eLife: latest articles by subject

The genetic control of rapid genome content divergence in Arabidopsis thaliana

daniel.koenig@ucr.edu (Christopher J Fiscus) — Thu, 10 Sep 2026 00:00:00 +0000

Genome evolution in eukaryotes is predominantly driven by the dynamics of repetitive sequences, which vary widely in both copy number and sequence composition. Rates of repeat evolution differ between and within species and are likely modulated by both genetics and environment. To uncover factors shaping the rate of genome content evolution, we analyzed 1043 resequenced Arabidopsis thaliana genomes using a novel K-mer-based approach to characterize genome content variation and identify hypervariable regions underlying differences in repeat abundance. We next treated repeat abundance as a quantitative trait and performed genome-wide association analyses across more than 400 repeat families to identify the genetic basis of copy number variation. Integrating these results through a meta-GWAS approach revealed both cis-acting variants and more than 50 candidate trans-acting loci associated with repeat abundance genome-wide. Cis-acting variation was predominantly localized to pericentromeric and centromeric regions, whereas trans-acting loci were enriched for candidate genes involved in DNA replication, DNA repair, and DNA methylation regulation. The results are consistent with purifying selection acting against mutations that accelerate genome content divergence, favoring alleles that constrain repeat expansion. Together, these findings provide new insights into the genetic architecture and evolutionary forces shaping genome evolution in A. thaliana and establish a framework for investigating these processes in other plant species.

Pre-Cambrian origin of envelope-carrying retrotransposons in metazoans

rippei.hayashi@anu.edu.au (Rippei Hayashi) — Fri, 28 Aug 2026 00:00:00 +0000

Retrotransposons or endogenous retroviruses (ERVs) essentially carry open reading frames of gag and pol, which are utilized to selfishly replicate themselves in the host germline genome. One rare example of ERVs that additionally carry envelope genes is Ty3/gypsy errantiviruses in Drosophila. Though they are structurally analogous to retroviruses, it remained unclear whether envelope-containing Ty3/gypsy elements represent recent, lineage-specific acquisitions of viral fusogens or an ancient association between retrotransposons and envelope-like genes. We systematically searched for intact envelope-containing ERVs that are homologous to Ty3/gypsy in invertebrate metazoan genomes and found that they are widespread across taxa, including ancient animals. such as cnidarians, ctenophores, and tunicates. Many elements occur as multiple highly similar copies in their respective genomes, consistent with recent genomic expansion in some host lineages. Envelope genes are classified into those that resemble glycoprotein F from paramyxoviruses and glycoprotein B from herpesviruses, and both types are equally abundant and widespread. Phylogenetic and structural analyses revealed that envelope genes have largely diverged with pol genes as well as with the host organisms throughout their evolutionary history and recombined infrequently, suggesting that the envelope acquisition to ERVs is ancient and likely dates to before the split of bilaterian and non-bilaterian animals in the Pre-Cambrian era.

Multiple molecular pathways to longevity with opposing gene expression programs defining distinct aging strategies in Caenorhabditis elegans

jeremy.vanraamsdonk@mcgill.ca (Aura A Tamez Gonzalez) — Thu, 20 Aug 2026 00:00:00 +0000

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived Caenorhabditis elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

Sibling chimerism among microglia in marmosets

rcdelros@broadinstitute.org (Alec Wysoker) — Fri, 14 Aug 2026 00:00:00 +0000

Chimerism happens rarely among most mammals, but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12–80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney, and many brain regions across a number of marmosets, using transcribed single-nucleotide polymorphisms (SNPs) to identify cells with the sibling’s genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20–52%) and macrophages (18–64%) but not among other resident cell types (neurons, glia, or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by genetic-sibling microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to recognize the effects of genes, mutations, and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.

Divergent C. elegans toxin alleles are suppressed by distinct mechanisms

szdralje@gmail.com (Daniel HW Leighton) — Tue, 11 Aug 2026 00:00:00 +0000

Toxin-antidote elements (TAs) are selfish DNA sequences that bias their transmission to the next generation. TAs typically consist of two linked genes: a toxin and an antidote. The toxin kills progeny that do not inherit the TA, while the antidote counteracts the toxin in progeny that inherit the TA. We previously discovered two TAs in Caenorhabditis elegans that follow the canonical TA model of two linked genes: peel-1/zeel-1 and sup-35/pha-1. Here, we report a new TA that exists in three distinct states across the C. elegans population. The canonical TA, which is found in isolates from the Hawaiian Islands, consists of two genes that encode a maternally deposited toxin (TMRL-1) and a zygotically expressed antidote (AMRL-1). The toxin induces larval lethality in embryos that do not inherit the antidote gene. A second version of the TA has lost the toxin gene but retains a partially functional antidote. Most C. elegans isolates, including the standard laboratory strain N2, carry a highly divergent allele of the toxin that has retained its activity, but have lost the antidote through pseudogenization. Multiple lines of evidence suggest that the N2 tmrl-1 allele is likely recognized by piRNAs, leading to MUT-16-dependent 22G small interfering RNA (siRNA) production and post-transcriptional silencing of the transcript. The N2 haplotype represents the first naturally occurring unlinked toxin-antidote system where the toxin is post-transcriptionally suppressed by endogenous small RNA pathways.

Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2

J.Guy@ed.ac.uk (Adrian Bird) — Mon, 10 Aug 2026 00:00:00 +0000

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

The cistrome response to hypoxia in human umbilical vein endothelial cells

bass@bio.fsu.edu (Ayush Singh) — Thu, 06 Aug 2026 00:00:00 +0000

Hypoxic stress triggers transcriptional signaling mainly through hypoxia-inducible transcription factors (HIFs), which bind hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (~1%) of known HREs are occupied by HIFs during hypoxia, suggesting the involvement of additional hypoxia-responsive factors. To address this gap, we utilized MNase-defined cistrome Occupancy Analysis sequencing (MOA-seq), with the term cistrome referring to all genomic regions where transcription factors and other trans-acting regulators are bound to cis-acting elements across the genome for a particular cell type or treatment. This MNase-based assay enables genome-wide, high-resolution (<30 bp) identification of transcription factor (TF) occupancy footprints embedded within larger regions, most of which were previously annotated as open or accessible chromatin. Applying this in situ cistrome mapping to fixed nuclei from endothelial cells under normoxia or hypoxia (1, 3, or 24 hr) revealed thousands of hypoxia-responsive genomic sites with dynamic TF footprints. The affected genes were enriched in canonical hypoxia-induced pathways, such as angiogenesis. Motif analysis identified over 100 candidate TFs potentially mediating these multifaceted genomic responses. By grouping hypoxia-modified occupancy signals across the hypoxia exposure times, we clustered differentially occupied MOA sites into defined 10 distinct TF kinetic clusters, half of which were associated with HIF1A. HIF1A-proximal binding sites suggested co-activators, while non-HIF1A clusters pointed to additional TFs that may have HIF1A-independent roles. This analysis provides insight into how multiple TF networks coordinate hypoxia responses and highlights the power of cistrome profiling to deepen our understanding of the complex genomic response to low oxygen conditions.

Methylation clocks fail to generalize across genetically admixed individuals

tony@capralab.org (Anthony J Griswold) — Tue, 04 Aug 2026 00:00:00 +0000

Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer’s disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here, we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.

Acute opioid responses are modulated by dynamic interactions of Oprm1 and Fgf12

labwilliams@gmail.com (Alexander S Hatoum) — Wed, 29 Jul 2026 00:00:00 +0000

We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the µ opioid receptor gene (Oprm1) on chromosome (Chr) 10 with a peak linkage of 12.4 (–logp). The B allele inherited from C57BL/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of locomotion emerged after approximately 100 min. This locus was located on Chr 16 with peak linkage of 10.6 in females and included one compelling candidate, fibroblast growth factor 12 (Fgf12). A strong and transient epistatic interaction existed between the Oprm1 and Fgf12 loci during a short time window (45–75 min). In heterogeneous stock rats, we demonstrated that Oprm1 and Fgf12 were co-expressed in one subtype of Drd1⁺ medium spiny neuron. A Bayesian network analysis supported an Oprm1-to-Fgf12 network that involves a MAP kinase cascade that modulates FGF12 phosphorylation and locomotor activation. OPRM1 and FGF12 networks in human genome-wide association study (GWAS) data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.

Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells

volker_soltys@eva.mpg.de (Dingwen Su) — Mon, 20 Jul 2026 00:00:00 +0000

Gene regulation underpins development and is an intricate biological process involving transcription, typically at promoters within accessible chromatin. To understand cell-type-specific regulatory networks, the ability to capture both transcription and chromatin accessibility simultaneously is crucial. However, joint measurements are technically challenging and current methodologies still face adoption challenges. Here, we present easySHARE-seq, an improvement on SHARE-seq for the simultaneous measurement of ATAC- and RNA-seq in single cells. We address several limitations of the previous method by improving the barcode and streamlining the protocol. As a result, easySHARE-seq libraries have a usable sequence of up to 300 bp (+200 bp increase), making it suitable for, e.g., investigation of allele-specific signals or variant discovery. Furthermore, easySHARE-seq libraries do not require a dedicated sequencing run thus saving costs. We applied easySHARE-seq to murine liver nuclei and recovered 19,664 nuclei with joint chromatin and expression profiles. By benchmarking against other combinatorial indexing-based techniques, we showed that we can recover over 1.5-fold more transcripts per cell while retaining high scalability and low cost. To showcase our method, we identified cell types, exploited the multiomic measurements to link cis-regulatory elements to their target genes and investigated liver-specific micro-scale changes. We conclude that easySHARE-seq improves upon previous methods and can produce high-quality multiomic datasets. We expect it to be applicable to a wide range of study designs.

Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity

thayerm@ohsu.edu (Athanasios E Vouzas) — Wed, 08 Jul 2026 00:00:00 +0000

Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 Mbb in size and can contain both protein-coding and noncoding genes. In different single-cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we identify syntenic loci in the mouse genome that display epigenetic regulation of allelic replication timing, highlighting the genomic organization and conservation of I/SC-associated regulation between human and mouse genomes. The allele-restricted regulation described here creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Alzheimer, Parkinson, epilepsy, deafness, and impaired intellectual development.

Optimised genome editing for precise DNA insertion and substitution using prime editors in zebrafish

s.scholpp@exeter.ac.uk (Amir Khan) — Tue, 07 Jul 2026 00:00:00 +0000

CRISPR/Cas9-mediated genome editing has rapidly become a popular tool for studying gene functions and generating genetically modified organisms. However, using this system, stochastic integration of random insertions and deletions restricts precise genome manipulation. Advanced CRISPR/Cas9 technologies using Prime Editors (PEs), Cas9 proteins fused with reverse transcriptase, enable programmed integration of short DNA modifications into the genome. However, its application in precise genome editing in animal models is challenging. Here, we utilise a nickase- and a nuclease-based PE to perform programmed short DNA substitutions and insertions at various loci in the zebrafish genome. Whereas nickase-based PE2 mediated a higher ratio of precise prime edits to the total edits, nuclease-based PEn was more efficient for short DNA modifications, achieving up to 27.3% precise insertion. To further evaluate our approach, we inserted a nuclear localisation signal into a reporter transgene to incorporate longer fragments by prime editing. These gene modifications were transmitted to the next generation. We show that PE-mediated prime editing can efficiently manipulate genome information in zebrafish without using exogenous donor DNA.

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

denard@arizona.edu (David Enard) — Tue, 07 Jul 2026 00:00:00 +0000

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic implications of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions; their expression is biased towards male germ cells, and they are enriched in functions related to meiosis and sperm biology. We tested the role of gorilla relaxed genes previously not implicated in male reproductive function using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

Mechanistic insights into transcriptional regulation of ARHGAP36 expression identify a factor predictive of neuroblastoma survival

olehmann@ualberta.ca (Armin M Gamper) — Mon, 06 Jul 2026 00:00:00 +0000

Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage-specific transcription factors that regulate neural crest migration, representing frequent drivers of malignancy. One such example is the forkhead transcription factor FOXC1, where gain of function is a feature of diverse cancers that is associated with an unfavorable prognosis. Using RNA-, ChIP-sequencing and CRISPR interference, we show that Foxc1 binds a locus in a region of closed chromatin to induce expression of Arhgap36, a tissue-specific inhibitor of protein kinase A. Because PKA is a core Hedgehog (Hh) pathway inhibitor, Foxc1’s induction of Arhgap36 expression increases Hh activity. The function of Sufu, a PKA substrate, and a second essential Hh pathway inhibitor, is likewise impaired. The resulting increased Hh pathway output is resistant to pharmacological inhibition of Smoothened, a phenotype of more aggressive cancers. The Foxc1–Arhgap36 relationship identified in murine cells was further evaluated in neuroblastoma, a neural crest-derived pediatric malignancy. This demonstrated in a cohort of 1348 patients that high levels of ARHGAP36 are predictive of improved 5-year survival. Accordingly, this study has identified as a novel transcription factor which enhances ARHGAP36 expression, one that induces Hh activity in multiple tissues during development. It also establishes a model by which increased levels of FOXC1 via ARHGAP36 and PKA inhibition dysregulate multiple facets of Hh signaling and provides evidence demonstrating relevance to a common neural-crest-derived malignancy.

A pilot study for whole proteome tagging in Caenorhabditis elegans

me2839@columbia.edu (Matthew Eroglu) — Wed, 24 Jun 2026 00:00:00 +0000

Tagging all proteins encoded by an animal genome with a fluorescent tag would open many windows to the discovery of unexpected patterns of protein expression and localization. To scale such an approach, it would be beneficial to introduce multiple, spectrally distinct fluorophore tags in parallel. As proof of concept for scalable pooled tagging, we undertook a pilot study in the nematode Caenorhabditis elegans, in which we set out to tag 30 different genetic loci with three different fluorophores, with three tags being introduced at a time. By choosing essential genes, predicted based on transcriptomics to cover a range of expression levels, we explore issues relating to disrupting gene function and visibility of tagged proteins. We demonstrate that such a tagging approach is highly efficient and indeed reveals unanticipated patterns of cellular and subcellular sites of protein expression and localization. We hope that this pilot study will motivate attempts to scale this tagging approach to more loci and, ultimately, the whole genome.

Constraints on the G1/S transition pathway may favor selection of multicellularity as a passenger phenotype

bertrand.daignan-fornier@u-bordeaux.fr (Bertrand Daignan-Fornier) — Thu, 18 Jun 2026 00:00:00 +0000

Multicellularity has emerged in the three branches of the tree of life. The formation of simple multicellular entities can either result from cells aggregating or staying together after mitosis. However, it is not yet fully understood how, once formed, these simple multicellular entities could be maintained or even selected for. Here, using the ace2 yeast snowflake model of simple multicellularity, we aimed at identifying genetic conditions favoring its maintenance. Growth-competition experiments revealed that, while the ace2 mutation by itself does not provide any fitness advantage or disadvantage, the ace2 snowflakes were strongly selected when combined with conditions affecting regulators of the G1/S transition of the cell cycle, such as Cln3 or Whi5. We show that this selection results from a faster exit from quiescence of the ace2 snowflake cells. Importantly, this advantage is not dependent on the multicellular phenotype, but rather on the ace2 genotype itself. We found that the ace2 selective advantage in the cln3 background fully depends on the KSS1 gene, a target of the Ace2 transcription factor. Finally, we show that phenotypes observed for ace2 mutants are phenocopied by the AMN1^368D allelic form found in ‘non-laboratory’ yeast strains, hence adding physiological relevance to these observations. Altogether, our results support the hypothesis that simple multicellularity could, in some cases, persist, not because it provides a direct selective advantage due to multicellularity itself, but rather as a ‘passenger’ phenotype that is maintained alongside other selected traits.

Genome reorganization and its functional impact during breast cancer progression

Gary.Stein@med.uvm.edu (Andrew Fritz) — Tue, 16 Jun 2026 00:00:00 +0000

Cancer progression involves extensive alterations in epigenetic and gene expression programs, but the accompanying changes in higher-order genome organization remain less well understood. Using high-resolution Micro-C mapping in the MCF10 cell model of breast cancer, we profiled chromatin compartments, topologically associated domains, and chromatin loops. We find large-scale compartmental shifts occur predominantly in early stages of cancer development, with more fine-scale structural changes in topologically associating domains and loops accumulating during the later transition to metastasis. Relating these chromatin features to gene expression and enhancer-associated histone marks revealed that many differentially expressed genes are physically connected to distal regulatory elements. While enhancer–promoter contact frequency and distal enhancer activity correlated with gene expression, strong changes in chromatin looping were relatively infrequent during progression, suggesting that alterations in chromatin contacts are not globally necessary, but may facilitate gene regulation at a subset of genes. These results elucidate the connection between gene regulation and genome remodeling in a cell-based cancer progression model.

Faroese whole genomes provide insight into ancestry and recent selection

fracimo@sund.ku.dk (Alba Refoyo-Martínez) — Tue, 16 Jun 2026 00:00:00 +0000

The Faroe Islands are home to descendants of a North Atlantic founder population with a unique history shaped by both migration and periods of relative isolation. Here, we investigate the genetic diversity, population structure, and demographic history of the islands by analyzing whole genome sequencing data from 40 participants in the Faroe Genome Project. This represents the first whole genome sequencing panel of this size from the Faroe Islands. We observed numerous putatively functional private alleles, including stop gain variants and high impact missense variants in the cohort. Faroese individuals had a higher proportion of their genomes contained in long runs of homozygosity than other European groups, including Finnish, suggesting a more recent or stronger bottleneck in the Faroese population. Signals of positive selection were identified at loci containing genes that play roles in vitamin D and dietary fat absorption and DNA repair, while increased diversity on lactase persistence haplotypes was observed. Fine-scale analysis of haplotype structure in present-day and ancient European genomes revealed genetic affinities with ancient Iron Age individuals from the North and West of Europe, providing evidence for potential contributions to the Faroese gene pool from Celtic and Viking populations as well as information about the temporal order in which these events happened. This study highlights the impact of evolutionary processes, such as ancient admixture, founder events, and positive selection, on the present-day genetic architecture of North Atlantic founder populations like the Faroe Islands.

Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease

diane@octant.bio (Abhay Hukku) — Wed, 10 Jun 2026 00:00:00 +0000

Tyrosine kinase 2 (TYK2) is a genetically defined target for autoimmune disease, with first-generation inhibitors showing clinical success in some but not all associated indications. A deeper understanding of TYK2 structure-function relationships, protein-ligand interactions, and the impact of human variants could inform next-generation therapeutics. Here, we applied deep mutational scanning (DMS) to assess >23,000 amino acid substitutions across two TYK2 functions: interferon alpha (IFN-α) signaling and protein abundance. This enabled high-resolution structure-function mapping and the identification of novel allosteric sites. By coupling DMS with inhibitor treatment, we uncovered variants that modulate compound potency. We also show that human variants – both common and rare – that are protective against autoimmune phenotypes reduce TYK2 protein abundance. Together, these findings demonstrate that DMS can prospectively reveal novel druggable sites, clarify structure-activity relationships (SAR), and highlight TYK2 degradation as a potential therapeutic strategy in autoimmunity.

Transcriptional responses to chronic oxidative stress require cholinergic activation of G-protein-coupled receptor signaling

michael.francis@umassmed.edu (Amy K Walker) — Mon, 08 Jun 2026 00:00:00 +0000

Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine-coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.

Chromosome-scale genome assembly of the European common cuttlefish Sepia officinalis

g.laurent@brain.mpg.de (David Hain) — Thu, 28 May 2026 00:00:00 +0000

Coleoid cephalopods, a subclass of mollusks that includes octopuses, cuttlefish, and squid, exhibit sophisticated biological features, such as dynamic and neurally driven camouflage behavior, inter-individual communication, single-lens camera-like eyes, the largest brains among invertebrates, and a distinctive embryonic development. The common cuttlefish Sepia officinalis has served as a model organism in various research fields, spanning biophysics, neurobiology, behavior, evolution, ecology, and biomechanics. More recently, it has become a model to investigate the neural mechanisms underlying cephalopod camouflage, using quantitative behavioral approaches alongside molecular techniques to characterize the identity, evolution, and development of neuronal cell types. Despite significant interest in this animal, a high-quality, annotated genome of this species is still lacking. To address this, we sequenced and assembled a chromosome-scale genome for S. officinalis. Our assembly spans 5.68 billion base pairs and comprises 1n=47 repeat-rich chromosome scaffolds. This was unexpected because the haploid karyotypes of other decapods indicate 46 chromosomes. Detailed comparisons of our data to those from published decapod genome assemblies and to another recent genome assembly of S. officinalis (itself suggesting 1n=49 chromosomes) in fact revealed clear homologies between 46 scaffolds across all the datasets. In-depth comparison of datasets reveals highly repetitive regions at discordant scaffold boundaries and suggests that the true karyotype of S. officinalis is probably 1n=46 chromosomes, a likely ancestral and if true, conserved decapod karyotype. Our results include a comprehensive gene annotation and full-length transcript prediction, which we used to characterize orthologous gene families across mollusks. We identified several large-scale expansions specific to cephalopods, with many genes specific to neural or non-neural tissues of adult S. officinalis. In summary, this genome should provide a valuable resource for future research on the evolution, brain organization, information processing, development, and behavior in this important clade.

In situ mutational screening and CRISPR interference define apterous cis-regulatory inputs during compartment boundary formation

gusag@mit.edu (Dimitri Bieli) — Fri, 22 May 2026 00:00:00 +0000

The establishment of tissue axes is fundamental during embryonic development. In the Drosophila wing, the anterior/posterior (AP) and the dorsal/ventral (DV) compartment boundaries provide the basic coordinates around which the tissue develops. These boundaries arise as a result of two lineage decisions, the acquisition of posterior fate by the selector gene engrailed (en) and dorsal fate by the selector gene apterous (ap). While the en expression domain is set up during embryogenesis, ap expression begins only during early wing development. Thus, the correct establishment of the ap expression pattern relative to en must be tightly controlled. Here, we functionally investigate the transcriptional inputs integrated by the early ap enhancer (apE) and their requirement for correct boundary formation. Detailed mutational analyses using CRISPR/Cas revealed a role for apE in positioning the DV boundary relative to the AP boundary, with apE mutants often displaying mirror-image anterior wing duplications. We then designed and applied methods to accomplish tissue-specific enhancer disruption via dCas9 expression. This approach allowed us to dissect the spatiotemporal requirement for apE function, clarifying the mechanism by which apE misregulation leads to AP defects. Base-pair-resolution analyses of apE uncovered a single HOX-binding site essential for wing development that, when mutated, led to wingless flies. We demonstrated that the transcription factors Pointed (Pnt), Homothorax (Hth), and Grain (Grn) are required for apE function, and the HOX gene Antennapedia (Antp) contributes to early wing development. Together, our results provide a comprehensive molecular basis of early ap activation and the developmental consequences of its misregulation, shedding light on how compartmental boundaries are set up during development.

Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes

ambro.van.hoof@uth.tmc.edu (Ambro van Hoof) — Mon, 18 May 2026 00:00:00 +0000

A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways are much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control, and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target, YDR514C, suppress the growth defect of an RNT1 deletion. Overexpression of YDR514C results in slow growth, further suggesting that Rnt1 may limit the expression of YDR514C to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.

Stranded short nascent strand sequencing reveals the topology of DNA replication origins in Trypanosoma brucei

slavica.stanojcic@umontpellier.fr (Bridlin Barckmann) — Fri, 15 May 2026 00:00:00 +0000

The universal features that define genomic regions acting as replication origins remain unclear. In this study, we mapped a set of origins in Trypanosoma brucei using stranded short nascent strand sequencing methods. Our results showed that DNA replication predominantly initiates in intergenic regions between poly(dA)- and poly(dT)-enriched sequences. G4 structures were detected in the vicinity of some origins and were embedded in poly(dA)-enriched sequences in a strand-specific manner: G4s on the plus strand were located upstream while those on the minus strand were located downstream of the centre. The origins' centres were found to be areas of low nucleosome occupancy, surrounded by regions of high nucleosome occupancy. Furthermore, our results demonstrate that 90% of replication origins overlap with a minor proportion of the previously reported RNA: DNA hybrids. These findings shed new light on the sequence and structural features that define the topology of replication origins in T. brucei. To further characterise replication dynamics at the single-molecule level, we employed DNA combing analysis.

Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila

dujuan9981@cau.edu.cn (Juan Du) — Fri, 08 May 2026 00:00:00 +0000

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl5^1bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.

Adapting clinical chemistry plasma as a source for liquid biopsies

weigu@stanford.edu (Benjamin A Pinsky) — Fri, 01 May 2026 00:00:00 +0000

Circulating cell-free DNA (cfDNA) is valuable for molecular testing, but typically requires specialized collection tubes or immediate processing. We investigated whether residual plasma from heparin separators, routinely used in clinical chemistry, could serve as an accessible and underused source for cfDNA. We analyzed matched plasma samples from healthy volunteers in two experiments: an immediate-processing comparison across EDTA, Streck, and heparin separator tubes (n=5), and a clinical-handling simulation comparing EDTA and heparin separator tubes under delayed processing at room temperature or 4°C (n=6). We also analyzed matched plasma samples from viral PCR-positive patients in a hospital cohort (n=38). Whole-genome sequencing and enriched methylation sequencing were performed to assess concordance across metagenomics, copy number, methylation, and fragmentomic features. Under immediate processing, heparin separator plasma showed high concordance with EDTA and Streck plasma for methylation patterns (Spearman’s ρ=0.65–0.70) and fragmentation features. In the Hospital Cohort, heparin separator plasma showed strong concordance with matched EDTA plasma for viral detection (Spearman’s ρ=0.95), copy number alteration profiling (Spearman’s ρ=0.72–0.96), and methylation patterns (Spearman’s ρ=0.50–0.83). These findings support the feasibility of using refrigerated, promptly processed residual plasma from routine clinical chemistry as a supplementary source for cfDNA biobanking and molecular analyses.

Teaching early-career researchers how to respond to peer reviewers

e.kalkhoven@umcutrecht.nl (Eric Kalkhoven) — Thu, 23 Apr 2026 00:00:00 +0000

The process of publishing a research article in a scientific journal inevitably involves revising the original version of the article to respond to the concerns raised by peer reviewers. In this article we describe a course module that introduces MSc students at Utrecht University in the Netherlands to this part of the publication process. During the module the students and an invited speaker actively discuss the revision process for a recent article by the speaker. Feedback from students and speakers on the module – which could be readily transferred to other courses in the life and biomedical sciences – has been largely positive.

Single-cell co-mapping reveals relationship between chromatin state and gene expression in early zebrafish development

v.bhardwaj@uu.nl (Alberto Griffa) — Tue, 21 Apr 2026 00:00:00 +0000

Establishing a cell type-specific chromatin landscape is crucial for the maintenance of cell identity during embryonic development. However, our knowledge of how this landscape is set during vertebrate embryogenesis has been limited, due to the lack of methods to jointly detect chromatin modifications and gene expression in the same cell. Here we present a multimodal measurement of full-length transcriptome and histone modifications in individual cells during early embryonic development in zebrafish. We show that before the formation of germ layers, the chromatin and transcription states of cells are uncoupled and become progressively connected during gastrulation and somitogenesis. Silencing of developmental genes is achieved by local spreading of repressive chromatin together with cell type-specific demethylation. Combining transcription factor (TF) expression and chromatin states within an interpretable machine learning model, we classify TFs as lineage-specific activators and repressors and identify a subset of TFs that are epigenetically regulated. Altogether, our data resolves the dynamic relationship between chromatin and transcription during early vertebrate development and clarifies how these two layers interact to establish cell identity.