GN/ New secrets about cat evolution revealed
Genetics biweekly vol.47, 30th October — 14th October
TL;DR
- By comparing genomes of several cat species, the project has helped researchers understand why cat genomes tend to have fewer complex genetic variations (such as rearrangements of DNA segments) than other mammal groups, like primates. It also revealed new insights into which parts of cat DNA are most likely to evolve rapidly and how they play a role in species differentiation.
- Cat hair could be the purr-fect way to catch criminals, according to researchers from the University of Leicester.
- Many hidden genetic variations can be detected with Chameleolyser, a new method. The information is already yielding new patient diagnoses and may also lead to the discovery of as-yet-unknown disease genes.
- Researchers have shown that sex differences in animals vary dramatically across species, organs, and developmental stages, and evolve quickly at the gene level but slowly at the cell type level.
- Scientists at the Francis Crick Institute and the Université Cote d’Azur, together with other labs in France and Switzerland, have identified a gene that is an early determining factor of ovary development in mice.
- An international team of researchers has discovered that formaldehyde, a widely spread pollutant and common metabolite in our body, interferes with the epigenetic programming of the cell. This finding expands the knowledge of formaldehyde, previously considered only as a DNA mutagen, and helps establish a further link with cancer.
- Mountains of used plastic bottles get thrown away every day, but microbes could potentially tackle this problem. Now, researchers report that they’ve developed a plastic-eating E. coli that can efficiently turn polyethylene terephthalate (PET) waste into adipic acid, which is used to make nylon materials, drugs and fragrances.
- Researchers have genetically engineered the first mice that get a human-like form of COVID-19, according to a study published online in Nature.
- Scientists have uncovered that proteins use a common chemical label as a shield to protect them from degradation, which in turn affects motility and aging.
- Cyanobacteria are a key species in Earth’s history, as they introduced atmospheric oxygen. The analysis of their evolution therefore provides important insights into the formation of modern aerobic ecosystems. For a long time, a certain type of fossil lipid, so-called 2-methylhopanes, was considered to be an important biomarker for Cyanobacteria in sediments, some of which are hundreds of millions of years old. However, this came into doubt when it turned out that not only Cyanobacteria but also Alphaproteobacteria are genetically capable of producing these lipids.
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
Single-haplotype comparative genomics provides insights into lineage-specific structural variation during cat evolution
by Kevin R. Bredemeyer, LaDeana Hillier, Andrew J. Harris, Graham M. Hughes, Nicole M. Foley, Colleen Lawless, Rachel A. Carroll, Jessica M. Storer, Mark A. Batzer, Edward S. Rice, Brian W. Davis, Terje Raudsepp, Stephen J. O’Brien, Leslie A. Lyons, Wesley C. Warren, William J. Murphy in Nature Genetics
Researchers at the Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS) and an interdisciplinary team of collaborators have uncovered new information about the history of cat evolution explaining how cats — including well-known species like lions, tigers, and domestic cats — evolved into different species and shedding light on how different genetic changes in cats relate to survival abilities like the ability to smell prey.
By comparing genomes of several cat species, the project, published today in Nature Genetics, has helped researchers understand why cat genomes tend to have fewer complex genetic variations (such as rearrangements of DNA segments) than other mammal groups, like primates. It also revealed new insights into which parts of cat DNA are most likely to evolve rapidly and how they play a role in species differentiation.
“Our goal was to better understand how cats evolved and the genetic basis of the trait differences between cat species,” said Dr. Bill Murphy, a VMBS professor of veterinary integrative biosciences who specializes in cat evolution. “We wanted to take advantage of some new technologies that allow us to create more complete cat genomic maps. “Our findings will open doors for people studying feline diseases, behavior, and conservation,” he said. “They’ll be working with a more complete understanding of the genetic differences that make each type of cat unique.”
Among the things the scientists were trying to better understand is why feline chromosomes — cellular structures containing the genetic information for traits like fur color, size, and sensory abilities — are more stable than in other mammal groups.
“We’ve known for a while now that cat chromosomes across species are very similar to each other,” Murphy said. “For example, the chromosomes of lions and domestic cats hardly differ at all. There appear to be far fewer duplications, rearrangements, and other types of variation than what are commonly found in great apes.”
In the primate order, this kind of genetic variation has led to the evolution of different species — including humans and great apes.
“The great ape genomes tend to break and rearrange, and even human genomes have very unstable regions,” Murphy said. “These variations may predispose certain individuals to have genetic conditions, like autism and other neurological disorders.”
The key to this variation between cats and apes, as Murphy found out, appears to be the frequency of something called segmental duplications — segments of DNA that are highly similar copies of other DNA segments found elsewhere in the genome.
“Primate genome researchers have been able to link these segmental duplications to chromosome rearrangements,” he said. The more segmental duplications you have in your DNA, the more likely the chromosomes are to rearrange, etc. “What we discovered by comparing a large number of cat species genomes is that cats have just a fraction of the segmental duplications found in other mammal groups — primates actually have seven times more of these duplications than cats. That’s a big difference, and now we believe we understand why cat genomes are more stable,” he said.
While cats may not have as many large genetic rearrangements in their DNA, they still have plenty of differences. Through their research, Murphy and his colleagues now better understand which parts of cat DNA cause those variations, especially the variations that define speciation, or the differences between species.
“It turns out that there’s a large region on the center of the X chromosome where most of the genetic rearrangements are happening,” Murphy said. “In fact, there’s one specific repetitive element within this region called DXZ4 that evidence tells us is largely responsible for the genetic isolation of at least two cat species, the domestic and jungle cat.”
DXZ4 is what Murphy calls a satellite repeat — it’s not a typical gene that codes for a physical trait like fur color, but, rather, it aids in the three-dimensional structure of the X chromosome and likely played an important role in cat speciation.
“We still don’t know the precise mechanism, but by comparing all these cat genomes, we can better measure the rate at which DXZ4 evolved in one species compared to all the others. What we learned is that DXZ4 is one of the most rapidly evolving parts of the cat genome; it’s evolving faster than 99.5% of the rest of the genome,” he explained. “Because of the rate at which it mutates, we were able to demonstrate why DXZ4 is probably linked to speciation,” Murphy said.
Using new, highly detailed genome sequences, the team also uncovered clearer links between the number of olfactory genes, which govern scent detection in cats and variation in social behavior and how they relate to their surroundings.
“Since cats are predators who rely heavily on smell to detect their prey, their sense of smell is a pretty important part of who they are,” he said. “Cats are a very diverse family, and we’ve always wanted to understand how genetic variation plays a role in different cat species’ ability to smell in their different environments.
“Lions and tigers have a pretty big difference between certain odorant genes involved in detecting pheromones, which are chemicals that different animals release into the environment to communicate information about identity, territory, or danger,” Murphy said. “We think the large difference has to do with lions being very social animals living in family groups and tigers living a solitary lifestyle. Lions may have a reduced reliance on pheromones and other odorants because they’re constantly around other lions, reflected in the fewer genes of this type in their genomes,” he said.
Tigers, on the other hand, need to be able to smell prey across very large territories as well as find mates.
“Tigers, in general, have large olfactory and pheromone receptor repertoires,” Murphy said. “We think this is directly tied to the size of their territories and the variety of environments in which they live.”
Domestic cats, on the other hand, appear to have lost a wide range of olfactory genes.
“If they don’t have to travel as far to find what they need because they’re living with people, it makes sense that natural selection wouldn’t preserve those genes,” he said.
Murphy shared that his favorite example from the project is the odorant receptors from the fishing cat, an aquatically adapted wild cat species living in Southeast Asia.
“We were able to show that fishing cats have retained many genes for detecting waterborne odorants, which is a pretty rare trait in terrestrial vertebrates,” he said. “All of the other cat species have lost these specific genes over time, but fishing cats still have them.”
This new information about olfactory genes in cats was made possible through a new approach to genome sequencing called trio binning, which allows researchers to sequence the most difficult regions of a genome.
This new technology also makes separating maternal and paternal DNA much easier.
“With trio binning, you can now take DNA from an F1 hybrid — an animal whose DNA is split 50–50 between parents of different species — and cleanly separate the maternal and paternal DNA, giving you two complete sets of DNA, one for each parent species,” Murphy said. “The process is much simpler, and the results are more complete.”
One of the most important conclusions from the project is that cat species may be similar in many ways, but their differences matter.
“These differences are showing us how these animals are perfectly suited for their natural environments,” Murphy said. “They’re not interchangeable, and that’s valuable information for conservationists and others working to preserve or restore species in their natural habitats. “For example, you can’t assume that tigers from Sumatra and Siberia are the same,” he said. “Their environments are wildly different, and those tiger populations have likely developed specialized genetic adaptations to help them survive in these very different places.”
It’s also important for scientists to realize that the sections of genomes that are the most difficult to assemble may just be the key to understanding crucial bodily systems like immunity and reproduction.
“Olfactory genes aren’t the only ones that have been challenging to sequence and study. Scientists have also struggled to sequence immune and reproductive genes, so previous studies are missing this kind of information. Imagine trying to study a genetic condition in cats, humans, or any species, for that matter, without having all the pieces; this is why assembling complete genomes matters,” Murphy said.
For now, Murphy and his team will continue applying the most advanced genome sequencing and assembly technologies to cat genomes in order to fill in as much information as possible about the world of cats.
Defining cat mitogenome variation and accounting for numts via multiplex amplification and Nanopore sequencing
by Emily C. Patterson, Gurdeep Matharu Lall, Rita Neumann, Barbara Ottolini, Federico Sacchini, Aiden P. Foster, Mark A. Jobling, Jon H. Wetton in Forensic Science International: Genetics
Cat hair could be the purr-fect way to catch criminals, according to researchers from the University of Leicester.
They have shown that a single cat hair contains DNA which could link a suspect and a crime-scene, or a victim.
Around 26 per cent of UK householders own a cat and with the average feline shedding thousands of hairs annually, it’s inevitable that once you leave, you’ll bear evidence of the furry resident. This is potentially useful in the forensic investigation of criminal activity.
While a human perpetrator may take pains not to leave their own DNA behind, transferred cat hair contains its own DNA that could provide a link between a suspect and a crime-scene, or a victim.
In a paper published in the journal Forensic Science International: Genetics earlier this month, researchers at the University of Leicester describe a sensitive method that can extract maximum DNA information from just one cat hair.
Emily Patterson, the lead author of the study and a Leicester PhD student, said: “Hair shed by your cat lacks the hair root, so it contains very little useable DNA. In practice we can only analyse mitochondrial DNA, which is passed from mothers to their offspring, and is shared among maternally related cats.”
This means that hair DNA cannot individually identify a cat, making it essential to maximise information in a forensic test.
However, a new method identified by the researchers enabled them to determine the sequence of the entire mitochondrial DNA, ensuring it is around ten times more discriminating than a previously used technique which looked at only a short fragment.
Dr Jon Wetton, from the University’s Department of Genetics & Genome Biology, co-led the study.
He said: “In a previous murder case we applied the earlier technique but were fortunate that the suspect’s cat had an uncommon mitochondrial variant, as most cat lineages couldn’t be distinguished from each other. But with our new approach virtually every cat has a rare DNA type and so the test will almost certainly be informative if hairs are found.”
The team tested the method in a lost cat case, where DNA from skeletal remains of a missing female cat could be matched with DNA from hair from her surviving male offspring.
Study co-lead, Professor of Genetics, Mark Jobling, added: “In criminal cases where there is no human DNA available to test, pet hair is a valuable source of linking evidence, and our method makes it much more powerful. The same approach could also be applied to other species — in particular, dogs.”
Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation
by Wouter Steyaert, Lonneke Haer-Wigman, Rolph Pfundt, Debby Hellebrekers, Marloes Steehouwer, Juliet Hampstead, Elke de Boer, Alexander Stegmann, Helger Yntema, Erik-Jan Kamsteeg, Han Brunner, Alexander Hoischen, Christian Gilissen in Nature Communications
Many hidden genetic variations can be detected with Chameleolyser, a new method developed in Nijmegen. The information is already yielding new patient diagnoses and may also lead to the discovery of as yet unknown disease genes, write Wouter Steyaert and Christian Gilissen of Radboudumc in Nature Communications.
Medical science has been using exome sequencing to map the genes of individual patients with rare diseases for about 15 years. With this technique, the DNA of a person’s approximately 20,000 human genes is cut into small pieces so the DNA letters can be read off. This creates a huge amount of tiny DNA fragments, which are then reassembled into whole genes like a jigsaw puzzle. The result is an overview of that single person’s 20,000 genes.
‘Unfortunately, such an overview is never quite complete,’ says Christian Gilissen, professor of Genome Bioinformatics. ‘That’s because of the evolution of our genome, our hereditary material. When copying DNA, things sometimes go wrong. Small pieces of DNA disappear or are added. Some pieces are copied more than once. It also happens that a copied gene is placed somewhere else in the genome, giving you a pseudogene in addition to the original gene. These genetic “sloppinesses” are very important because they are the engine of evolution. This is how genetic changes arise. Changes that can be without effect or beneficial, but sometimes also cause new diseases.’
Zooming in on the gene and pseudogenes for a moment. The gene has a function, the pseudogen usually does not. Over time, small changes, mutations, can occur in both the gene and pseudogen. But gene and pseudogen are so similar that when sequencing it is not clear which piece belongs to the gene and which to the pseudogene.
Gilissen: ‘For this reason, these DNA regions are not included in the analysis. A mutation found may originate from the pseudogen and have no meaning. If you add that mutation to the normal gene, you would make a wrong diagnosis. We don’t want that.’
With Wouter Steyaert, Gilissen developed a method — Chameleolyser — that detects gene and pseudogen combinations in existing exome sequencing data and can also visualize the genetic variations between them. Steyaert:
‘We are now picking up a lot of genetic variation that was previously invisible. Per exome, we find about sixty additional genetic variants. For a number of people, this data allowed us to definitively determine the cause of their disease. With a new sequencing technique from PacBio, which analyzes longer stretches of DNA, we have established the reliability of our method.’
The new method is interesting because it can be applied to already existing exome sequencing data. Thus, no new studies in patients are necessary. Any sequencing center in the world can apply the method.
‘Such a large-scale analysis can also provide new biological insights,’ Gilissen says. ‘In many disorders, the genetic cause can only be determined in half of the patients. We think we will also find new disease genes in those gene-pseudogen combinations. For some of those patients, that may be where the genetic cause for their condition lies.’
Sex-biased gene expression across mammalian organ development and evolution
by Leticia Rodríguez-Montes, Svetlana Ovchinnikova, Xuefei Yuan, Tania Studer, Ioannis Sarropoulos, Simon Anders, Henrik Kaessmann, Margarida Cardoso-Moreira in Science
Researchers at the Francis Crick Institute and Heidelberg University in Germany have shown that sex differences in animals vary dramatically across species, organs and developmental stages, and evolve quickly at the gene level but slowly at the cell type level.
Mammals have different traits depending on sex, like antlers in male deer. These are known as ‘sexually dimorphic’ traits, and include differences which aren’t visible, such as in internal organs. However, researchers didn’t know when and where sex differences emerge, and which genes and cells are responsible for them.
In this study, published today in Science, the researchers analysed the activity of genes in males and females over time in humans and four species (mice, rats, rabbits, opossums and chickens), covering the development of five organs (brain, cerebellum, heart, kidney and liver), into adulthood in the animals and up to birth in humans1.
The researchers discovered that the organs which are different between the sexes vary across species. For example, the liver and the kidney were the most sexually dimorphic in rats and mice, whereas in rabbits, the heart was the most sexually dimorphic and liver and kidney not at all.
The researchers also found that, in all animals and humans, few sex differences occurred while organs were developing. Instead, they increased sharply around sexual maturity.
The researchers then investigated the genes responsible for sex differences, finding that different genes are ‘sex-biased’ (expressed differently depending on sex) across species. Only a very small number of sex-biased genes were shared across species, suggesting that sex differences have evolved quickly. The few genes that were shared were usually located on the sex (X and Y) chromosomes.
Although sex-biased genes differed between species, the study showed that the types of cells that are sexually dimorphic are the same across species. For example, in mice and rats, different genes were sex biased in the liver, but, in both cases, the sex-biased genes were active in the hepatocytes, the main type of cell in the liver. This may explain why there are sex differences in drug processing in the liver.
Leticia Rodríguez-Montes, PhD student at Heidelberg University, and first author, said: “It was interesting to see that despite the fast evolution of sex differences, a few genes located on the X and Y sex chromosomes showed differences between the sexes in all mammalian species. These probably serve as basic genetic triggers for the development of traits specific to each sex in all mammals.”
Margarida Cardoso Moreira, Group Leader of the Evolutionary Developmental Biology Laboratory at the Crick, and co-leader of the study with Henrik Kaessmann at Heidelberg University, said:
“By taking an evolutionary approach, we’ve observed that sex differences evolve fast at the gene level but slowly at the cell level. This has implications for how we use animal models to understand sex differences in humans, as it’s helpful to know that a particular cell type is sexually dimorphic across species, even if there are other differences.
“It was also surprising to us that there are so few sex differences until sexual maturity. We were expecting most differences to occur in adults because this is when sex differences are most visible, but we also expected to see a gradual increase in sex differences during organ development, instead of an abrupt rise around sexual maturity. This research is another piece in the puzzle of understanding why we are sexually dimorphic and how this impacts us.”
The −KTS splice variant of WT1 is essential for ovarian determination in mice
by Elodie P. Gregoire, Marie-Cécile De Cian, Roberta Migale, Aitana Perea-Gomez, Sébastien Schaub, Natividad Bellido-Carreras, Isabelle Stévant, Chloé Mayère, Yasmine Neirijnck, Agnès Loubat, Paul Rivaud, Miriam Llorian Sopena, Simon Lachambre, Margot M. Linssen, Peter Hohenstein, Robin Lovell-Badge, Serge Nef, Frédéric Chalmel, Andreas Schedl, Marie-Christine Chaboissier in Science
Researchers at the Francis Crick Institute and the Université Cote d’Azur, together with other labs in France and Switzerland, have identified a gene which is an early determining factor of ovary development in mice.
Typically, mice with XY sex chromosomes develop testes, and mice with XX chromosomes develop ovaries. Whether early gonads become ovaries or testes is due to cells either becoming Sertoli cells for testes, or pregranulosa cells for ovaries. This decision results from the coordinated activity of a set of genes, such as the Sry gene on the Y chromosome which has a short window of time to drive testes development. If this doesn’t happen, the gonads default to become ovaries.
In research published in Science, the team investigated the role of another gene, Wt1, in sex development in mice. They produced mice with genetic alterations in this gene to understand its effect.
They found that one form of the WT1 protein (-KTS) was essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form in both XY and XX mice.
They then looked at mice where Wt1 was mutated to only make the -KTS form of the protein. Here the researchers saw that twice as much -KTS was produced to compensate for the lack of other forms of the protein.
The higher amounts of -KTS reduced the expression of Sry in XY gonads and increased genes involved in ovarian development. The production of SRY never reached the level needed to trigger testes development.
This meant that an XY mouse developed female gonads in the presence of too much -KTS, showing that the -KTS form of WT1 is an early trigger for female gonad development, regardless of XX or XY chromosomes.
In humans, mutations in WT1 can lead to Frasier syndrome, which causes impaired kidney function and gonad development. It impacts people with both XX and XY chromosomes, but notably leads to ovaries in people with XY chromosomes, although these degenerate prior to birth.
Robin Lovell-Badge, Group Leader of the Stem Cell Biology and Developmental Genetics Laboratory at the Crick, said: “We have known about Wt1 and its variants for a long time, but the true role of the -KTS version has been hiding in plain sight until now! This discovery should help us understand the very early stages of gonad development when critical decisions that affect not only the fate of the gonad, but the sex of the rest of the body, take place in just a few cells.”
Marie-Christine Chaboissier, group leader in the Institut de Biologie Valrose, at the Université Cote d’Azur, said:
“When Sry, the testis determining gene, was identified in the early nineties, it was hoped that the other main players involved in the choice of making testes or ovaries would rapidly emerge. But although many other genes required have gradually fallen into place, it has taken until now, with a collaborative effort involving five European teams, to find an equivalent master ovarian determinant. It is perhaps a little ironic that this long-sought factor is a variant of the Wt1 gene which was also described at the same time, however, with the complexity of the gene and the system, we needed the modern tools of molecular genetics to obtain the proof.”
Elodie Gregoire, a senior scientist (‘ingenieure d’études’) in the Chaboissier lab at Université Cote d’Azur, said:
“Because the -KTS variant of WT1 acts so early, it represents an ideal entry point to decipher the regulatory gene networks involved in initiating ovary development, which may in turn help to identify the molecular and genetic basis of spontaneous or unexplained disorders of sex development.”
As well as fulfilling an important piece of the puzzle for sex determination, this discovery will help researchers understand how WT1 acts in other systems, like kidney development and Wilms tumour, a type of kidney cancer. It may also give clues to the mechanisms underlying how cell fate is decided more generally.
Formaldehyde regulates S -adenosylmethionine biosynthesis and one-carbon metabolism
by Vanha N. Pham, Kevin J. Bruemmer, Joel D. W. Toh, Eva J. Ge, Logan Tenney, Carl C. Ward, Felix A. Dingler, Christopher L. Millington, Carlos A. Garcia-Prieto, Mia C. Pulos-Holmes, Nicholas T. Ingolia, Lucas B. Pontel, Manel Esteller, Ketan J. Patel, Daniel K. Nomura, Christopher J. Chang in Science
An international team of researchers has discovered that formaldehyde, a widely spread pollutant and common metabolite in our body, interferes in the epigenetic programming of the cell. This finding expands the knowledge of formaldehyde, previously considered only as a DNA mutagen, and helps establishing a further link with cancer. Dr. Lucas Pontel, group leader at the Josep Carreras Leukaemia Research Institute and Dr. Manel Esteller, group leader and director of the institution, sign the paper as collaborator authors, which has been published at Science.
Epigenetics, the chemical mechanisms that controls the activity of genes, allows our cells, tissues and organs to adapt to the changing circumstances of the environment around us. This advantage can become a drawback, though, as this epigenetic regulation can be more easily altered by toxins than the more stable genetic sequence of the DNA.
An article recently published at Science with the collaboration of the groups of Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute (IJC-CERCA), ICREA Research Professor and Chairman of Genetics at the University of Barcelona, and Dr. Lucas Pontel, Ramon y Cajal Fellow also of the Josep Carreras Institute, demonstrates that the substance called formaldehyde, commonly present in various household and cosmetic products, in polluted air, and widely used in construction, is a powerful modifier of normal epigenetic patterns.
The publication is led by Dr. Christopher J. Chang, of the University of California Berkeley in the United States, whose research group is pioneer in the study of the effects of various chemical products on cell metabolism. The research has focused on investigating the effects of high concentrations of formaldehyde in the body, a substance already been associated with an increased risk of developing cancer (nasopharyngeal tumours and leukaemia), hepatic degeneration due to fatty liver (steatosis) and asthma.
Dr. Esteller points out that this is relevant because:
“formaldehyde enters our body mainly during our breathing and, because it dissolves well in an aqueous medium, it ends up reaching all the cells of our body.”
“This substance is especially concentrated in various products used in construction, furniture manufacturing, the textile industry and some hair products,” comments Dr. Esteller. Going a step further, Dr. Pontel stresses this vision pointing out that “formaldehyde is not only a significant environmental hazard, often found in polluted fumes, but it can also be generated within our bodies through the metabolism of common dietary substances like the sweetener aspartame. Moreover, our cells are continually producing formaldehyde, a known mutagen that can lead to cancer.”
As an overview of the research, Dr. Esteller points out that “we have discovered that formaldehyde is an inhibitor of the MAT1A protein, which is the main producer of S-Adenosyl-L-Methionine (SAM) and this last molecule is the universal donor of the chemical group “methyl” that regulates epigenetic activity. Specifically, we found that exposure to formaldehyde induced a reduction in SAM content and caused the loss of methylation of histones, proteins that package our DNA and control the function of thousands of genes.”
Altogether, this work reveals an even more concerning aspect of formaldehyde’s toxicity.
Dr. Pontel summarizes it as “we have discovered that formaldehyde has the capacity to modify the epigenetic landscape of our cells, which might contribute to the well-documented carcinogenic properties of formaldehyde.”
The epigenetic changes caused by the toxic agent could directly contribute to the origin of the mentioned diseases, beyond its known mutagenic properties.
On this regard, Dr. Esteller informs that “International health authorities are already restricting the use of formaldehyde as much as possible, but there are still areas of work where high levels of it are used, such as in the manufacture of resins, the production of plastic, industrial foundries or the cosmetics industry. In addition, it also originates during the combustion of automobile gasoline and in tobacco smoke, thus, environmental and health policies aimed at reducing our exposure to the characterized substance should be promoted.”
Microbial Upcycling of Waste PET to Adipic Acid
by Marcos Valenzuela-Ortega, Jack T. Suitor, Mirren F. M. White, Trevor Hinchcliffe, Stephen Wallace in ACS Central Science
Mountains of used plastic bottles get thrown away every day, but microbes could potentially tackle this problem. Now, researchers in ACS Central Science report that they’ve developed a plastic-eating E. coli that can efficiently turn polyethylene terephthalate (PET) waste into adipic acid, which is used to make nylon materials, drugs and fragrances.
Previously, a team of researchers including Stephen Wallace engineered a strain of E. coli to transform the main component in old PET bottles, terephthalic acid, into something tastier and more valuable: the vanilla flavor compound vanillin. At the same time, other researchers engineered microbes to metabolize terephthalic acid into a variety of small molecules, including short acids. So, Wallace and a new team from the University of Edinburgh wanted to expand E. coli’s biosynthetic pathways to include the metabolism of terephthalic acid into adipic acid, a feedstock for many everyday products that’s typically generated from fossil fuels using energy-intensive processes.
The team developed a new E. coli strain that produced enzymes that could transform terephthalic acid into compounds such as muconic acid and adipic acid. Then, to transform the muconic acid into adipic acid, they used a second type of E. coli, which produced hydrogen gas, and a palladium catalyst. In experiments, the team found that attaching the engineered microbial cells to alginate hydrogel beads improved their efficiency, and up to 79% of the terephthalic acid was converted into adipic acid. Using real-world samples of terephthalic acid from a discarded bottle and a coating taken from waste packaging labels, the engineered E. coli system efficiently produced adipic acid. In the future, the researchers say they will look for pathways to biosynthesize additional higher-value products.
Mouse genome rewriting and tailoring of three important disease loci
by Weimin Zhang, Ilona Golynker, Ran Brosh, Alvaro Fajardo, Yinan Zhu, Aleksandra M. Wudzinska, Raquel Ordoñez, André M. Ribeiro-dos-Santos, Lucia Carrau, Payal Damani-Yokota, Stephen T. Yeung, Camille Khairallah, Antonio Vela Gartner, Noor Chalhoub, Emily Huang, Hannah J. Ashe, Kamal M. Khanna, Matthew T. Maurano, Sang Yong Kim, Benjamin R. tenOever, Jef D. Boeke in Nature
Researchers have genetically engineered the first mice that get a human-like form of COVID-19, according to a study published online November 1in Nature.
Led by researchers from NYU Grossman School of Medicine, the new work created lab mice with human genetic material for ACE2 — a protein snagged by the pandemic virus so it can attach to human cells as part of the infection. The mice with this genetic change developed symptoms similar to young humans infected with the virus causing COVID-19, instead of dying upon infection as had occurred with prior mouse models.
“That these mice survive creates the first animal model that mimics the form of COVID-19 seen in most people — down to the immune system cells activated and comparable symptoms,” said senior study author Jef Boeke, the Sol and Judith Bergstein Director of the Institute for Systems Genetics at NYU Langone Health. “This has been a major missing piece in efforts to develop new drugs against this virus.”
“Given that mice have been the lead genetic model for decades,” added Boeke, “there are thousands of existing mouse lines that can now be crossbred with our humanized ACE2 mice to study how the body reacts differently to the virus in patients with diabetes or obesity, or as people age.”
The new study revolves around a new method to edit DNA, the 3 billion “letters” of the genetic code that serve as instructions for building our cells and bodies.
While famous techniques like CRISPR enable the editing of DNA editing just one or a few letters at a time, some challenges require changes throughout genes that can be up to 2 million letters long. In such cases, it may be more efficient to build DNA from scratch, with far-flung changes made in large swaths of code pre-assembled and then swapped into a cell in place of its natural counterpart. Because human genes are so complex, Boeke’s lab first developed its “genome writing” approach in yeast, one-celled fungi that share many features with human cells but that are simpler and easier to study.
More recently, Boeke’s team adapted their yeast techniques to the mammalian genetic code, which is made up of not just of genes that encode proteins, but also of many switches that turn on different genes at different levels in different cell types. By studying this poorly understood “dark matter” that regulates genes, the research team was able to design living mice with cells that had more human-like levels of ACE gene activity for the first time. The study authors used yeast cells to assemble DNA sequences of up to 200,000 letters in a single step, and then delivered these “naked” DNAs into mouse embryonic stem cells using their new delivery method, mSwAP-In.
Overcoming the size limits of past methods, mSwAP-In delivered a humanized mouse model of COVID-19 pathology by “overwriting” 72 kilobases (kb) of mouse Ace2 code with 180 kb of the human ACE2 gene and its regulatory DNA.
To accomplish this cross-species swap, the study method cut into a key spot in the DNA code around the natural gene, swapped in a synthetic counterpart in steps, and with each addition, added a quality control mechanism so that only cells with the synthetic gene survived. The research team then worked with Sang Yong Kim at NYU’s Rodent Genome Engineering Lab using a stem cell technique called “tetraploid complementation” to create a living mouse whose cells included the overwritten genes.
In addition, the researchers had previously designed a synthetic version of the gene Trp53, the mouse version of the human gene TP53, and swapped it into mouse cells. The protein encoded by this gene coordinates the cell’s response to damaged DNA, and can even instruct cells containing it to die to prevent the build-up of cancerous cells. When this “guardian of the genome” itself becomes faulty, it is a major contributor to human cancers.
Whereas the ACE2 experiments had swapped in an unchanged version of a human gene, the synthetic, swapped-in Trp53 gene had been designed to no longer include a combination of molecular code letters — cytosine © next to guanine (G) — known to be vulnerable to random, cancer-causing changes. The researchers overwrote key CG “hotspots” with code containing a different DNA letter in adenine (A).
“The AG switch left the gene’s function intact, but lessened its vulnerability to mutation, with the swap predicted to lead to a 10-to-50 fold lower mutation rate,” said first author Weimin Zhang, PhD, a post-doctoral scholar in Boeke’s lab. “Our goal is to demonstrate in a living test animal that this swap leads to fewer mutations and fewer resulting tumors, and those experiments are being planned.”
N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
by Sylvia Varland, Rui Duarte Silva, Ine Kjosås, Alexandra Faustino, Annelies Bogaert, Maximilian Billmann, Hadi Boukhatmi, Barbara Kellen, Michael Costanzo, Adrian Drazic, Camilla Osberg, Katherine Chan, Xiang Zhang, Amy Hin Yan Tong, Simonetta Andreazza, Juliette J. Lee, Lyudmila Nedyalkova, Matej Ušaj, Alexander J. Whitworth, Brenda J. Andrews, Jason Moffat, Chad L. Myers, Kris Gevaert, Charles Boone, Rui Gonçalo Martinho, Thomas Arnesen in Nature Communications
Proteins are key to all processes in our cells and understanding their functions and regulation is of major importance.
“For many years, we have known that nearly all human proteins are modified by a specific chemical group, but its functional impact has remained undefined,” says professor Thomas Arnesen at the Department of Biomedicine, University of Bergen.
He explains:
“One of the most common protein modifications in human cells is N-terminal acetylation, which is an addition of a small chemical group (acetyl) at the starting tip (N-terminus) of a protein. The modification is launched by a group of enzymes called N-terminal acetyltransferases (NATs).” Despite being “everywhere” in human cells, the functional role of this modification remains mysterious, Arnesen explains.
He is an investigator of a new study that reveals that a core function of this protein modification is to protect proteins from degradation, and this is essential for normal longevity and motility.
To address this question, molecular biologist and researcher Sylvia Varland spent two years at the Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Canada, supported by a FRIPRO mobility grant from the Research Council of Norway.
Here, she used the established CRISPR-Cas9 technology and powerful screening platforms available in one of the best scientific environments to define the functional roles of the human NAT enzymes. Sylvia focused on one of the major human NAT enzymes, NatC, and the genome-wide screening of human NatC KO cells revealed many human genes likely to be involved in the function of N-terminal acetylation.
“Without the inspiring scientific environment at the Donnelly Center combined with financial support from Marie Sklodowska-Curie Actions this study would not have seen the light of day,” says Varland.
Back in the Arnesen lab at UiB, Sylvia explored the molecular implications of her genetic findings with the help from PhD student Ine Kjosås and other lab members. Biochemical, cell biology and proteomics experiments demonstrated that N-terminal acetylation acts as shield to protect many proteins from protein degradation. Proteins lacking N-terminal acetylation were recognized by the cellular degradation machinery.
“N-terminal acetylation has the power to dictate a protein’s lifetime and affects our cells in numerous ways,” says Varland. “This is true for humans, and it is also true in fruit flies, which is a very useful model to study this protein modification,” she continues.
In parallel, a research group by investigator Rui Martinho at the University of Aveiro in Portugal was working on the organismal impact of NatC-mediated N-terminal acetylation using a fruit fly model (Drosophila).
Postdoctoral researcher Rui Silva and fellow students carried out studies with flies lacking N-terminal acetylation. The two teams decided to merge their efforts and have for the last two years coordinated their experiments. Flies lacking NatC were viable, but these flies displayed decreased longevity and decreased motility with age. These effects could be partially reversed by expressing a protein conserved between fly and human found to be a key target of NatC protection.
In conclusion, using an unbiased and global genetic screen combined with cellular phenotyping, the team uncovered a general function for N-terminal acetylation in protecting proteins from degradation in human cells.
The molecular investigations defined the cellular components (ubiquitin ligases) responsible for degrading a major class of human proteins when lacking N-terminal acetylation. The role of NatC-mediated protection of specific proteins is evident both in human cells and in fruit fly. The impact of these pathways on longevity and motility in aged individuals underscores the vital role of protein N-terminal acetylation.
“This work untangles some of the secrets and shows how N-terminal acetylation shape individual protein fate,” Thomas Arnesen concludes.
Genetics re-establish the utility of 2-methylhopanes as cyanobacterial biomarkers before 750 million years ago
by Yosuke Hoshino, Benjamin J. Nettersheim, David A. Gold, Christian Hallmann, Galina Vinnichenko, Lennart M. van Maldegem, Caleb Bishop, Jochen J. Brocks, Eric A. Gaucher in Nature Ecology & Evolution
Cyanobacteria are a key species in Earth’s history, as they introduced atmospheric oxygen for the first time. The analysis of their evolution therefore provides important insights into the formation of modern aerobic ecosystems. For a long time, a certain type of fossil lipid, so-called 2-methylhopanes, was considered to be an important biomarker for Cyanobacteria in sediments, some of which are hundreds of millions of years old. However, this came into doubt when it turned out that not only Cyanobacteria but also Alphaproteobacteria are genetically capable of producing these lipids.
An international research team led by Yosuke Hoshino from the GFZ German Research Centre for Geosciences and Benjamin Nettersheim from MARUM — Center for Marine Environmental Sciences at the University of Bremen has now studied the phylogenetic diversification and distribution of the genes — including HpnP — that are responsible for the synthesis of the parent lipids for 2-methylhopanes: The researchers have deciphered when these genes were acquired by certain groups of organisms. They were able to show that HpnP was probably already present in the last common ancestor of Cyanobacteria more than two billion years ago, while the gene only appeared in Alphaproteobacteria about 750 million years ago. For the times before that, 2-methylhopanes can therefore serve as a clear biomarker for oxygen-producing Cyanobacteria.
The study, which has now been published in the journal Nature Ecology & Evolution, shows how genetics, in interaction with sedimentology, paleobiology and geochemistry, can improve the diagnostic value of biomarkers and refine the reconstruction of early ecosystems.
Cyanobacteria played a crucial role in transforming the Earth from its initial oxygen-free state to a modern, oxygen-rich system in which increasingly complex life is possible. Cyanobacteria were probably the only relevant group of organisms that converted inorganic substances into organic ones (so-called primary producers) and produced oxygen for long stretches of the Precambrian (the first four billion or so years of Earth’s history, from its beginnings to about 540 million years ago). Therefore, the analysis of their evolution is of great importance for understanding the common history of life and Earth.
In principle, the fossil remains of whole Cyanobacteria can serve as an indicator of the presence of oxygenic photosynthesis in the geological past. However, due to preservational biases and ambiguities in recognizing fossil cyanobacterial cells, geochemists rather use fossilised diagnostic lipids, such as 2-methylhopanes. 2-Methylhopanoids (non-fossilised parent molecules) are produced by the bacteria and — in contrast to the bacteria themselves- can be fossilised and detected in sedimentary rocks even after hundreds of millions of years in good quality and in quantities corresponding to their original occurrence.
However, there have recently been doubts about the suitability of 2-methylhopane as a biomarker for Cyanobacteria: the discovery of the lipid biosynthesis gene revealed that Alphaproteobacteria are also capable of producing these lipids. This means that temporally tracing oxygen-producing processes on Earth by 2-methylhopanes is no longer possible.
An international research team led by Yosuke Hoshino and Christian Hallmann, scientists in GFZ Section 3.2 “Organic Geochemistry,” and Benjamin Nettersheim from MARUM at the University of Bremen has now systematically investigated which organisms other than Cyanobacteria possess the genes (abbreviated as the SC and HpnP genes) necessary for the production of 2-methylhopanoids, and when they acquired those genes during the course of evolution. In this way, the team was able to show that the fossil lipid 2-methylhopane can still be used as a clear biomarker for the existence of Cyanobacteria for times dating back more than 750 million years.
In addition, the researchers have created an integrated record of 2-methylhopane production over the course of Earth’s history. For this, they combined their molecular data with new sediment analyses carried out under high-purity conditions.
“The method we proposed is in principle applicable to any organic matter in geological archives and has great potential to trace the evolution of different ecosystems with much higher temporal and spatial resolution than before,” Hoshino sums up.
For the analysis of the genetic relationships, Hoshino searched publicly available databases, containing millions of gene and protein sequences, for organisms with the SC and HpnP genes. Based on this genetic data set, he created so-called phylogenetic trees, which provide information on how the SC and HpnP genes were transferred between different organisms and whether the gene transfer took place vertically via inheritance or horizontally between evolutionarily unrelated organisms. Furthermore, the researchers were also able to determine when individual gene transfers took place in the evolutionary history of the genes by comparing previous studies that utilized the so-called molecular clock technique that takes into account the DNA mutation rate and estimates the timeline for the gene evolution.
In addition, because Precambrian biomarker records are extremely sensitive to contamination, the researchers used an ultra-clean method to extract organic matter from sediment cores. The geological samples in the form of cores were collected by several co-authors from 16 countries. They represent different geological periods from the Paleoproterozoic (2.5 billion years ago) to the present. The relative abundance of 2-methylhopanes was then measured in the organic matter.
There are many bacteria that possess both SC and HpnP genes, but they are mainly Cyanobacteria and Alphaproteobacteria. Each group is found to have acquired the two genes independently. This is in contrast to earlier studies that concluded that Cyanobacteria acquired these genes from Alphaproteobacteria at a late stage in their evolution. The new study further revealed that the common ancestor of Cyanobacteria already possessed both genes more than 2.4 billion years ago, when oxygen began to accumulate in the atmosphere during the so-called Great Oxidation Event.
In contrast, Alphaproteobacteria acquired the SC and HpnP genes at the earliest only 750 million years ago. Before that, 2-methylhopanoids were thus only produced by Cyanobacteria. The researchers interpret a slightly delayed increase of sedimentary 2-methylhopanes around 600 million years ago as a sign of the global spread of Alphaproteobacteria, which may have favored the concurrent evolutionary rise of eukaryotic algae.
“The individual analytical methods mentioned above are not new, but few researchers have attempted to perform comprehensive analyses for SC and HpnP and to integrate genetic data with sedimentary biomarker data before, as this requires combining two completely different scientific disciplines — molecular biology and organic geochemistry,” says Hoshino. “The source of sedimentary 2-methylhopanes has been a topic of long debate,” adds Christian Hallmann. — “This new study not only provides clarity about the diagnosticity of 2-methylhopanes and the role of Cyanobacteria in deep time; its methodology offers a new avenue forward to refine the diagnosticity of, in theory, any biomarker lipid once the biosynthesis genes are known.”
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