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Joseph Gleeson and colleagues report that mutations in TMEM216 cause Joubert, Meckel and related syndromes. They further show that TMEM216 localizes to the base of cilia and that its loss leads to defects in ciliogenesis and centrosome docking.

Conventional diffraction cannot determine short-range order at concentrations that disrupt ionic mobility. Real-space transforms of single-crystal diffuse scattering now allow us to measure ionic correlation length scales in sodium-intercalated V₂O₅.

A mega-analysis of whole-genome data from seven populations demonstrates substantial hidden heritability for educational attainment and reproductive behaviour, highlighting the importance of sample-specific gene–environment interaction in complex traits.

Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.

Proteoforms arise as protein isoforms or as protein haplotypes, which are the result of genetic variation. Here, the authors develop Haplosaurus, a database that computes protein haplotypes genome-wide from existing genotype data and analyse protein haplotype variability in the 1000 Genomes dataset.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

Nitrile-oxide electrophiles were identified as covalent inhibitors of GPX4 that exhibit increased selectivity and reduced off-target effects relative to chloroacetamide-based inhibitors.

Ghorani et al. use a multiomics approach to characterize the effect of tumour mutational burden on the differentiation of CD4 and CD8 T cell subpopulations in non-small cell lung cancer.

A new ice core from West Antarctica shows that, during the last ice age, abrupt Northern Hemisphere climate variations were followed two centuries later by a response in Antarctica, suggesting an oceanic propagation of the climate signal to the Southern Hemisphere high latitudes.

Targeted cancer therapy requires knowledge of driver aberrations. Here the authors perform large-scale transcriptome analysis, and show that gene fusions in NRG1, NF1and Hippo pathway genes are recurrent mostly among lung cancers lacking known driver mutations.

Large-scale genomic analysis of somatic point mutations in exomes from tumour–normal pairs across 21 cancer types identifies most known cancer genes in these tumour types as well as 33 genes not known to be significantly mutated, and down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies.

Detailed clinical and virologic characteristics of the first 12 individuals with COVID-19 in the United States from the US Centers for Disease Control and Prevention.

Yuan and colleagues developed an artificial intelligence-based method to derive growth patterns and morphological features from hematoxylin and eosin-stained slides of lung adenocarcinoma samples, for improved tumor grading and patient prognostication.

The transcriptional role of c-Myc in maintaining tissue homeostasis is still unclear. Using mice conditionally expressing an activated form of c-Myc in the epidermis, and genome-wide approaches, Frye and colleagues show that c-Myc modulates the expression of the epidermal differentiation complex locus in the skin by displacing or recruiting specific transcriptional regulators. c-Myc activity is negatively regulated in vivo in this context by Sin3a.

The nucleotide diversity present in maize exceeds that in humans by an order of magnitude, and it has been challenging to characterize the high levels of diversity in this important crop. Doreen Ware and colleagues have identified 55 million SNPs in 103 domesticated and pre-domestication Zea mays varieties, as well as in a representative from the sister genus Tripsacum.

Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of autism spectrum disorder (ASD) families and find that common polygenic variation acts additively with de novo variants to contribute to ASD risk.

JAK2 phosphorylates H3-Y41 residues to exclude the heterochromatin factor HP1α from chromatin. JAK2 is found to be required for maintenance of mouse embryonic stem cells through its action on the Nanog promoter. A mutant form of JAK2 associated with a myeloproliferative disorder allows embryonic stem cells to self renew in absence of cytokines.

Ammar Al-Chalabi, Jan Veldink and colleagues perform a genome-wide association study for amyotrophic lateral sclerosis (ALS) in 15,156 cases and 26,242 controls. They identify three new genome-wide-significant variants and establish ALS as a complex trait with a polygenic architecture, but with a distinct and important role for low-frequency variants.

A nanomechanical sensor can quantify the concentration of active free drugs in human serum.

Computational design incorporating modular buried hydrogen networks produces highly orthogonal protein heterodimers.

BayesS estimates SNP-based heritability, polygenicity, and the relationship between effect size and minor allele frequency using genome-wide SNP data. Applying BayesS to UK Biobank data identifies signatures of natural selection for 23 complex traits.

A single dose of the ChAdOx1 nCoV-19 vaccine elicits antibodies and cytokine-producing T cells that might help control or prevent SARS-CoV-2 infection.

Hoare et al. find that NOTCH1 regulates the switch between two distinct senescence-associated secretomes—the TGF-β pathway and pro-inflammatory cytokines—and that its inhibition promotes clearance of oncogene-induced senescent liver cells.

Chromatin-associated protein complexes play a critical role in the regulation of gene expression in health and disease. Here, the authors describe a sensitive mass spectrometry-based method to monitor the dynamic interactions of endogenous chromatin-associated protein complexes in clinical samples.

Notch can drive senescence in a cell contact dependent manner. Here the authors show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously via the JAG1-NOTCH-HMGA1 interplay during senescence.

To infect humans, Trypanosoma brucei rhodesiense relies on its SRA protein to subvert host trypanolytic factors, TLF1 and TLF2. This study reveals the structure of SRA and explores how it interacts with TLFs, elucidating how the parasite avoids host immunity.

A biocompatible device built from naturally dissolving components and controlled by wireless technology enables programmable electrical stimulation of injured rodent peripheral nerves to accelerate regeneration and recovery.

Jian Yang and colleagues present a method, GREML-LDMS, to estimate heritability for complex human traits using whole-genome sequencing data or imputation with the 1000 Genomes Project reference panel. Using the heritability estimates from GREML-LDMS, they find that there is negligible missing heritability for human height and BMI.

To increase the policy relevance of ecosystem service benefits research, studies need to better predict the impact of specific decisions, according to an analysis of the literature.

Arul Chinnaiyan and colleagues identify NAB2-STAT6 fusions in 52 of 52 solitary fibrous tumor cases. Overexpression of this fusion induced cell proliferation, which could be suppressed by knockdown of EGR1.

A large-scale study that analyses gene copy number changes in lung cancer identifies 31 recurrent focal events, which include amplification of the transcription factor NKX2.1 (also called TTF1), shown to act as an oncogene.

Recent advances in structural biology techniques and computational simulations have enhanced our understanding of the conformational dynamics of G protein-coupled receptors and their interactions with ligands. This Review highlights how such advances may be used in the discovery and optimization of drugs that target G protein-coupled receptors, focusing on three categories: allosteric modulators, biased ligands, and bivalent and bitopic compounds.

Rett syndrome is caused by mutations in MeCP2, and this study identifies a site on MeCP2, T308, whose phosphorylation is regulated by neuronal activity: phosphorylation of T308 blocks the interaction of MeCP2 with the NCoR co-repressor complex, suppressing MeCP2's ability to repress transcription, and mice carrying mutations of MeCP2 T308 show Rett-syndrome-related symptoms.