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GN/ DNA sequence enhances understanding origins of jaws

Genetics biweekly vol.42, 16th November — 30th November

TL;DR

  • Researchers have discovered and characterized a DNA sequence found in jawed vertebrates, such as sharks and humans, but absent in jawless vertebrates, such as lampreys. This DNA is important for the shaping of the joint surfaces during embryo development.
  • A new study points to introners, one of several proposed mechanisms for the creation of introns, as an explanation for the origins of most introns across species.
  • Understanding how bats tolerate viral infections without developing symptoms may lead to better ways of combating human disease.
  • Researchers demonstrate in a zebrafish model that two proteins prevent scar formation in the brain, thereby improving the ability of tissue to regenerate.
  • Hollow spheres made of MYC proteins open new doors in cancer research, scientists report.
  • A team of researchers has identified a group of human DNA sequences driving changes in brain development, digestion and immunity that seem to have evolved rapidly after our family line split from that of the chimpanzees, but before we split with the Neanderthals.
  • Researchers have discovered a new height-reducing gene Rht13 which means that seeds can be planted deeper in the soil giving access to moisture, without the adverse effect on seedling emergence seen with existing wheat varieties.
  • The Sox9 gene is upregulated in the absence of sex-determining Y chromosome and Sry gene in Amami spiny rat.
  • A research group has revealed a new system that allows them to control the behavior of the nematode worm Caenorhabditis elegans, using two different animal opsins, a type of light-sensitive protein.
  • A team of researchers has discovered new insights into the evolution of color patterns in frogs and toads — collectively known as anurans. Animal color patterns can help them camouflage with their surroundings and avoid detection from preys or predators. Many anurans have a light stripe along their back, which, when observed from above, creates the optical illusion that the animal is split in two halves and confuses visually-oriented predators. Although this color pattern is widespread in frogs around the world, little is known regarding its evolution or genetic origin.
  • 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

  1. The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
  2. Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
  3. 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

A novel cis-regulatory element drives early expression of Nkx3.2 in the gnathostome primary jaw joint

by Laura Waldmann, Jake Leyhr, Beata Filipek-Górniok, Hanqing Zhang, Amin Allalou, Tatjana Haitina in eLife

Researchers at Uppsala University have discovered and characterised a DNA sequence found in jawed vertebrates, such as sharks and humans, but absent in jawless vertebrates, such as lampreys. This DNA is important for the shaping of the joint surfaces during embryo development.

The vast majority of vertebrate species living today, including humans, belong to the jawed vertebrate group. The development of articulating jaws during vertebrate evolution was one of the most significant evolutionary transitions from jawless to jawed vertebrates, taking place at least 423 million years ago. The lower and upper jaws were initially connected by the primary jaw joint. However, during the evolution of mammals this moved to the middle ear to enhance hearing and was replaced by the secondary jaw joint, which is how humans are constructed today.

Graphical summary of the study.

The primary jaw joint is formed during embryonic development and has an active gene which contains sequence information for a specific protein — transcription factor Nkx3.2. This protein has long been thought to have played a major role in the evolution of this jaw joint, but little was known before about how its gene activity is regulated in the jaw joint cells.

Typically, genes are activated with help from DNA sequences, known as enhancers, that do not contain gene sequence information. Furthermore, such ‘regulatory’ DNA can contribute to the activation of the gene only in a certain cell type and can be conserved among different animal species.

Gene synteny around Nkx3.2 is well conserved in vertebrate genomes.

“We searched through the genome sequences of many different vertebrate species and only found the DNA sequence near the Nkx3.2 gene in jawed vertebrates — not in jawless ones. When we injected these DNA sequences from jawed vertebrates into zebrafish embryos, they were all activated in the jaw joint cells. The fact that their ability to activate has been preserved for over 400 million years shows how important it is for jawed vertebrates,” notes Tatjana Haitina, researcher at Uppsala University, who led the study.

Zebrafish jaw joint regulatory sequence 1 (JRS1) enhancer drives mCherry reporter gene expression in jaw joint-forming chondroprogenitor cells and partly overlaps with sox10:egfp expressing cells.

“In experiments where we deleted the newly discovered DNA sequence from the zebrafish genome using the CRISPR/Cas9 technique, we saw that the early activation of the Nkx3.2 gene was reduced, which caused defects in the jaw joint shape. It turned out that these defects were later repaired, suggesting that there is additional regulatory DNA somewhere in the genome that controls the activation of the Nkx3.2 gene and is waiting to be discovered,” adds Jake Leyhr, doctoral student student in the research team.

The researchers hope that their discovery is an important step towards eventually understanding the process behind the origins of vertebrate jaws.

Transposable elements drive intron gain in diverse eukaryotes

by Landen Gozashti, Scott W. Roy, Bryan Thornlow, Alexander Kramer, Manuel Ares, Russell Corbett-Detig in Proceedings of the National Academy of Sciences

One of the most long-standing, fundamental mysteries of biology surrounds the poorly understood origins of introns. Introns are segments of noncoding DNA that must be removed from the genetic code before it is translated in the process of making proteins. Introns are an ancient feature found across all eukaryotic life, a wide range of organisms that spans all animals, plants, fungi, and protists, but are absent in prokaryotic genomes such as those of bacteria. There is a massive variation in the number of introns found in different species’ genomes, even between closely related species.

Now, a new study led by scientists at UC Santa Cruz points to introners, one of several proposed mechanisms for the creation of introns discovered in 2009, as an explanation for the origins of most introns across species. The researchers believe that introners are the only likely explanation for intron burst events, in which thousands of introns show up in a genome seemingly all at once, and they find evidence of this in species across the tree of life.

“[This study] provides a plausible explanation for the vast majority of origins of introns,” said Russell Corbett-Detig, associate professor of biomolecular engineering and senior author on the study. “There’s other mechanisms out there, but this is the only one that I know of that could generate thousands and thousands of introns all at once in the genome. If true, this suggests that we’ve uncovered a core process driving something that’s really special about eukaryotic genomes — we have these introns, we have genomic complexity.”

Diversity and characteristics of Introners across eukaryotes. Results are shown from 130 genomes representing 32 lineages with putatively independent acquisitions of Introners (different colors).

Introns are important because they allow for alternative splicing, which in turn allows one gene to code for multiple transcripts and therefore serve multiple complex cellular functions. Introns can also affect gene expression, the rate at which genes get turned on to make proteins and other non-coding RNA. Introns ultimately have a neutral to slightly negative effect on the species they exist in because when the splicing of introns is not carried out correctly, the gene they live in can be harmed and even die. Such missed splicing instances are the cause of some cancers.

Corbett-Detig and his colleagues searched the genomes of 3,325 eukaryotic species — all of the species for which we have access to high-quality reference genomes — to find out how common introner-derived introns are, and in which groups of species they are seen most frequently. They found a total of 27,563 introner-derived introns in the genomes of 175 species, meaning evidence of introners could be seen in 5.2% of surveyed species. This evidence was found in species of all types, from animals to single-cell protists — organisms whose last common ancestor lived over 1.7 billion years ago. The diversity of species in which they are found suggests introners are both the fundamental and most widespread source of introns across the tree of life.

“It’s diverse — it isn’t like there’s one little chunk of the tree of life that has this going on,” Corbett-Detig said. “You see this in a pretty big range of species, which suggests it’s a pretty general mechanism.”

This analysis can only detect evidence of introners going back some millions of years, a relatively short time span when it comes to evolutionary history. It’s likely that intron bursts could have occurred in some species, such as humans, at a time beyond the scope of this analysis — meaning this study probably vastly underestimates the true scope of introner-dervied introns across all eukaryotes.

Relative to other introns, Introners are more efficiently spliced but less frequently found in highly expressed genes. (A) Explanation of PSI. Species with greater PSI coefficients (above 0, red) have Introners spliced in more frequently than other introns in the same genome. (B) Introners are more efficiently spliced than other introns in most species, as indicated by PSI coefficients less or equal to 0 for 31/36 species. (c) Introners are overrepresented in lowly expressed genes for most species. Relative log-normalized gene expression values for Introner-containing genes relative to other Intron-containing genes are shown.

In the ecosystem of the genome, introners can be thought of as a parasite with the goal to survive and replicate itself. When an introner enters a new organism, that new host has never seen that element before and has no way to defend itself, allowing it to proliferate in a new species.

“Everything in evolution is a conflict and these elements, [including introners], are selfish pieces of DNA,” said Landen Gozashti, the paper’s first author who developed the study’s analysis methods as an undergraduate at UCSC and is now a graduate student at Harvard University. “They only want to replicate, and the only reason they don’t want to kill their host is because that kills them.”

In being spliced out of the DNA sequence before translation of the gene into proteins occurs, the introners found a way to have less impact on the fitness of the host gene, allowing them to persist through the generations of the host species’ evolution. The researchers found that introners-derived introns seem to splice better than other types of introns, to limit their negative effects on the gene so that both the introner and the host can better survive.

While all introners were found across all types of species, results showed that marine organisms were 6.5 times more likely to have introners than land species. The researchers think this is likely due to a phenomena called horizontal gene transfer, in which genes transfer from one species to a different one, as opposed to the typical vertical transfer via mating and the passing of genes from parent to child. Horizontal gene transfer has already been known to occur more commonly in marine environments, especially between single-cell species with complex ecologies.

Introners can travel this way because they belong to a class of genomic elements called transposable elements, which have the ability to move beyond the cell environment in which they live, making them mechanistically well-equipped to travel between species via horizontal gene transfer. As introners transferred from one species to another in marine environments, they vastly expanded their presence across the tree of life. Considering we know that all species evolved from marine organisms, it could have been that land species gained introns from intron bursts far back in their evolutionary history.

“If your ancestors were marine organisms, which they all were, there’s a good chance that a lot of your introns are sort of inherited from a similar [introner burst] event back then,” Corbett-Detig said. “This might have been very important in our evolutionary past.”

More introners were also found across fungal species, which are also known to have higher rates of horizontal gene transfer, further supporting the idea that this phenomena drives itroner gain. In future research, Corbett-Detig plans to look for proof of horizontal gene transfer in the form of nearly identical introners in two different species. He has set up data mining pipelines so that as the global community of genomics researchers contribute new species’ genomes to data repositories, his algorithm will search each new genome’s introners and compare it to all of the known introners to look for similarities.

This study presents a challenge to one of the overarching theories of genome evolution as to what drives genomic complexity in eukaryotes. The theory also posits that at a point in evolution, many species had low effective population sizes, meaning very few organisms in a species were producing offspring to create their next generation. This allowed elements known to have slightly negative effects on the population to accumulate in the genome.

Following this theory, itroners, which are neutral to slightly deleterious, would be seen more commonly in populations with lower effective populations — but the researchers found the opposite. For example, they found that Symbiodinium, a protist known to have a much higher effective population size than humans, land plants, and other invertebrates, is the species that seems to be gaining the most introns of those surveyed. But this research points toward complexity arising not from an adaptation created by the genome itself but as a response to conflict caused by the invading transposable element, the introner, as it tries to proliferate. As introners and other elements struggle to survive and persist, this conflict drives genome complexity.

Single-cell transcriptome analysis of the in vivo response to viral infection in the cave nectar bat Eonycteris spelaea

by Akshamal M. Gamage, Wharton O.Y. Chan, Feng Zhu,et al in Immunity

Scientists at Duke-NUS Medical School and colleagues in Singapore have sequenced the response to viral infection in colony-bred cave nectar bats (Eonycteris spelaea) at single-cell resolution. The findings contribute to insights into bat immunity that could be harnessed to protect human health.

Bats harbour many types of viruses. Even when they are infected with viruses deadly to humans, they show no notable signs or symptoms of disease.

“It is our hope that by understanding how bats’ immune responses protect them from infections, we may find clues that will help humans to better combat viral infections,” explained Dr Akshamal Gamage, Research Fellow with Duke-NUS’ Emerging Infectious Diseases (EID) Programme and a co-first author of the study.

“And knowing how to better fight viral infections can aid in the development of treatments that will help us to be more bat-like — by falling sick less and ageing better,” added Mr Wharton Chan, an MD-PhD candidate at Duke-NUS who is also a co-first author of the study.

In this study, the scientists investigated bat immune responses to Malacca virus, a double-stranded RNA virus that uses bats as its natural reservoir. This virus also causes mild respiratory disease in humans. The team used single-cell transcriptome sequencing to study lung immune responses to infections at the cellular level, identifying the different types of immune cells in bats — some of which are different from those in other mammals, including humans — and uncovering what they do in response to such viral infections. They found that a type of white blood cell, called neutrophils, showed a very high expression of a gene called IDO1, which is known to play a role in mediating immune suppression in humans. The scientists believe that IDO1 expression in cave nectar bats could play an important role in limiting inflammation following infection.

Dr Feng Zhu, Research Fellow with the EID Programme and a co-first author of the study, said, “We also found marked anti-viral gene signatures in white blood cells known as monocytes and alveolar macrophages, which — in a sense — consume viral particles and then teach T cells how to recognise the virus. This observation is interesting as it shows that bats clearly activate an immune response following infection despite showing few outward symptoms or pathology.”

The team also identified an unusual diversity and abundance of T cells and natural killer cells — named for their ability to kill tumour cells and cells infected with a virus — in the cave nectar bat, which are broadly activated to respond to the infection.

“This is the first study that details the bat immune response to in vivo infection at the single-cell transcriptome level,” said Professor Linfa Wang, senior author of the study from the EID Programme. “We believe that our work serves as a key guide to inform further investigations into uncovering the remarkable biology of bats. Moving forward, besides studies into viral disease tolerance, we also hope to uncover clues to longevity from bats as long-lived mammals and also learn how these nectarivorous bats can live on the high sugar diet in nectar without getting diabetes.”

High-performance optical control of GPCR signaling by bistable animal opsins MosOpn3 and LamPP in a molecular property–dependent manner

by Mitsumasa Koyanagi, Baoguo Shen, Takashi Nagata, Lanfang Sun, Seiji Wada, Satomi Kamimura, Eriko Kage-Nakadai, Akihisa Terakita in Proceedings of the National Academy of Sciences

Is it possible to control an animal’s or a cell’s behavior using light? In recent years, remarkable progress in optogenetics has been made as research methods come close to realizing this goal.

A research group led by Professors Mitsumasa Koyanagi and Akihisa Terakita of the Graduate School of Science, and Professor Eriko Kage-Nakadai of the Graduate School of Human Life and Ecology at Osaka Metropolitan University has revealed a new system that allows them to control the behavior of the nematode worm Caenorhabditis elegans, using two different light-sensitive proteins called opsins.

Examination of the functionality of MosOpn3 in ASH neurons of C. elegans.

A light-sensitive opsin isolated from mosquitos was introduced into C. elegans’sensory cells responsible for avoidance behavior that makes the worm move away after sensing a chemical or physical stimulus. The group found that exposing the worms to white light triggered this avoidance behavior, with a sensitivity approximately 7,000 times higher than that observed with channelrhodopsin-2, a common optogenetic protein. Likewise, a UV-sensitive opsin first found in the pineal organ of lampreys was introduced into motor neurons of C. elegans. After that the worms stopped moving when exposed to UV light and began moving again when exposed to green light. This stop-start behavior was repeated many times, switching between the UV and green lights, indicating that the opsin could be switched on and off without destroying the protein.

“Both the mosquito and lamprey opsins we used are members of the G protein-coupled receptor (GPCR) family of receptors — which are used to sense various stimuli including smell, taste, hormones, and neurotransmitters — demonstrating that this system using light can be used to manipulate various GPCRs and their subsequent intracellular signaling and physiological responses,” said Professor Koyanagi.

Importantly, both opsins tested are bistable, meaning they can switch between stable forms when active and inactive without photobleaching or breaking down, allowing them to be used again after absorbing a different wavelength of light. The difference between the wavelengths of UV and green lights is large enough that inactive UV-sensitive opsin can recover, allowing for color-dependent on-and-off optogenetic control of GPCR signaling.

“The high-performance optogenetic tool based on bistable animal GPCR opsins reported here is a breakthrough, not only in a wide range of biological research, but might contribute to the field of drug discovery where it has already received considerable attention,” concluded Professor Terakita.

TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

by Alessandro Zambusi, Klara Tereza Novoselc, Saskia Hutten, et al in Nature Neuroscience

LMU researchers demonstrate in a zebrafish model that two proteins prevent scar formation in the brain, thereby improving the ability of tissue to regenerate.

Whereas cells regularly renew themselves in most endogenous tissues, the number of nerve cells in the human brain and spinal cord remains constant. Although nerve cells can regenerate in the brains of adult mammals, as LMU scientist Professor Magdalena Götz has previously shown, young neurons in brain injury patients are unable to integrate into existing neural networks and survive, outside of two specific areas of the brain. This appears to be due to glial cells, which form the supporting tissue in the brain. Microglia in particular trigger inflammations and lead to scars that isolate the injured site from the healthy brain, but on the long run prevent proper incorporation of new neurons to the circuitry. How the body regulates such mechanisms was previously unknown. Now a team led by LMU cell biologist Prof. Jovica Ninkovic has demonstrated that reducing the reactivity of microglia is crucial to preventing chronic inflammations and tissue scars and thus to improving regeneration capability.

Identification of microglia in scRNA-seq dataset.

In contrast to mammals, the central nervous system (CNS) of zebrafish has exceptional regenerative powers. In the case of injury, neural stem cells generate long-lived neurons, among other responses. Furthermore, CNS injuries prompt merely transitory reactivity of glial cells in zebrafish, which facilitates the integration of nerve cells into injured regions of the tissue.

“The idea was to tease out the differences between zebrafish and mammals so as to understand which signaling pathways in the human brain inhibit regeneration — and how we might be able to intervene,” says Ninkovic.

The scientists deliberately inflicted CNS lesions in zebrafish, prompting the activation of microglia. At the same time, the researchers found an accumulation of lipid droplets and TDP-43 condensates in the lesions. To date, the protein TDP-43 has been primarily associated with neurodegenerative diseases.

Granulin also played an important role in the zebrafish model. This protein contributed to the removal of the lipid droplets and TDP-43 condensates, whereupon the microglia transitioned from their activated to their resting form. The unscarred regeneration of the injury was the outcome. Zebrafish with experimentally induced granulin deficiency, by contrast, exhibited poor regeneration of the injury similar to what we see in mammals. “We suspect therefore that granulin plays an important role in the regeneration of nerves in zebrafish,” says Ninkovic.

To further pursue the comparison between humans and zebrafish, Ninkovic’s team investigated material from patients who had died of brain injuries. Here, too, there was a correlation between the extent of microglia activation and the accumulation of lipid droplets and TDP-43 condensates. The corresponding signaling pathways in human tissue were therefore comparable with those in zebrafish.

The LMU researcher sees “potential for novel therapeutic applications in humans.” As the next step, he is planning to investigate whether known low-molecular-weight compounds are suitable for inhibiting signaling pathways of microglia activation, thereby promoting the healing of neural lesions. Zebrafish models will be used again in this pre-clinical phase.

MYC multimers shield stalled replication forks from RNA polymerase

by Daniel Solvie, Apoorva Baluapuri, Leonie Uhl, et al in Nature

Hollow spheres made of MYC proteins open new doors in cancer research. Würzburg scientists have discovered them and report about this breakthrough.

MYC genes and their proteins play a central role in the emergence and development of almost all cancers. They drive the uncontrolled growth and altered metabolism of tumour cells. And they help tumours hide from the immune system. MYC proteins also show an activity that was previously unknown — and which is now opening new doors for cancer research: They form hollow spheres that protect particularly sensitive parts of the genome. If these MYC spheres are destroyed, cancer cells will die.

This was reported by a research team led by Martin Eilers and Elmar Wolf from the Institute of Biochemistry and Molecular Biology at Julius-Maximilians-Universität Würzburg (JMU, Bavaria, Germany). The researchers are convinced that their discovery is a game changer for cancer research, an important breakthrough on the way to new therapeutic strategies.

Further characterization of MYC Multimers.

What the researchers discovered: When cells in the lab are kept under stress conditions similar to those found in fast-growing tumour cells, the MYC proteins in the cell nucleus rearrange themselves in a dramatic way. They join together to form hollow spheres consisting of thousands of MYC proteins.

The hollow spheres surround and protect individual, particularly sensitive sites in the genome — precisely the sites where two types of enzymes can collide: Enzymes that read DNA to synthesize RNA and enzymes that duplicate DNA. Both can be thought of as two trains travelling on only one track, on DNA. The hollow spheres thus prevent the two enzymes from colliding. The Würzburg team was able to confirm this observation in cancer cells. If the protective function of the protein spheres is switched off experimentally, collisions of the enzymes occur and, as a consequence, multiple breaks occur in the DNA — which ultimately kill the cancer cells.

“These observations revolutionize our understanding of why MYC proteins are so crucial for the growth of tumor cells,” says Martin Eilers. The new findings also raise the question of whether drugs can be developed that specifically prevent the formation of the hollow spheres. To drive this development forward, Eilers and Wolf have started a company. Together with JMU and partners from the pharmaceutical industry, the search for drugs that interfere with the newly discovered functions of the MYC proteins has begun.

“The fact that investors made it possible for us to set up so quickly is certainly not an everyday occurrence,” say the JMU professors. They also consider this as a sign that they have made a discovery that is very promising.

Turnover of mammal sex chromosomes in the Sry -deficient Amami spiny rat is due to male-specific upregulation of Sox9

by Miho Terao, Yuya Ogawa, Shuji Takada, Rei Kajitani, Miki Okuno, Yuta Mochimaru, Kentaro Matsuoka, Takehiko Itoh, Atsushi Toyoda, Tomohiro Kono, Takamichi Jogahara, Shusei Mizushima, Asato Kuroiwa in Proceedings of the National Academy of Sciences

The Sox9 gene is upregulated in the absence of sex-determining Y chromosome and Sry gene in Amami spiny rat.

In mammals, the distinction between male and female at the chromosomal level is due to the X and Y chromosomes. Typically, females have two X chromosomes (XX) while males have an X and a Y chromosome (XY). The Sry gene on the Y chromosome triggers the formation of the testes. However, there exist a handful of rodent species in which the Y chromosome has disappeared, taking with it the Sry gene. The mechanism by which testes development occurs in these species is not fully understood, and is subject to much research.

A team of researchers led by Professor Asato Kuroiwa at Hokkaido University has uncovered the genetic basis for sexual differentiation in the Amami spiny rat, one of the species the lacks a Y chromosome and the Sry gene.

In the Amami spiny rat, the Enh14 region is duplicated. The two copies of Enh14 act in concert to upregulate Sox9, which causes the differentiation of the testes.

The Amami spiny rat is an endangered rodent found only on Amami Oshima, Japan. It is one of just four mammals known to lack a Y chromosome, alongside its close relative the Tokunoshima spiny rat, as well as the Transcaucasian mole vole and the Zaisan mole vole. In the Amami spiny rat, the the Sry gene is completely absent; thus, it has evolved a novel, unknown sex-determining mechanism independent of Sry.

The research team collected tissue samples from three male and three female Amami spiny rats, and used them to generate genome sequences for each individual. Intensive analysis unveiled a DNA sequence duplication that was present only in the males. This duplicated region was located upstream of the gene Sox9 on chromosome 3.

In mammals, Sox9 is the target of Sry, and is responsible for the differentiation of the testes. It has been studied in detail, and many regulatory elements that control the expression of Sox9 are known.

The researchers revealed that the sequence duplication in Amami spiny rats was a new regulatory element, which upregulated Sox9 in the absence of Sry. They were able to map its position on the chromosomes relative to Sox9, and confirmed that it was similar to a potential Sox9 enhancer in mice called Enh14. They hypothesise that the two copies of Enh14 work in concert to upregulate the expression of Sox9. When they introduced the sequence into mice genomes by gene editing technology, the female (XX) mice embryos showed a gene expression that induced testis formation.

This study is the first discovery of a male-specific genetic element directly related to sex-determining mechanism in mammals that is independent of Sry. It shows that the the sex-determination mechanism in the Amami spiny rat has moved to chromosome 3, an autosome — the first example of a translocation of sex-determination mechanism in mammals. Future work will focus on investigating the exact mechanism by which Enh14 acts, as well as identifying other elements of this novel mechanism. However, it is unknown if this mechanism can be extended to all four rodent species that lack a Y chromosome, especially to the distantly related mole voles.

Adaptive sequence divergence forged new neurodevelopmental enhancers in humans

by Riley J. Mangan, Fernando C. Alsina, Federica Mosti, Jesús Emiliano Sotelo-Fonseca, Daniel A. Snellings, Eric H. Au, Juliana Carvalho, Laya Sathyan, Graham D. Johnson, Timothy E. Reddy, Debra L. Silver, Craig B. Lowe in Cell

A team of Duke researchers has identified a group of human DNA sequences driving changes in brain development, digestion and immunity that seem to have evolved rapidly after our family line split from that of the chimpanzees, but before we split with the Neanderthals.

Our brains are bigger, and are guts are shorter than our ape peers.

“A lot of the traits that we think of as uniquely human, and human-specific, probably appear during that time period,” in the 7.5 million years since the split with the common ancestor we share with the chimpanzee, said Craig Lowe, Ph.D., an assistant professor of molecular genetics and microbiology in the Duke School of Medicine.

Specifically, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced like hackers, regulate genes. They are the switches that tell nearby genes when to turn on and off. The rapid evolution of these regions of the genome seems to have served as a fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences developed into regulatory regions, and they were more finely tuned to adapt to environmental or developmental cues. By and large, those changes were advantageous to our species.

“They seem especially specific in causing genes to turn on, we think just in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” Lowe said.

HAQERs, the fastest-evolved regions of the human genome.

A lot of this genomic innovation was found in brain development and the GI tract.

“We see lots of regulatory elements that are turning on in these tissues,” Lowe said. “These are the tissues where humans are refining which genes are expressed and at what level.”

Today, our brains are larger than other apes, and our guts are shorter. “People have hypothesized that those two are even linked, because they are two really expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is that there wasn’t really one mutation that gave you a large brain and one mutation that really struck the gut, it was probably many of these small changes over time.”

To produce the new findings, Lowe’s lab collaborated with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology to tap their expertise. Reddy’s lab is capable of looking at millions of genetic switches at once and Silver is watching switches in action in developing mouse brains.

“Our contribution was, if we could bring both of those technologies together, then we could look at hundreds of switches in this sort of complex developing tissue, which you can’t really get from a cell line,” Lowe said.

“We wanted to identify switches that were totally new in humans,” Lowe said. Computationally, they were able to infer what the human-chimp ancestor’s DNA would have been like, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genome sequences of these other post-chimpanzee relatives thanks to databases created from the pioneering work of 2022 Nobel laureate Svante Pääbo.

“So, we know the Neanderthal sequence, but let’s test that Neanderthal sequence and see if it can really turn on genes or not,” which they did dozens of times.

Genomic context of HAQERs with hominin-specific neurodevelopmental regulatory innovation; features of disease-linked variation overlapping HAQERs.

“And we showed that, whoa, this really is a switch that turns on and off genes,” Lowe said. “It was really fun to see that new gene regulation came from totally new switches, rather than just sort of rewiring switches that already existed.”

Along with the positive traits that HAQERs gave humans, they can also be implicated in some diseases. Most of us have remarkably similar HAQER sequences, but there are some variances, “and we were able to show that those variants tend to correlate with certain diseases,” Lowe said, namely hypertension, neuroblastoma, unipolar depression, bipolar depression and schizophrenia. The mechanisms of action aren’t known yet, and more research will have to be done in these areas, Lowe said.

“Maybe human-specific diseases or human-specific susceptibilities to these diseases are going to be preferentially mapped back to these new genetic switches that only exist in humans,” Lowe said.

An autoactive NB-LRR gene causes Rht13 dwarfism in wheat

by Philippa Borrill, Rohit Mago, Tianyuan Xu, Brett Ford, et al in Proceedings of the National Academy of Sciences

Reduced height, or semi-dwarf, wheat varieties with improved drought resilience may soon be grown in fields across the globe following an exciting scientific discovery.

Researchers at the John Innes Centre in collaboration with an international team of researchers have discovered a new height-reducing gene Rht13 which means that seeds can be planted deeper in the soil giving access to moisture, without the adverse effect on seedling emergence seen with existing wheat varieties. Varieties of wheat with the Rht13 gene could be rapidly bred into wheat varieties to enable farmers to grow reduced-height wheat in drier soil conditions.

“We have found a new mechanism that can make reduced-height wheat varieties without some of the disadvantages associated with the conventional semi-dwarfing genes. The discovery of the gene, its effects and exact location on the wheat genome, means that we can give breeders a perfect genetic marker to allow them to breed more climate-resilient wheat,” said John Innes Centre group leader Dr Philippa Borrill corresponding author of the study.

Phenotypic characteristics of Magnif (Rht-B13a) and Magnif M (Rht-B13b).

The study suggests that additional agronomic benefits of the new semi-dwarfing gene may include stiffer stems, better able to withstand stormier weather. Since the 1960s and the “Green Revolution,” reduced height genes have increased global wheat yields because the short-stemmed wheat they produce puts more investment into the grains rather than into the stems and has improved standing ability. However, the Green Revolution genes bred into wheat also have a significant disadvantage: when these varieties are planted deeper to access moisture in water limited environments, they can fail to reach the surface of the soil.

The newly discovered Rht13 dwarf gene overcomes this problem of seedling emergence because the gene acts in tissues higher up in the wheat stem. So, the dwarfing mechanism only takes effect once the seedling has fully emerged. This gives farmers a significant advantage when planting deeper in dry conditions. The discovery of the Rht13 dwarfing gene was made possible by recent advances in wheat genomic research, principally the publication in 2020 of the Pan Genome, an atlas of 15 wheat genomes collected from around the world. Earlier studies had identified the Rht13 locus — the region of DNA — as located on chromosome 7B on the wheat genome but the underlying gene had not been identified.

Validation that the S240F mutation in Rht-B13b causes a reduction in height.

In collaboration with the group of Wolfgang Spielmeyer at CSIRO Australia, researchers used RNA and chromosome sequencing to track down the new semi-dwarfing gene. They found a one- point mutation change — a single letter change in a sequence of DNA — and this variation on the Rht13 locus encodes an autoactive NB-LRR gene, a defence related gene, that is switched on all the time. Experiments testing the effects of the gene in a range of transgenic wheat plants confirmed that the Rht13 variation represents a new class of reduced height gene — more commonly associated with disease resistance as opposed to widely used Green Revolution genes (Rht-B1b and Rht-D1b)) which are associated with hormones and therefore affect overall growth.

“This is an exciting discovery because it opens a new way to use these autoactive NB-LRR genes in breeding in agriculture.” explains Dr Borrill. “In dry environments, the alternative reduced height gene will allow farmers to sow seeds at depth — and not have to gamble on the seedlings emerging. We think the stiffer stems could result in less lodging — where stems fall over — and the upregulation of a pathogen related dwarfing gene may help to enhance resistance response to certain pathogens.”

The next step for this research will be to test how this gene works in diverse agronomic environments from the UK to Australia. The research team are also investigating how the mechanism works and are exploring the hypothesis that it may be down to molecular restrictions on the cell wall preventing elongation.

Genomic Analyses Reveal Association of ASIP with a Recurrently evolving Adaptive Color Pattern in Frogs

by Sandra Goutte, Imtiyaz Hariyani, Kole Deroy Utzinger, Yann Bourgeois, Stéphane Boissinot in Molecular Biology and Evolution

A team of researchers from NYU Abu Dhabi (NYUAD) has discovered new insights into the evolution of color patterns in frogs and toads — collectively known as anurans. Animal color patterns can help them camouflage with their surroundings and avoid detection from preys or predators. Many anurans have a light stripe along their back, which, when observed from above, creates the optical illusion that the animal is split in two halves and confuses visually-oriented predators. Although this color pattern is widespread in frogs around the world, little is known regarding its evolution or genetic origin.

The researchers of the Evolutionary Genomics Lab at NYUAD completed a broad-scale comparative analysis, which included over 2,700 species of anurans, to further the understanding of the evolutionary history of the vertebral stripe. They found that the vertebral stripe has evolved hundreds of times and is selected for in terrestrial habitats where visual predators coming directly from above — such as mammals or birds — are more prevalent. In contrast, the pattern was lost significantly more often in arboreal lineages — those living in trees — than in other habitats. While beneficial to frogs living on the ground, this color pattern may thus be disadvantageous to frogs living in trees.

The evolution of the vertebral stripe in anurans.

To understand the genetic basis of the pattern, the researchers focused on the Ethiopian grass frog species Ptychadena robeensis, which is polymorphic — meaning that it presents the vertebral stripe trait in multiple forms — wide, thin or absent. They found that the gene ASIP is linked to the stripe pattern in that species. This genetic variation affects the level of expression of ASIP in the different morphs, a higher expression leading to a wide stripe and a lower expression leading to a thin stripe.

They also compared the genes of closely-related species of frogs and found that, while they present the same stripe patterns, they do not share the genetic variation found in P. robeensis. This led the researchers to the conclusion that the stripe alleles found in P. robeensis evolved recently. The researchers further conclude that the vertebral stripe evolves rapidly in anurans, which may allow species to adapt to environmental changes or variable conditions.

The vertebral stripe in Ethiopian Ptychadena. (A) Polymorphism of the vertebral stripe (wide or thin striped, or unstriped) in the Ptychadena neumanni species complex (phylogeny based on 500,000 genome-wide distributed SNPs, reproduced from Hariyani et al. in preparation). Presence of the morph is indicated in blue, absence in white. (B) Adult Ptychadena robeensis presenting the three possible vertebral stripe morphs. From left to right: wide striped, thin striped, unstriped.

This study is the first large-scale study of the adaptive value of the anuran vertebral stripe, whose evolutionary history has, until now, not been well understood. This study also establishes a link between the ASIP gene and a color pattern in anurans for the first time. ASIP is a well-studied gene in mammals, known to be linked to melanin production and color variation. The fact that it is linked to color patterns in frogs opens new research avenues on anuran color patterns and comparative studies across vertebrates.

“Our findings establish that the vertebral stripe in frogs and toads holds a great potential in the field of evolutionary biology as it represents a clear example of repeated evolution. Studying this color pattern in other species can thus help us understand to which extent evolution predictably employs the same molecular paths when identical phenotypes evolve under similar selection pressures,” said Sandra Goutte, PhD, a research associate at the Evolutionary Genomics Lab at NYUAD. “The identification of ASIP’s role in the coloration of anurans by our team can also guide future comparative studies across vertebrates.”

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