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Different agonists produce equilibria of at least four distinct active states of the G-protein-bound M2 muscarinic acetylcholine receptor, each with a different ability to activate G proteins.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

In mice, tissue-mimetic cells appear in thymus in two distinct waves, creating two distinct pools of mimetic cells, each expressing antigens characteristic of different cell types.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

The role of ancestry in target discovery remains to be systematically explored. Here, the authors analyse data from 611 genome scale CRISPR/Cas9 viability experiments in human cell line models as part of The Cancer Dependency Map and identify ancestry-associated genetic dependencies.

Panos Deloukas, Nilesh Samani and colleagues report a large-scale association analysis using the Metabochip array in 63,746 coronary artery disease cases and 130,681 controls. They identify 15 susceptibility loci, refine previous associations and use network analysis to highlight biological pathways.

In this Opinion article, Thomas Boehm proposes that quality-control mechanisms, such as the MHC peptide-presentation system, that tame immunoreceptor self-reactivity might be derived from an ancestral mechanism that guided sexual selection and similarly used information contained in intracellular peptide sequences.

Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.

Extant jawless vertebrates, such as lampreys and hagfishes, express variable lymphocyte receptors (VLRs) that are different from adaptive immune receptors in mammals. Here, the authors show that, in addition to the well-described five VLRs, a sixth VLR is expressed in lamprey T-like cells and evolved at least 250 million years ago.

Here, Thomas Boehm considers the commonalities that underlie the adaptive immune systems of jawless and jawed vertebrates, including functionally distinct B- and T-like cells and anatomically segregated sites for their generation, as well somatically diversified and clonally expressed antigen receptors. The features that distinguish the adaptive immune systems in these vertebrate groups are also considered.

varVAMP is open-source software for designing primers for tiled-amplicon sequencing and qPCR. It simplifies primer design for viral pathogens with high genomic variability by including sequence variations into primer sequences.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

iNKT cells recognise glycolipids via their T cell receptors. Here the authors implicate tnpo3 in the regulation of splicing of pre-mRNA encoding cognate TCR α chain for iNKT cells.

The genomic landscape of hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) remains to be explored. Here, the authors perform multiomic analysis on 94 tumours from 79 patients and identify the molecular features of metastatic disease and treatment response.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

Erik Ingelsson and colleagues report a large-scale genome-wide meta-analysis for associations to the extremes of anthropometric traits, including body mass index, height, waist-to-hip ratio and clinical obesity. They identify four loci newly associated with height and seven loci newly associated with clinical obesity and find overlap in the genetic structure and distribution of variants identified for these extremes of the trait distributions and for the general population.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

Tracheal tuft cells have been shown to facilitate the recruitment of immune cells during infection of the airways. Here the authors show that P. aeruginosa lung infection in mice activates tuft cells to release ATP which subsequently activates DC and promotes IL-17A secreting T cells.

Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Here the authors report that homozygous dnmt1 mutant zebrafish are essentially normal, with the exception of impaired lymphopoiesis, with impaired larval (but not adult) T cell development being transmitted to subsequent generations by genotypically wildtype fish.

TCRα repertoire diversity is best explained by species-specific extents of sequence microhomologies marking the ends of recombining elements, and germline sequence composition of rearranging elements determines the degree of diversity of somatically generated antigen receptors.

Two populations of thymic progenitors are identified, an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor type biased towards medullary epithelium.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Mark McCarthy and colleagues identify twelve new risk loci for type 2 diabetes through a large-scale genome-wide association and replication study in individuals of European ancestry. The identified loci affect both beta-cell function and insulin action and are enriched for genes involved in cell cycle regulation.

Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.

Clinical and genetic phenotyping of consanguineous family cases of neonatal syndromic diabetes and type 2 diabetes, combined with in-depth functional studies in pluripotent stem cells, reveals a role for genetic variants of ONECUT1 in monogenic and multifactorial diabetes.

The relatedness of animals influences their behaviour, but how do they detect their kin? It seems that nasal sensory neurons differentiate between minute structural differences in urinary peptides that reflect genetic variation.

Jawless fishes, the 'sister' group of jawed vertebrates, use leucine-rich repeat–containing proteins as antigen receptors. New work shows that the two isotypes of variable lymphocyte receptors are expressed in distinct lymphocyte lineages, which indicates that lymphocytes resembling T cells and B cells are an ancient feature of all vertebrates.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

Cells expressing variable lymphocyte receptor C (VLRC) genes that encode VLRC receptors, which are used by jawless vertebrates to react with antigens, are defined as a second T-cell-like lymphocyte subset (the first being VLRA-bearing cells); distinct properties of these two T-cell-like subsets are reminiscent of the distinction between αβ and γδ T cells in jawed vertebrates.

Jawless fish were recently shown to possess T- and B-like lymphocytes expressing diverse assembled antigen receptors. This study identifies and characterizes lympho-epithelial thymus-like structures at the tips of gill filaments of lamprey larvae, thus providing evidence that the similarities underlying the adaptive immune systems of both types of vertebrate appear to extend to primary lymphoid organs.

This study maps global tree composition in forests and assesses the impacts of historical forest cover loss and climate change. The results highlight the need for preserving the remaining large forest biomes, while regenerating degraded forests in a way that provides resilience against climate change.

Transmission of influenza A viruses (IAV) between hosts and replication within host impose genetic bottlenecks, constraining viral diversity and adaptation. Here, Amato et al. perform site-specific inoculation of barcoded IAV of ferrets and track viral diversity as infection spreads to the lower respiratory tract and conclude that narrow population bottlenecks are an important feature of the within-host infection dynamics.