smokers and workers in high-pollution-exposure occupations.
“I come from an Appalachian background,” Kelley said. “And, you know, I’d go to funerals that were in some old house — an in-the-living-room-with-a-casket kind of deal — and I’d look at people in there, and they’d be 39 or 42 and look like they were 80 because of their occupation and their nutrition.”
Many West Virginians also have comorbidities, such as diabetes, enhanced cardiovascular disease, stroke and renal issues, that complicate the situation further.
Although there are drugs, called senolytics, that help to slow the aging process, Kelley believes it is best to prevent premature aging through lifestyle change. He says that focusing on slowing the aging process through preventive measures can improve the outcome for each comorbidity and add more healthy years to people’s lives.
“The impact is less on lifespan and more on healthspan,” he said. “If you could get people better access to healthcare, better education, easier ways for them to participate in healthier eating and a healthier lifestyle, then you could improve the overall economic burden on the population of West Virginia and have a much better outcome all the way around.”
Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19
by Zhenhua Li, Zhenzhen Wang, Phuong-Uyen C. Dinh, Dashuai Zhu, Kristen D. Popowski, Halle Lutz, Shiqi Hu, Mark G. Lewis, Anthony Cook, Hanne Andersen, Jack Greenhouse, Laurent Pessaint, Leonard J. Lobo, Ke Cheng in Nature Nanotechnology
Nanodecoys made from human lung spheroid cells (LSCs) can bind to and neutralize SARS-CoV-2, promoting viral clearance and reducing lung injury in a macaque model of COVID-19. By mimicking the receptor that the virus binds to rather than targeting the virus itself, nanodecoy therapy could remain effective against emerging variants of the virus.
SARS-CoV-2 enters a cell when its spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell’s surface. LSCs — a natural mixture of lung epithelial stem cells and mesenchymal cells — also express ACE2, making them a perfect vehicle for tricking the virus.
“If you think of the spike protein as a key and the cell’s ACE2 receptor as a lock, then what we are doing with the nanodecoys is overwhelming the virus with fake locks so that it cannot find the ones that let it enter lung cells,” says Ke Cheng, corresponding author of the research. “The fake locks bind and trap the virus, preventing it from infecting cells and replicating, and the body’s immune system takes care of the rest.”
Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at North Carolina State University and a professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering.
Cheng and colleagues from NC State and UNC-CH converted individual LSCs into nanovesicles, or tiny cell membrane bubbles with ACE2 receptors and other lung cell-specific proteins on the surface.
They confirmed that the spike protein did bind to the ACE2 receptors on the decoys in vitro, then used a fabricated SARS-Co-V-2 mimic virus for in vivo testing in a mouse model. The decoys were delivered via inhalation therapy. In mice, the nanodecoys remained in the lungs for 72 hours after one dose and accelerated clearance of the mimic virus.
Finally, a contract research organization conducted a pilot study in a macaque model and found that inhalation therapy with the nanodecoys accelerated viral clearance, and reduced inflammation and fibrosis in the lungs. Although no toxicity was noted in either the mouse or macaque study, further study will be necessary to translate this therapy for human testing and determine exactly how the nanodecoys are cleared by the body.
“These nanodecoys are essentially cell ‘ghosts,’ and one LSC can generate around 11,000 of them,” Cheng says. “Deploying millions of these decoys exponentially increases the surface area of fake binding sites for trapping the virus, and their small size basically turns them into little bite-sized snacks for macrophages, so they are cleared very efficiently.”
The researchers point out three other benefits of the LSC nanodecoys. First, they can be delivered non-invasively to the lungs via inhalation therapy. Second, since the nanodecoys are acellular — there’s nothing living inside — they can be easily preserved and remain stable longer, enabling off-the-shelf use. Finally, LSCs are already in use in other clinical trials, so there is an increased likelihood of being able to use them in the near future.
“By focusing on the body’s defenses rather than a virus that will keep mutating we have the potential to create a therapy that will be useful long-term,” Cheng says. “As long as the virus needs to enter the lung cell, we can keep tricking it.”
Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3
by Laura Santini, Florian Halbritter, Fabian Titz-Teixeira, Toru Suzuki, Maki Asami, Xiaoyan Ma, Julia Ramesmayer, Andreas Lackner, Nick Warr, Florian Pauler, Simon Hippenmeyer, Ernest Laue, Matthias Farlik, Christoph Bock, Andreas Beyer, Anthony C. F. Perry, Martin Leeb in Nature Communications
Biologists at the Universities of Bath and Vienna have discovered 71 new ‘imprinted’ genes in the mouse genome, a finding that takes them a step closer to unravelling some of the mysteries of epigenetics — an area of science that describes how genes are switched on (and off) in different cells, at different stages in development and adulthood.
To understand the importance of imprinted genes to inheritance, we need to step back and ask how inheritance works in general. Most of the thirty trillion cells in a person’s body contain genes that come from both their mother and father, with each parent contributing one version of each gene. The unique combination of genes goes part of the way to making an individual unique. Usually, each gene in a pair is equally active or inactive in a given cell. This is not the case for imprinted genes. These genes — which make up less than one percent of the total of 20,000+ genes — tend to be more active (sometimes much more active) in one parental version than the other.
Until now, researchers were aware of around 130 well-documented imprinted genes in the mouse genome — the new additions take this number to over 200.
Professor Tony Perry, who led the research from the Department of Biology & Biochemistry at Bath in the UK, said: “Imprinting affects an important family of genes, with different implications for health and disease, so the seventy-plus new ones add an important piece of the jigsaw.”
Close examination of the newly identified genes has allowed Professor Perry and his colleagues to make a second important discovery: the switching on and off of imprinted genes is not always related to DNA methylation, where methyl groups are added to genomic DNA- a process that is known to repress gene activity, switching them off). DNA methylation was the first known type of imprint, and was discovered around thirty years ago. From the results of the new work, it seems that a greater contribution to imprinting is made by histones — structures that are wrapped up with genomic DNA in chromosomes.
Although scientists have known for some time that histones act as ‘dimmer’ switches for genes, fading them off (or back on), until now it was thought that DNA methylation provided the major switch for imprinted gene activity. The findings from the new study cast doubt on this assumption: many of the newly identified genes were found to be associated with changes to the histone 3 lysine 27 (H3K27me3), and only a minority with DNA methylation.
Scientists have yet to work out how one parental version of a given gene can be switched (or faded) on or off and maintained that way while the other is in the opposite state. It is known that much of the on/off switching occurs during the formation of gametes (sperm and egg), but the precise mechanisms remain unclear. This new study points to the intriguing possibility that some imprinted genes may not be marked in gametes, but become active later in development, or even in adulthood.
Although it only involves a small proportion of genes, imprinting is important in later life. If it goes wrong, and the imprinted gene copy from one parent is switched on when it should be off (or vice versa), disease or death occur. Faulty imprinted genes are associated with many diseases, including neurological and metabolic disorders, and cancer.
“We may underestimate how important the relationship between imprinting and disease is, as well as the relationship of imprinting to the inheritance of parentally-acquired disease, such as obesity,” said Professor Perry. “Hopefully, this improved picture of imprinting will increase our understanding of disease.”
Spatiotemporally confined red light-controlled gene delivery at single-cell resolution using adeno-associated viral vectors
by Maximilian Hörner, Carolina Jerez-Longres, Anna Hudek, Sebastian Hook, O. Sascha Yousefi, Wolfgang W. A. Schamel, Cindy Hörner, Matias D. Zurbriggen, Haifeng Ye, Hanna J. Wagner, Wilfried Weber in Science Advances
Researchers develop technology to introduce genes into single cells in a targeted manner.
The ability to insert desirable genes into animal or human cells is the basis of modern life science research and of widespread biomedical applications. The methods used to date for this purpose are mostly non-specific, making it difficult for scientists to control which cell will or will not take up a gene. For this gene transfer, the target genes are often packaged into “viral vectors.” These are viruses in which part of the genetic material has been replaced by the target genes. When researchers add these viral vectors to cells, the vectors introduce the genes into the cells. This is the principle behind some of the current SARS-CoV-2 vaccines such as those from AstraZeneca or Johnson&Johnson. However, it is difficult — even impossible — to control into which cells the target genes enter, since the viral vectors tend to dock non-specifically onto all cells of a certain cell type.
A team of researchers from the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies at the University of Freiburg, led by Dr. Maximilian Hörner, Prof. Dr. Wolfgang Schamel and Prof. Dr. Wilfried Weber, has developed a new technology that enables them to introduce target genes in a controlled manner and thereby control processes in individual selected cells.
In their new method, the Freiburg researchers introduce the genetic information with an optical remote control. As a result, only cells that are illuminated with red light take up the desired genes. To do this, the scientists modified a type of viral vector known as an AAV vector, which is already in clinical use. “We took away the viral vector’s ability to dock with cells,” Hörner explains, “which is an essential step before the genetic material can be introduced.”
To enable this control by light, the researchers have taken a red light photoreceptor system from the plant Arabidopsis thaliana (thale cress). This system consists of two proteins, PhyB and PIF, which bind to each other as soon as PhyB is illuminated with red light. The Freiburg team placed the protein PIF on the surface of the viral vector and modified the other protein PhyB so that it could bind to human cells. Once this modified vector, called OptoAAV, is in a cell culture along with the cell-binding protein, the protein binds to all cells. “If a selected cell is now illuminated with red light, the modified vector can bind to this cell and introduce the target genes into the illuminated cell,” Hörner explains.
This new approach allows the researchers to introduce target genes into the desired cells within a tissue culture. The scientists also succeeded in illuminating the tissue culture successively at different locations, thus enabling the targeted introduction of different genes into different cells within a culture. With this technique, it is now possible to control desired processes in individual cells. This is essential for understanding how a single cell communicates with cells in its environment, for example, to control the development or regeneration of an organ. “As these viral vectors become more widely used in the therapeutic field,” Weber says, “we think this new technology has the potential to make such biomedical applications more precise.”
Isolation and Analysis of Donor Chromosomal Genes Whose Deficiency Is Responsible for Accelerating Bacterial and Trans-Kingdom Conjugations by IncP1 T4SS Machinery
by Fatin Iffah Rasyiqah Mohamad Zoolkefli, Kazuki Moriguchi, Yunjae Cho, Kazuya Kiyokawa, Shinji Yamamoto, Katsunori Suzuki in Frontiers in Microbiology
Researchers now have a better understanding of the mechanism underlying how certain bacteria can transfer genetic material across taxonomic kingdoms, including to fungi and protists. Their work could have applications in changing how bacteria perform certain functions or react to changes in their environment.
Bacteria do not sexually reproduce, but that does not stop them from exchanging genetic information as it evolves and adapts. During conjugal transfer, a bacterium can connect to another bacterium to pass along DNA and proteins. Escherichia coli bacteria, commonly called E. coli, can transfer at least one of these gene-containing plasmids to organisms across taxonomic kingdoms, including to fungi and protists. Now, researchers from Hiroshima University have a better understanding of this genetic hat trick, which has potential applications as a tool to promote desired characteristics or suppress harmful ones across genetic hosts.
Plasmids transfer from one bacterium — the donor — to another — the recipient. A particular kind of plasmid, called IncP1, can be hosted by a variety of bacteria and, seemingly as a result of its broad hosts, can transfer DNA to recipients beyond bacteria. The hypothesis is that the plasmid contains genes cultivated from different hosts and donors, resulting in this unique ability.
“Although conjugation factors encoded on plasmids have been extensively analyzed, those on the donor chromosome have not,” said paper author Kazuki Moriguchi, associate professor, Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University.
There have been some studies on the various genes, according to Moriguchi, but the function of the genes was not examined, so it is not clear how they were related to the conjugation mechanism.
In this study, the researchers conducted a genome-wide survey on an extensive collection of bacteria mutants as donors to yeast. The mutants were engineered to have specific genes “knocked out” in order to study how the overall system performs without the presence of that specific gene, allowing researchers to infer information about the gene’s function.
“We focused on ‘up’ mutants that have the ability to accelerate conjugative transfer to both prokaryotes and eukaryotes as they could be potent donor strains applicable to gene introduction tools,” Moriguchi said, noting how IncP1’s ability to transmit genetic material across kingdoms could be used to develop precise tools to introduce genes capable of changing how the bacteria perform certain functions or react to changes in their environments.
Out of 3,884 mutants surveyed, three were identified that could conjugate across E. coli or from E. coli to yeast without accumulating genetic material, indicating that the genes worked together. The researchers analyzed the genes but were unable to elucidate the exact target or targets of conjugation mechanism that allows for cross-kingdom transfer. However, their analysis did reveal how the genes appear to work.
Two of the genes work to repress the unknown target in the E. coli donor. Simultaneously, the third gene is inactivated, allowing another unknown target to resume activity.
“The results suggest that the unknown target factors of these three genes form a complex in order to activate or repress the conjugation, either directly or indirectly at an identical step or steps of the IncP1 conjugation machinery, although the exact mechanism beyond this phenomenon remains unknown,” Moriguchi said.
According to Moriguchi, the data collected in this study can help facilitate the breeding of donor strains from various bacteria, each of which carries a high affinity with target organisms in addition to having a high conjugation ability.
Transcriptional processing of an unnatural base pair by eukaryotic RNA polymerase II
by Juntaek Oh, Ji Shin, Ilona Christy Unarta, Wei Wang, Aaron W. Feldman, Rebekah J. Karadeema, Liang Xu, Jun Xu, Jenny Chong, Ramanarayanan Krishnamurthy, Xuhui Huang, Floyd E. Romesberg, Dong Wang in Nature Chemical Biology
If the genome is the recipe of life, base pairs are the individual ingredients listed. These chemical structures form DNA, and every living organism on Earth has just four. The specific arrangements of these four base pairs — A, T, C, G — make us who and what we are.
So it was a big surprise when Scripps Research scientists revealed in 2014 that they could introduce two new, unnatural base pairs (they called them X and Y for short) into the genetic code of living bacteria in the lab. It was like two never-seen-before ingredients tossed into the recipe, hypothetically expanding the variety of dishes a cell can whip up.
Researchers immediately saw the potential applications: With more control and selection, they might be able to use cells as tiny kitchens to cook up new medicines and vaccines. But just because there are more letters in a genetic recipe doesn’t mean the cell can read them, or knows what to do with them — or that any of it works in the cells of organisms more complicated than bacteria. A team led by researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego helped address these hurdles.
The team revealed that yeast cell machinery seamlessly “reads” the unnatural X and Y ingredients, the way it would A, C, T and G, and translates them into RNA, which could eventually be translated into proteins, the basis for just about every part of the cell. Unlike bacteria, yeast are eukaryotes, part of the same multicellular class of life as animals, plants and fungi. (A note about safety: These synthetic cells can’t survive without special liquid food provided in the lab.)
“Now we can see exactly how eukaryotic cell machinery interacts with unnatural base pairs, but it’s not perfect, there’s room to improve in terms of selectivity and efficiency,” said author Dong Wang, PhD, professor in the Skaggs School of Pharmacy. “It’s our hope that this finding will have a profound impact in the field by enabling the design of more effective, next-generation unnatural base pairs.”
Wang’s lab has long studied RNA polymerase II, an essential enzyme found in every fungal, plant and animal cell. RNA Pol II reads the DNA recipe and helps convert the genetic code into messenger RNA. (That mRNA then carries that genetic recipe out of the nucleus and into the cytoplasm, where it’s translated and used to assemble proteins as instructed.) In the past, the team has studied the structure of RNA Pol II and how it responds to normal genetic recipe hiccups such as DNA damage caused by radiation.
In their latest study, Wang’s team revealed for the first time step-by-step what it looks like, structurally speaking, when eukaryotic RNA Pol II picks up and incorporates unnatural base pairs as it transcribes a piece of DNA. In doing so, they discovered, for example, that RNA Pol II is selective — it can bind X or Y on one strand of a double-stranded DNA genome, but not the other.
“What we have now is a unique view of what is and what is not well recognized by RNA Pol II,” said Wang, who is also professor at UC San Diego School of Medicine and Department of Chemistry and Biochemistry. “This knowledge is important for us to design new unnatural base pairs that can be used by host RNA polymerases.”
Molecular and cellular basis of acid taste sensation in Drosophila
by Tingwei Mi, John O. Mack, Christopher M. Lee, Yali V. Zhang in Nature Communications
Sour taste does not have the nearly universal appeal that sweet taste does. Slightly sour foods or drinks such as yogurt and lemon juice are yummy to many, but such highly sour foods as spoiled milk are yucky, even dangerous. Like humans, many other animals, including insects, prefer slightly acidic over very acidic foods.
Evolutionary biologists surmise that the need for sour detection to be finely tuned is a two-sided coin: slightly acidic foods can enhance digestion and stimulate saliva production; relative sour-to-sweet taste can signal optimal ripeness of fruit; and extremely sour food, as with bitter taste, is a warning to what not to ingest. However, despite this usefulness, how do animals discern different concentrations of acid to produce contrasting feeding behaviors using the same sour-taste system?
A research group led by Yali Zhang, PhD, Principal Investigator at the Monell Chemical Senses Center, has recently addressed this long-standing question. Using the fruit fly as a research model, Zhang and his team set out to elucidate how animals tell the difference between low and high concentrations of acid. “We chose flies because they not only help us identify the genetic components involved in taste transduction, they also exhibit pronounced and distinct taste responses to a range of concentrations of acid compared to other animal models,” said Zhang.
His team, including authors Tingwei Mi, John Mack, and Christopher Lee from the Monell Center and University of Pennsylvania, found that flies use two distinct types of gustatory (taste) receptor neurons (GRNs), which are analogous to taste receptor cells in mammals, to discriminate slightly from highly sour foods. One group of GRNs are maximally activated by low acidity, while the other group displayed its best responses to high acidity. When tasting an acidic food, the fly’s brain evaluates the activation of both neuron populations and decides whether to choose or reject the acidic food, based on which type of neurons win.
“We were thrilled to discover that a fly’s acid-taste behavior is dictated by a ‘tug-of-war’ between low- and high-acid-sensitive taste receptor cells,” said Zhang. This binary sour-taste system can explain why many animals, including humans, are attracted to low but repulsed by high concentrations of acids.
In addition, Zhang’s group identified a fly protein called Otopetrin-like (OtopLa), which has an analogous counterpart in humans, as a long sought-after sour taste receptor. OtopLa forms a proton-selective ion channel that is specifically required for attractive sour taste response. Remarkably, mutant flies lacking OtopLa are averse to low concentrations of acid as well as repulsed by higher concentrations.
“To my knowledge, OtopLa is the first taste receptor to be identified that is evolutionarily conserved between insects and mammals,” said Zhang. This work overturns the established view that insects and mammals make use of different classes of taste receptors.
“I believe our research on fly acid sensation can greatly advance our understanding of sour taste coding in other animals, including humans,” said Zhang.
Microscopy and chemical analyses reveal flavone-based woolly fibres extrude from micron-sized holes in glandular trichomes of Dionysia tapetodes
by Matthieu Bourdon, Josephine Gaynord, Karin H. Müller, Gareth Evans, Simon Wallis, Paul Aston, David R. Spring, Raymond Wightman in BMC Plant Biology
Like the movie version of Spider-Man who shoots spider webs from holes in his wrists, a little alpine plant has been found to eject cobweb-like threads from tiny holes in specialised cells on its leaves. It’s these tiny holes that have taken plant scientists by surprise because puncturing the surface of a plant cell would normally cause it to explode like a water balloon.
The small perennial cushion-shaped plant with bright yellow flowers, Dionysia tapetodes, is in the primula family and naturally occurs in Turkmenistan and north-eastern Iran, and through the mountains of Afghanistan to the border of Pakistan. What makes it unusual is its leaves, which are covered in long silky fibres that resemble fine cobwebs called ‘woolly farina’.
Quite a few of its primula relatives have leaves coated with a fine powder consisting almost entirely from flavone, which is a class of flavonoid. Flavonoids are small specialised molecules involved in plant metabolism and are recognised for their anti-inflammatory and antioxidant properties. But this Dionysia species does not have flavone powder on its leaves, instead it has very fine wool just 1–2 microns thick — far thinner than a human hair, which is about 75 microns.
As part of an ongoing collaboration between the University of Cambridge’s plant science research institute Sainsbury Laboratory Cambridge University (SLCU) and Cambridge University Botanic Garden (CUBG), Dionysia was selected from the Botanic Garden’s living collection of 8,000 cultivated plant species to be analysed at SLCU’s Microscopy Core Facilities.
“The woolly farina threads seem to cover the entire leaf surface with long threads even connecting leaf-to-leaf,” said Paul Aston, who is the Botanic Garden Alpine and Woodland Supervisor. “Nobody knew what this wool was or how it was made and so we thought that this would be an interesting specimen to study. There are many things that plants make that we do not yet know about — this is especially true for alpine plants where we see many unusual adaptations to the harsh high altitude environments they live in.”
Samples were analysed using advanced light and electron microscopes, which revealed the micron-diameter wool had distinct parallel grooves running along their length. But the most surprising observation was how the wool was emerging from the leaves.
“The leaves are covered in tiny hairs called trichomes. Each trichome has a spherical shaped glandular cell at the end — like a stalk with a single round cell at the tip — and we could see the threads emerging straight out of the glandular cell,” said Dr Raymond Wightman, who is the Microscopy Core Facility Manager in the University of Cambridge’s Sainsbury Laboratory. “But we know that plant cells are surrounded by a cell wall that protects and retains pressure within the cell. Poking holes through the cell membrane and cell wall would cause the cell to burst — like puncturing a water balloon.”
So how were the threads getting out without exploding the cell?
Using a powerful electron microscope at the Cambridge Advanced Imaging Centre (CAIC), they sectioned the glandular cells and when they zoomed in could see tiny gaps in the cells just large enough to thread a single woolly farina fibre through.
“The plant manufactures the fibre inside the cell and then threads it through the gaps that are just wide enough for it,” said Dr Matthieu Bourdon who is a researcher at SLCU and co author of the report published in BMC Plant Biology. “There is a distinct opening in the plasma membrane, cell wall and cuticle creating a hole that forms a tight seal around the fibre — we could even see wax on the cell surface acting like a plug to seal any gaps. We observed multiple fibres being extruded from individual glandular cells at specific spots across its surface. The plant must be concentrating the flavone building blocks within the cells at these specific exit sites to be able to produce the elongating fibre.”
Dr Wightman also analysed the chemistry of the fibres to find what they are made from using the Institute’s Raman microscope, but the wool’s complex structure required further analysis using specialist equipment and skills from the University’s Yusuf Hamied Department of Chemistry.
“The analysis of the woolly farina sample was challenging because of the small size of the sample and the similarity of the chemicals that it was made up of, said Dr Josephine Gaynord, PhD graduate from the University of Cambridge’s Department of Chemistry and who undertook the further analysis using advanced chromatography, mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy techniques. “It helped that we knew the majority of the sample was flavone, a chemical that we could buy and compare to the woolly farina sample. Thanks to some excellent support from the NMR team in the Department of Chemistry we were able to run bespoke analysis and provide possible structures for the modified flavones that were present. It would be very interesting to follow this work up in the future.”
Wightman said they were expecting the fibres to be made up of flavonoids similar to the powdery coating on the leaves of some other primula species, but were intrigued by how this species was able to turn flavones into such stable wool-like fibres. “We found the wool produced by Dionysia tapetodes has a special chemical structure that is a mix of flavone and flavone derivatives that may use hydrogen bonding between molecules to form the elongated fibres. This means inside the cell these flavones need to be mixed precisely while being added to the end of the fibre so that they exit the gap as one continuous thread — like squeezing a continuous line of toothpaste from a tube.”
“While it is not known what purpose the woolly farina serves, it is thought it could be a protective measure offering tolerance to freezing, drought and/or blocking high UV,” said Simon Wallis, Alpine and Woodland Assistant at CUBG. “This latter theory is supported by observations that we have made from our alpine collection, comparing the wool-producing Dionysia tapetodes with a subset of Dionysia tapetodes that do not have woolly farina and are more susceptible to sun scorching.”
The team is interested in further exploring the properties of these fibres to determine if they might be a useful biomaterial.
Polθ reverse transcribes RNA and promotes RNA-templated DNA repair
by Gurushankar Chandramouly, Jiemin Zhao, Shane McDevitt, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Taylor Treddinick, Felicia Wednesday Lopezcolorado, Tatiana Kent, Labiba A. Siddique, Joseph Mallon, Jacklyn Huhn, Zainab Shoda, Ekaterina Kashkina, Alessandra Brambati, Jeremy M. Stark, Xiaojiang S. Chen, Richard T. Pomerantz in Science Advances
Cells contain machinery that duplicates DNA into a new set that goes into a newly formed cell. That same class of machines, called polymerases, also build RNA messages, which are like notes copied from the central DNA repository of recipes, so they can be read more efficiently into proteins. But polymerases were thought to only work in one direction DNA into DNA or RNA. This prevents RNA messages from being rewritten back into the master recipe book of genomic DNA. Now, Thomas Jefferson University researchers provide the first evidence that RNA segments can be written back into DNA, which potentially challenges the central dogma in biology and could have wide implications affecting many fields of biology.
“This work opens the door to many other studies that will help us understand the significance of having a mechanism for converting RNA messages into DNA in our own cells,” says Richard Pomerantz, PhD, associate professor of biochemistry and molecular biology at Thomas Jefferson University. “The reality that a human polymerase can do this with high efficiency, raises many questions.” For example, this finding suggests that RNA messages can be used as templates for repairing or re-writing genomic DNA.
Together with first author Gurushankar Chandramouly and other collaborators, Dr. Pomerantz’s team started by investigating one very unusual polymerase, called polymerase theta. Of the 14 DNA polymerases in mammalian cells, only three do the bulk of the work of duplicating the entire genome to prepare for cell division. The remaining 11 are mostly involved in detecting and making repairs when there’s a break or error in the DNA strands. Polymerase theta repairs DNA, but is very error-prone and makes many errors or mutations. The researchers therefore noticed that some of polymerase theta’s “bad” qualities were ones it shared with another cellular machine, albeit one more common in viruses — the reverse transcriptase. Like Pol theta, HIV reverse transcriptase acts as a DNA polymerase, but can also bind RNA and read RNA back into a DNA strand.
In a series of elegant experiments, the researchers tested polymerase theta against the reverse transcriptase from HIV, which is one of the best studied of its kind. They showed that polymerase theta was capable of converting RNA messages into DNA, which it did as well as HIV reverse transcriptase, and that it actually did a better job than when duplicating DNA to DNA. Polymerase theta was more efficient and introduced fewer errors when using an RNA template to write new DNA messages, than when duplicating DNA into DNA, suggesting that this function could be its primary purpose in the cell.
The group collaborated with Dr. Xiaojiang S. Chen’s lab at USC and used x-ray crystallography to define the structure and found that this molecule was able to change shape in order to accommodate the more bulky RNA molecule — a feat unique among polymerases.
“Our research suggests that polymerase theta’s main function is to act as a reverse transcriptase,” says Dr. Pomerantz. “In healthy cells, the purpose of this molecule may be toward RNA-mediated DNA repair. In unhealthy cells, such as cancer cells, polymerase theta is highly expressed and promotes cancer cell growth and drug resistance. It will be exciting to further understand how polymerase theta’s activity on RNA contributes to DNA repair and cancer-cell proliferation.”
Divergent evolution toward sex chromosome-specific gene regulation in Drosophila
by Raffaella Villa, Pravin Kumar Ankush Jagtap, Andreas W. Thomae, Aline Campos Sparr, Ignasi Forné, Janosch Hennig, Tobias Straub, Peter B. Becker in Genes & Development
Fruit flies have found at least two solutions to the problem of sorting their sex chromosomes: a matter of life and death.
Sex determination in animals often depends on the unequal segregation of specific chromosomes. Female cells generally possess two X chromosomes, while male cells contain one X and one Y chromosome. The latter, which is inherited from the male parent, has far fewer genes than the X. In the fruit fly Drosophila, male cells make up for the fact that they have only one X chromosome by boosting the level of expression of all of its genes by a factor of 2. This phenomenon, which is known as dosage compensation, requires that the X chromosome in males be regulated differently from all the others. A team of molecular biologists at Ludwig-Maximilians-Universitaet (LMU) in Munichs Biomedical Center led by Professor Peter Becker has now shown that, over the course of 40 million years, members of the genus Drosophila have discovered at least two different ways of making this vital distinction.
“In light of the significance of dosage compensation, one might expect that the principles behind the specific recognition of the X chromosome in males would be highly conserved,” says Becker. “In other words, the process should work in essentially the same way in all Drosophila species. However, when we compared the two species Drosophila melanogaster and Drosophila virilis, we discovered, to our surprise, that they use distinct mechanisms for this purpose.” Significantly, the primary components involved in dosage compensation — the proteins MSL2 and CLAMP, together with the non-coding RNA roX — are found in both species. So their last common ancestor presumably possessed the genes that code for these products.
The two species diverged about 40 million years ago, and since then they have evolved in parallel. The new study shows that, during this period, the mediators of dosage compensation and their binding sites on the X chromosome have evolved in different ways. As a result, the relative influence of, and the interactions between, the components have changed. Among other things, in D. melanogaster the copy numbers of certain DNA sequences on the X chromosome have increased. In parallel, the DNA-binding domain of the MSL2 protein has acquired the ability to recognize these sequences, and they now play a critical role in the recognition of the X chromosome in this species.
In D. virilis, on the other hand, these sequences have not been amplified. Their recognition by MSL2 therefore depends on its interaction with the CLAMP protein to a much greater extent than in the case of D. melanogaster — even though the CLAMP protein can also bind to many sequences on the other chromosomes. “We assume that the non-coding roX RNA inhibits the binding of MSL2 at these sites,” says Becker. The study has therefore uncovered a new role for this RNA. Up until now, researchers had assumed that roX comes into play not at the level of sequence recognition, but at a later stage in the dosage compensation process.
These findings have interesting evolutionary implications. “As the sex chromosomes continue to diversify, the emergence of alternative but equally effective solutions to the problem of balancing the activity of the genome demonstrates that evolution is not a deterministic process,” Becker points out.
Summix: A method for detecting and adjusting for population structure in genetic summary data
by Ian S. Arriaga-MacKenzie, Gregory Matesi, Samuel Chen, Alexandria Ronco, Katie M. Marker, Jordan R. Hall, Ryan Scherenberg, Mobin Khajeh-Sharafabadi, Yinfei Wu, Christopher R. Gignoux, Megan Null, Audrey E. Hendricks in The American Journal of Human Genetics
In a new study, researchers announced the development of a new method to increase the utility and equity of large genetic databases. The research was conducted by Audrey Hendricks, an associate professor of statistics at the University of Colorado Denver (CU Denver).
Summix, the new method developed by Hendricks and her team of CU Denver undergraduate and graduate students, estimates the genetic ancestry in databases and adjusts the information to match the ancestry of a person or sample of people. This method leads large genetic databases to become more useful for people of various ancestries such as African American or Latinx, as they are underrepresented in genetic databases and studies. Hendricks compares this method to translating a book from English to another language.
“Think of DNA as the words of our body,” says Hendricks. “All of the words of our body make the instruction book that makes each of us up. Right now, it’s like the DNA books are only written in English so the information in the library is not as useful for people who don’t speak English. We’re working to create books in the library that are more universal.”
According to Hendricks, individuals and samples from understudied populations, such as African American and Latnix, are the most likely to lack large public resources with precisely matched ancestry data. As a result, researchers working with those populations often resort to the closest, but still poorly matched ancestral group. This leads to biased results in the very populations where high-quality research is needed the most.
The team showed the effectiveness of Summix in over 5,000 simulation scenarios and in the widely used Genome Aggregation Database (gnomAD), a publicly available genetic resource. They found Summix’s estimates of ancestry proportions to be highly accurate (within 0.001%) and the ancestry-adjusted genetic information to be less biased. The Summix method is available in open access software increasing the utility of the method and its applications.
“Most people are a combination of multiple continental (e.g. African and European) or finer scale (e.g. Italian and German) ancestries,” said Hendricks. “As healthcare moves forward with precision medicine, matching the unique ancestral make-up of each person will become increasingly important. The ability of Summix to update a genetic resource to match the ancestry of an individual is an important step in this direction and helps to increase the utility and equity of genetic summary data.”
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