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Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

A study comparing the pattern of single-nucleotide variation between unique and duplicated regions of the human genome shows that mutation rate and interlocus gene conversion are elevated in duplicated regions.

Mutations in human pluripotent stem cells (PSC) and whether any form during culture prior to use in a human clinical context are a concern. Here, the authors use hPSCs derived to cGMP standards and show they have low mutation rates after culture, noting this decreases on culturing in low (5%) oxygen conditions.

Previous work shows that a small population of quiescent SOX2⁺ medulloblastoma (MB) stem cells can drive tumour growth in early tumorigenesis and relapse. Here, the authors identify OLIG2 as a transcriptional mediator of the transition from quiescent to rapidly proliferating progenitor states and therapeutically target this axis in preclinical models of MB.

This Resource combines amplicon sequencing, shotgun metagenomic sequencing and untargeted metabolomics to provide a global view of microbial–metabolite associations across Earth’s environments.

Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

CRISPR/Cas9-mediated gene editing is an emerging strategy to treat Duchenne muscular dystrophy. Here the authors develop multiple CRISPR/Cas9-based approaches to correct different dystrophin gene mutations, and show significant restoration of dystrophin expression in skeletal and cardiac muscle in mice.

Platelets derive from large precursor cells (megakaryocytes) in the bone marrow. Düttinget al. show that megakaryocyte polarization and platelet biogenesis in the bone-marrow sinusoids are directed by adhesion receptor GPIb signalling and resulting balanced antagonism between RhoA (stop-signal) and Cdc42 (go-signal).

Within microbial communities, microorganisms adopt different lifestyle strategies to use the available resources. Here, the authors use an integrated ‘multi-omic’ approach to study niche breadth (generalist versus specialist lifestyles) in oleaginous microbial assemblages from an anoxic wastewater treatment tank.

Placental dysfunction can have catastrophic or barely discernible effects ranging from miscarriage to apparently normal birth. Here the authors present a comprehensive analysis of the human placental transcriptome and identify circular RNAs and piRNAs.

Dogs exhibit remarkable variation in colour patterns. Here, the authors identify structural variants of independent regulatory modules for ventral and hair cycle expression of the ASIP gene that explain five distinctive dog colour patterns and trace back the origin of one colour pattern to an extinct canid.

Westermann and colleagues define four subtypes of neuroblastoma based on super-enhancer profiles in primary patient samples, which could be linked to distinct clinical outcomes and cell identity characteristics.

Nease and colleagues demonstrate that the methyltransferase FTSJ1 mediates selenocysteine-specific tRNA methylation of selenoproteins, which protects melanoma cells against oxidative stress and promotes metastasis.

Magnetic metamaterials can be designed to provide models of frustrated systems that allow theoretical predictions to be experimentally tested. Here the authors realise a 2D XY model with dipolar interactions and find behaviour consistent with predictions of a low-temperature ordered state.

The bacterial genus Rickettsia includes vector-borne pathogens and arthropod symbionts that are close relatives of symbionts of microeukaryotes classified under the genus ‘Candidatus Megaira’. Here, Davison et al. clarify the evolutionary relationships between these organisms by assembling 28 genomes of understudied species, and propose that a distinct clade known as Torix Rickettsia should be considered a separate genus.

FUS/EWS/TAF15 (FET) fusion oncoproteins contain low complexity domain which forms biomolecular condensates that recruit RNA polymerase II. Here the authors develop a single-molecule assay to visualize this phenomenon providing in vitro evidence to support causative relationship between the formation of condensates on DNA and gene transcription. Furthermore, they also determine a threshold number of fusion-binding DNA satellite elements required for the formation of FET protein condensates.

Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease.

DNA methylation variation is associated with human obesity but a whether it plays a causal role in disease pathogenesis is unclear. Here, the authors perfom an integrative genomic study in human adipocytes to show that DNA methylation variations contribute to obesity and type 2 diabetes susceptibility, revealing underlying genomic and molecular mechanisms.

Mutations in the chromatin modifier Chd7 have been associated with CHARGE syndrome and other developmental disorders. Here the authors show that Chd7 is required for the activation of genes essential for cerebellar granule cell differentiation, and that disrupting Chd7 leads to cerebellar hypoplasia in mice.

It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.

During ageing, S-adenosylmethionine (SAM) is depleted from muscle stem cells (MuSCs) because of increased synthesis of the polyamine spermidine, leading to loss of heterochromatin and dysfunction of MuSCs. SAM restoration rescues the mouse MuSC defects.

Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.

Enzyme promiscuity seeds evolutionary innovation, but how flexible a single enzyme can be (re-)used during evolution remains unclear. Here, the authors show that various evolutionary trajectories applied to succinate semialdehyde dehydrogenase can compensate for the loss of two different functions in E. coli.

A new study reveals that bacterial partners supply essential metabolites to the vital microalgal symbionts of corals, including metabolites that boost symbiont growth. This breakthrough increases our understanding of coral microbial ecology and also opens the door to innovative ways of protecting coral reefs.

The Moderna (mRNA-1273) and Pfizer–BioNTech (BNT162b2) vaccines elicit anti-RBD antibodies similar to those elicited through natural infection with SARS-CoV-2, but their potent neutralizing activity was reduced or abolished by new viral variants of concern.

Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.

The internal amplification of Low-Gain Avalanche Diode sensors can enhance the signal-to-noise ratio, improving the detection of low-energy X-rays. In this work, the authors demonstrate a single photon counting hybrid pixel detector detecting X-ray energies down to 550 eV, and test it in ptychographic imaging at the Fe L₃-edge.

Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.

A combination of genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling enables the discovery of therapeutically targetable tumor dependencies in rare tumors.

Atmospheric methane may be consumed by microorganisms in soil, but the mechanisms behind high-affinity methane oxidization remain poorly understood. Here, Jia et al. show that known methanotrophic bacteria are responsible for atmospheric methane uptake in periodically drained wetland ecosystems.

Rudloff et al. examine the kinetics of CD8⁺ T cell dysfunction/exhaustion. Tumor-specific CD8⁺ T cells in the tumor environment exhibit epigenetic modifications within hours, before cell division. The findings suggest a temporal relationship between tumor antigen exposure, chromatin remodeling and dysfunction ‘imprinting’.

Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.

Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.

Stuart Cook and colleagues study the role of TTN (titin)-truncating variants using a combination of heart physiology experiments in rats and genomic analysis in humans. Their data show that TTN variants are associated with a range of cardiac phenotypes in healthy individuals and in patients with dilated cardiomyopathy.

Soils from 30 grasslands across Europe were subjected to 4 contrasting extreme climatic events under drought, flood, freezing and heat conditions, with the results suggesting that soil microbiomes from different climates share unified responses to extreme climatic events.

This protocol describes a high-throughput sequencing approach to identifying regulators of bacterial gene expression based on transposon insertion mutagenesis in a strain harboring a fluorescent reporter.

The authors demonstrate efficient and direct correction of the DNA mutation causing Haemoglobin E β-thalassaemia with CRISPR Cas9 base editors. The work includes profiling of off-target effects using deep neural networks.

Integrated analyses reveal that multiomics captured the heterogeneity of metabolic states accompanying obesity and changes in metabolic health in response to lifestyle intervention that are not apparent in body mass index measurements.

Single-cell transcriptome profiling of mouse embryos and newborn pups is combined with previously published data to construct a tree of cell-type relationships tracing development from zygote to birth.

Transposon based screens carried out in mice can identify genes critical for tumourigensis. Here, the authors describe transposon screens in mouse models of breast cancer and highlight a large group of tumour suppressors that could underlie selection for common chromosome arm losses in cancer.

Using experiments in organoids and in vivo in mice, the authors show that Apc-mutant cells act as supercompetitors to initiate the formation of adenomas.

Killer whales have evolved into specialized ecotypes based on hunting strategies and ecological niches. Here, Andrew Foote and colleagues sequenced the whole genome of individual killer whales representing 5 different ecotypes from North Pacific and Antarctic, and show expansion of small founder groups to adapt to specific ecological niches.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

A small molecule can bypass the RNA-editing enzyme ADAR1 to directly activate the Z-form nucleic acid sensor ZBP1, induce necroptosis in tumour fibroblasts and reverse resistance to immune checkpoint blockade in mouse models of melanoma.

It is known that invasive lung adenocarcinomas evolve from pre-cancerous dysplastic lesions. In this study, the authors show that evolution of pre-cancerous lesions is accompanied by DNA methylation alterations, and that global hypomethylation correlates with immune infiltration, mutational burden and copy number alterations.