https://www.seqanswers.com/ News about the latest advances and discoveries in sequencing and related technologies. en Tue, 21 Apr 2026 09:49:27 GMT vBulletin 60 https://www.seqanswers.com/images/misc/rss.png https://www.seqanswers.com/ https://www.seqanswers.com/forum/news/327256-sequencing-reveals-hidden-mutations-in-autoimmune-disease Wed, 15 Apr 2026 14:32:57 GMT New research suggests that autoimmune diseases may be driven by DNA changes in immune cells that remove natural restraints on the immune system. The... New research suggests that autoimmune diseases may be driven by DNA changes in immune cells that remove natural restraints on the immune system. The study, led by researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, and the University of Cambridge, used advanced sequencing and related DNA analysis methods to identify previously unseen mutations that may contribute to thyroid autoimmunity.

The work, published in Nature, focuses on autoimmune disease as a broad category of conditions in which the immune system attacks healthy cells in the body. These diseases, which include rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes, affect an estimated 5 to 10% of the global population. Yet their molecular basis has remained poorly understood. The study points to somatic mutations, or DNA changes acquired during life rather than inherited, as an overlooked factor outside of cancer.

Somatic mutations have long been suspected to play a role in autoimmunity, but studying them has been difficult. Recent advances in DNA sequencing have made it possible to investigate these changes more precisely. In this study, the researchers used NanoSeq, a method they recently developed, to detect rare mutations that traditional sequencing methods would miss. They examined samples from patients with Hashimoto’s and Graves’ disease, two major causes of thyroid dysfunction, to see whether immune-cell mutations were present.

Their analysis found that many B cells carried inactivating mutations in genes that normally help regulate immune activity. Using additional techniques that examine single cells and microscopic regions of tissue, the team found that multiple B-cell clones in each patient carried several mutations. Two immune-checkpoint genes, TNFRSF14 and CD274, also known as PDL1, were repeatedly lost in separate clones. Some mutated clones had accumulated as many as six driver mutations over many years, suggesting that these changes built up long before symptoms appeared.

The findings provide the strongest evidence yet that somatic mutations may contribute to a common autoimmune disease. The researchers describe this as a hidden form of somatic evolution in B cells during autoimmunity. They also note, however, that more research is needed to determine whether the mutations directly cause disease or instead worsen it over time.

The study raises the possibility that sequencing-based approaches could eventually support more precise diagnosis and treatment. Since autoimmune disease is now often treated by broadly suppressing the immune system, identifying the specific mutations involved could open the door to more targeted strategies.

Publication details: Nicola, P.A., Lawson, A.R.J., Tidd, A. et al. Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity. Nature (2026). https://doi.org/10.1038/s41586-026-10493-9]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327256-sequencing-reveals-hidden-mutations-in-autoimmune-disease https://www.seqanswers.com/forum/news/327252-engineers-develop-compact-crispr-nuclease-for-in-body-editing Mon, 13 Apr 2026 17:31:57 GMT Clinical use of CRISPR-based gene editing has mostly involved modifying cells outside the body before reintroducing them. A key challenge has been... Clinical use of CRISPR-based gene editing has mostly involved modifying cells outside the body before reintroducing them. A key challenge has been that the most reliable gene-editing tools exceed the size limits of viral delivery systems needed to reach specific cells or tissues inside patients.

A University of Texas at Austin team, working with Metagenomi Therapeutics, created a smaller CRISPR nuclease called Al3Cas12f. This naturally occurring bacterial enzyme fits within adeno-associated virus vectors while maintaining strong gene-editing performance. The researchers published their findings in Nature Structural & Molecular Biology.

Metagenomi identified Al3Cas12f for its compact size and efficiency. UT Austin scientists then analyzed and refined it, producing an enhanced version that worked better in human cells. Study co-author David Taylor, said, "We uncovered mechanistic features that explain why some Cas12f enzymes are more efficient than others." He added that this knowledge allows for rational design of improved variants that retain a small size suitable for delivery. Taylor also noted, "Importantly, we also identified Al3Cas12f as a highly efficient nuclease across multiple genomic targets, making it a strong candidate for future therapeutic development."

AAV vectors can carry instructions for about 1,000 amino acids, but top nucleases are too large. This has restricted CRISPR applications to accessible tissues like blood and bone marrow. Smaller Cas12f nucleases (400-700 amino acids) had potential but underperformed in human cells until this study.

The team found Al3Cas12f outperformed two other Cas12f enzymes previously used in mice to edit muscular dystrophy genes. Using cryo-electron microscopy and machine learning, they modeled its structure and DNA interactions. Al3Cas12f showed a larger interface between components for greater stability. Taylor explained, "The expanded interface means the enzyme is much more stable. Compared to the others we looked at, Al3Cas12f basically comes preassembled and ready to go shortly after its pieces are produced."

The researchers engineered variants, with Al3Cas12f RKK achieving over 80% efficiency in human leukemia cells. They targeted genes linked to cancer, atherosclerosis and ALS.

Next steps include testing RKK in AAV vectors. The work was supported by NIH's National Institute of General Medical Sciences. Erica Brown, Acting NIGMS Director, said, "Smart delivery of gene-editing systems is a powerful notion with broad clinical implications, and this basic science finding takes us a significant step toward that future."

Publication details: Guan, K., Ocampo, R.F., Matheus Carnevali, P.B. et al. Comparative characterization of Cas12f orthologs reveals mechanistic features underlying enhanced genome editing efficiency. Nat Struct Mol Biol (2026). https://doi.org/10.1038/s41594-026-01788-6]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327252-engineers-develop-compact-crispr-nuclease-for-in-body-editing https://www.seqanswers.com/forum/news/327251-cipher-seq-reveals-immune-cell-activity Wed, 08 Apr 2026 12:52:08 GMT A new single-cell method called CIPHER-seq is giving scientists an unprecedented view of immune cell behavior, connecting genetic signals to... A new single-cell method called CIPHER-seq is giving scientists an unprecedented view of immune cell behavior, connecting genetic signals to real-time protein activity. Developed by researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, in collaboration with teams at the University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, the approach simultaneously measures RNA and proteins within the same cell. The study, published in Scientific Reports, highlights how this dual readout strengthens the understanding of cancer, inflammation, and treatment resistance.

Single-cell RNA sequencing has become a vital tool for decoding immune functions, revealing which genes are turned on or off in thousands of cells at once. But RNA alone represents potential—it outlines a cell’s intention, not necessarily its current state. Proteins, conversely, perform cellular tasks and provide a direct measure of activity. The gap between RNA and protein levels becomes especially important when analyzing cytokines, small proteins that orchestrate immune responses and govern inflammation, tumor growth, or regression. As Emiliano Cocco, co-senior author of the study, noted, “In immune cells, RNA and protein don’t always rise and fall together.” RNA fluctuations happen quickly, while protein changes unfold more slowly and persist longer.

To bridge this gap, CIPHER-seq—short for Cytokine Intracellular Protein High-throughput Expression with RNA sequencing—was engineered to capture multiple data layers from the same immune cell: RNA transcripts, surface proteins, intracellular proteins, and cytokines before release. This integrated approach yields a more complete and accurate picture of how immune cells function.

Importantly, the method minimizes stress on cells during sample preparation. When compared with conventional techniques, CIPHER-seq preserved cell integrity far better, avoiding mitochondrial damage and artificial stress signals that can distort results. “We wanted a method that lets cells stay as close as possible to their natural state,” said Justin Taylor, co-senior author. Testing confirmed that the platform effectively tracked cytokine responses such as interferon-gamma and tumor necrosis factor, including the timing of their appearance and progression.

By combining transcriptomic and proteomic data, CIPHER-seq reveals the sequential steps of immune activation—showing RNA signals first and protein changes shortly after. “It’s like seeing the plan before the action,” said first author Avni Bhalgat. “Cytokines help determine whether immune cells attack cancer, ignore it or even help tumors grow. Understanding how and when immune cells produce these signals is critical.”

Publication details: Bhalgat, A., Micin, K., Affer, M. et al. CIPHER-seq enables intracellular multimodal profiling of cytokine responses in single immune cells. Sci Rep 16, 9693 (2026). https://doi.org/10.1038/s41598-026-44946-y]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327251-cipher-seq-reveals-immune-cell-activity https://www.seqanswers.com/forum/news/327250-wgs-confirms-p-ransonneti-lacks-luciferase-gene-and-steals-bioluminescence-from-prey Mon, 06 Apr 2026 18:36:39 GMT Whole-genome sequencing has provided definitive proof that the fish Parapriacanthus ransonneti lacks the luciferase gene essential for... Whole-genome sequencing has provided definitive proof that the fish Parapriacanthus ransonneti lacks the luciferase gene essential for bioluminescence, relying instead on proteins acquired from its prey. This marks the first genomic evidence of kleptoproteinism, where an organism uses functional elements obtained externally rather than from its own genome.

Biological functions generally follow the central dogma of molecular biology, depending on genes encoded within an organism's genome. Kleptobiology encompasses cases where organisms acquire and employ components from other species. The research team had previously observed that P. ransonneti consumes bioluminescent ostracods, known as sea fireflies, and utilizes their luciferase enzyme to produce light.

A complete genomic analysis was necessary to determine whether the fish possessed the luciferase gene or had obtained it via horizontal gene transfer from its prey. The team generated a high-quality draft genome of P. ransonneti using advanced sequencing technologies. Their comprehensive examination revealed no ostracod-derived luciferase genes and no evidence of horizontally transferred genes throughout the fish's genome.

"These results provide compelling and conclusive evidence that this fish does not possess the genetic blueprint for bioluminescence," said Manabu Bessho-Uehara, first author of the study published in Scientific Reports. "Instead, it relies entirely on proteins obtained from its prey, representing a truly unique form of biological adaptation."

This work establishes the first genomic confirmation of kleptoproteinism. The findings hold evolutionary importance and spark investigation into how proteins survive ingestion, resist digestion, and maintain functionality within the predator. Such knowledge could aid development of oral drug delivery systems for therapeutic proteins.

Publication details: Bessho-Uehara, M., Yamaguchi, K., Koeda, K. et al. Absence of the luciferase gene in the genome of the kleptoprotein bioluminescent fish Parapriacanthus ransonneti. Sci Rep 16, 9211 (2026). https://doi.org/10.1038/s41598-026-43942-6]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327250-wgs-confirms-p-ransonneti-lacks-luciferase-gene-and-steals-bioluminescence-from-prey https://www.seqanswers.com/forum/news/327249-unique-workflow-expands-functional-analysis-of-fungal-genes Tue, 31 Mar 2026 13:34:03 GMT RNA sequencing (RNA-seq) has become a foundational method for identifying which genes are active within an organism. However, connecting these gene... RNA sequencing (RNA-seq) has become a foundational method for identifying which genes are active within an organism. However, connecting these gene expression profiles to actual biological functions in fungi has been technically difficult. Many existing software tools are designed to handle a wide variety of species, which limits their ability to accommodate the unique genetic characteristics of fungi. Adding to this challenge, a large number of non-model fungal species lack the complete, high-quality reference genomes that most traditional analytical tools depend upon.

To overcome these limitations, a research team led by Professor Hidemasa Bono at Hiroshima University developed a workflow tailored specifically for fungi. The system is designed to support downstream functional analysis even in cases where a reference genome is unavailable. According to Bono, “While RNA sequencing has become easier with next-generation sequencers, existing general-purpose tools fail to capture fungal-specific features, leaving a high proportion of genes functionally uncharacterized. This limitation has been a major obstacle for downstream analyses such as functional enrichment analysis and genome editing applications.” The team’s workflow addresses this gap by improving the accuracy of functional interpretation in fungal transcriptomes and helping identify biologically significant genes that had not been previously recognized.

The study, published in the Journal of Fungi, evaluated the workflow using RNA-seq data from 57 samples of shiitake mushroom (Lentinula edodes strain H600) and 20 samples from the plant pathogen Asian soybean rust (Phakopsora pachyrhizi). These two organisms, representing both an edible mushroom and an agricultural pathogen, provided a meaningful test of the method’s performance. The workflow accurately annotated more than 96% of protein-coding transcripts, surpassing current general annotation tools in functional detection.

In addition to accuracy, the system showed flexibility by handling both short-read RNA-seq and full-length transcript sequencing (Iso-Seq) data. Rather than relying on pre-existing reference genomes, it matched sequences with specialized fungal databases and analyzed patterns of gene expression. Bono explained, “This improvement enables more comprehensive functional enrichment analysis that better reflects actual biological phenomena occurring during fungal development and pathogenesis.”

The new workflow allows researchers to identify functionally important transcripts in a wide range of fungal species. It supports applications such as CRISPR-based genome editing and advances biotechnological exploration, offering a refined approach for understanding fungal biology across diverse species.

Publication details: Morihara N, Bono H. Functional Annotation Workflow for Fungal Transcriptomes. Journal of Fungi. 2026; 12(2):116. https://doi.org/10.3390/jof12020116
]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327249-unique-workflow-expands-functional-analysis-of-fungal-genes https://www.seqanswers.com/forum/news/327248-karolinska-initiative-integrates-whole-genome-sequencing-to-improve-rare-disease-diagnosis Mon, 30 Mar 2026 19:29:30 GMT A decade-long collaboration between Karolinska Institutet, Karolinska University Hospital, and SciLifeLab has successfully integrated whole genome... A decade-long collaboration between Karolinska Institutet, Karolinska University Hospital, and SciLifeLab has successfully integrated whole genome sequencing into routine diagnostic investigations for rare diseases at Karolinska University Hospital. According to findings published in Genome Medicine, more than 15,000 patients have undergone sequencing, with 23% receiving a genetic diagnosis.

The new study outlines how this integration evolved into a functioning clinical model built on collaboration between healthcare professionals and genomic scientists. It presents data from 15,644 individuals, showing how multidisciplinary teamwork has made genome sequencing a practical tool in routine care.

The study shows that a genetic cause of disease could be identified in 3,538 individuals, corresponding to 23% These diagnoses involved variants in more than 1,500 different genes, highlighting the diversity and complexity of rare diseases.

“For many patients with suspected rare diseases, receiving a genetic diagnosis is highly significant. It can provide an explanation for their condition and help guide treatment, follow‑up, and family planning. Whole genome sequencing allows us to detect genetic changes that would otherwise remain unnoticed,” says first author Anna Lindstrand.

Patients who obtained diagnoses represented a broad range of medical areas, with a substantial portion being children. Many might not have been diagnosed through traditional methods. “In several cases, for example, in congenital metabolic disorders and severe epilepsies, we have been able to offer targeted treatment as a direct result of the diagnosis, preventing severe disease or early death,” explains senior author Anna Wedell.

The approach relies on close coordination between clinicians, laboratory experts, and bioinformaticians. This structure enables customized analyses for each patient’s presentation and rapid translation of results into clinical recommendations. “By bringing together clinical medicine and advanced genomics, we have established a joint approach. I see this as part of a broader shift in the healthcare system towards more precise and personalised care in Sweden, and the model could form an important foundation for that development,” Wedell adds.

Publication details: Lindstrand, A., Lagerstedt-Robinson, K., Jemt, A. et al. The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation. Genome Med 18, 30 (2026). https://doi.org/10.1186/s13073-026-01611-3
]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327248-karolinska-initiative-integrates-whole-genome-sequencing-to-improve-rare-disease-diagnosis https://www.seqanswers.com/forum/news/327246-novel-method-optimizes-plasmid-creation Thu, 26 Mar 2026 11:37:43 GMT In a recent Nature Communications paper (https://www.nature.com/articles/s41467-026-68907-1), Rice University professor James Chappell and... In a recent Nature Communications paper, Rice University professor James Chappell and collaborators introduced a novel way to improve plasmids—circular DNA molecules essential to molecular biology research since the 1970s. Instead of designing experiments around plasmids’ long‑standing limitations, the team redesigned part of the plasmid itself, specifically the origin of replication (ORI), which governs how plasmids duplicate inside cells.

“For decades, we’ve been designing experiments around two major limitations of plasmids: fixed copy numbers and incompatibility,” said Chappell. “While functional, such workarounds are clunky. We created a synthetic version of a part of the plasmid called the origin of replication that allows us to modify the plasmid instead of modifying the experiment.”

Typically, plasmids placed in bacterial cells use the cell’s internal machinery to replicate and produce proteins. Each plasmid generates fragments of a stop signal, called negative regulators, that attach to the ORI. When a sufficient number of regulators bind, plasmid replication ceases, maintaining a constant number of copies per cell. This copy number directly influences protein production—more plasmids yield more protein. Achieving reliable control over this process is vital for experiment design and outcomes.

Another persistent challenge is ORI incompatibility. There are roughly 27 classes of ORIs, and if two plasmids with similar ORIs coexist in one cell, their negative regulators mix, lowering protein production. This limitation typically prevents researchers from using several plasmids together.

To address these issues, Chappell’s team, in partnership with Matt Lakin at the University of New Mexico, engineered a synthetic ORI divided into two functional modules. One module dictates which stop signals are used, and the other sets how many are required to stop replication. This gives investigators precise control over copy number and compatibility within the same cell.

“Instead of using the natural stop signals, we used synthetically engineered RNA control elements,” said Baiyang Liu, first author of the study. “We have large libraries of unique RNA control elements that can be used in plasmids, meaning that we can potentially put large numbers of plasmids into a cell without incompatibility issues affecting plasmid replication.”

Testing showed that six plasmids with synthetic ORIs successfully replicated to their programmed copy numbers and expressed proteins as intended. The synthetic ORIs also responded dynamically to changes in cell conditions. As Chappell noted, the modular design “lets each researcher modify the plasmids to fit their experiments, simplifying their workflow and expanding experimental possibilities.”

Publication details: Liu, B., Seet, Z.R.D., Peng, X. et al. Engineering plasmids with synthetic origins of replication. Nat Commun 17, 2255 (2026). https://doi.org/10.1038/s41467-026-68907-1
]]> News SEQadmin2 https://www.seqanswers.com/forum/news/327246-novel-method-optimizes-plasmid-creation https://www.seqanswers.com/forum/news/327245-new-digital-database-maps-bacterial-capsule-type-and-strain Wed, 25 Mar 2026 11:37:31 GMT A large-scale genetic study has identified the five capsule types driving most multidrug-resistant bloodstream infections caused by E. coli.... A large-scale genetic study has identified the five capsule types driving most multidrug-resistant bloodstream infections caused by E. coli. Researchers from the Wellcome Sanger Institute, University of Oslo, and collaborators examined over 18,000 bacterial genomes from samples worldwide to map this protective armor and explore ways to target it. Published in Nature Microbiology, the work identifies 90 capsule types, with only 34% previously known.

E. coli is the leading cause of bloodstream infections globally. While most strains reside harmlessly in the gut, some invade the bloodstream or urinary tract, causing mild to severe infections, especially in those with weakened immune systems. Antibiotic resistance complicates treatment, with over 40% of U.K. E. coli bloodstream infections resistant to a key antibiotic.

Protective capsules shield E. coli from the immune system and treatments, varying by strain with distinct antigens suitable for vaccine targets. Traditional capsule mapping proved labor-intensive, so the team created a digital database from 18,000 genetically analyzed samples, including nearly 8,000 from people aged from newborns to over 80.

This effort uncovered far greater diversity than expected—90 types total, including 69 new ones. Capsule prevalence differs by region: high-resource areas like the U.K.. show distinct patterns compared to Malawi and Pakistan. Five types (K1, K5, K52, K2, K14) drive over 50% of U.K., Norway, and France bloodstream and urinary tract infections. A related set (K1, K5, K52, K2, K100) accounts for 70% of multidrug-resistant cases in Europe. K1 and K5 appear globally, but low- and middle-income countries exhibit more strain variety in serious infections.

The study also shows E. coli swaps capsule-encoding genes across strains, adapting its armor. This blueprint aids targeted vaccines and treatments against dangerous strains, sparing beneficial gut bacteria. Global data proves essential, as capsule types vary by location.

Dr Rebecca Gladstone, first and corresponding author at the University of Oslo, said: "By creating a digital library from over 18,000 bacterial genomes, we can see the true complexity of how E. coli protects itself, and how this armor is encoded in the genes. This research has expanded our scientific map from just a handful of known bacterial shields to a comprehensive database of 90 unique types, including nearly two-thirds that were previously unknown. Ultimately, this database provides the missing blueprint to identify strains most likely to cause serious infections, and design targeted vaccines and treatments to stop these."

Publication details: Gladstone, R.A., Pesonen, M., Pöntinen, A.K. et al. Identification of transporter-dependent capsular loci associated with the invasive potential of Escherichia coli. Nat Microbiol (2026). https://doi.org/10.1038/s41564-026-02283-w
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