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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

Rare loss-of-function mutations in SETD1A are associated with schizophrenia, but how SETD1A haploinsufficiency leads to disease phenotypes remains unknown. Here, authors show that SETD1A regulates genes at common schizophrenia risk loci regulating genomic stability and synaptic function.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

An exploratory analysis of the phase 3 ECOSPOR III trial shows that a higher dosage of the oral microbiome therapeutic VOWST led to enhanced pharmacokinetics, increased species engraftment and altered microbiome and metabolite profiles, providing mechanistic insights into how it may prevent Clostridioides difficile infection recurrence.

Many approaches exist to process data from individual imaging modalities, but integrating them is challenging. The authors develop an automated resource that enables co-registered network- and tract-level analysis of macroscopic in-vivo imaging and microscopic imaging of cleared tissue.

This work introduces Deep-STARmap and Deep-RIBOmap, imaging-based sequencing platforms designed to profile transcriptional and translational activity in thick tissue blocks.

A large, open dataset containing parallel recordings from six visual cortical and two thalamic areas of the mouse brain is presented, from which the relative timing of activity in response to visual stimuli and behaviour is used to construct a hierarchy scheme that corresponds to anatomical connectivity data.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Using mouse lines in which subsets of neurons are genetically labelled, the authors provide generalized anatomical rules for connections within and between the cortex and thalamus.

The dorsal peduncular area of the mouse brain functions as a network hub that integrates diverse cortical and thalamic inputs to regulate neuroendocrine and autonomic responses.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

This study explores the genetic structure of hepatitis C virus outbreaks in rural U.S communities affected by the opioid crisis. Analysis of intra-host viral populations from 692 participants reveals hidden transmission networks.

ESPRESSO leverages functional information obtained from organelles for deep spatiotemporal phenotyping of single cells.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Clarke et al. presents a framework for spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Applying this approach, they revealed region-specific metabolic diversity and dysregulation in both normal and diseased mouse brains.

The authors present a multicenter database to investigate the neural correlates of dreaming, including physiological, behavioral and experiential data. This database could boost the research on the mechanisms of dreaming in humans and the signatures of consciousness.

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.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

The authors conducted prospective multimodal monitoring of simultaneous brain and heart function to define physiological changes during the human dying process leading to circulatory arrest.

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.

Multiplexed error-robust fluorescence in situ hybridization (MERFISH) together with deep-learning-based nucleus segmentation enabled the construction of a highly detailed and informative spatially resolved single-cell atlas of human fetal cortical development.

Consuming microplastics is known to harm marine wildlife in several ways, but effects on the microbiome are understudied. Here the authors demonstrate that two species of wild seabirds with larger amounts of microplastic in their guts had fewer commensal gut microbial species but more pathogens.

The expression of each of the roughly 22,000 genes of the mouse genome has been mapped, at cellular resolution, across all major structures of the mouse brain, revealing that 80% of all genes appear to be expressed in the brain.

Neural networks fundamentally dictate function. Here, the authors show thirteen uniquely connected neuron populations within the anterior thalamic nuclei, suggesting multiple parallel subnetworks support its emotional and cognitive functions.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

The number of individuals in a given space influences animal interactions and network dynamics. Here the authors identify general rules underlying density dependence in animal networks and reveal some fundamental differences between spatial and social dynamics.

3D brain atlases enable spatial data integration across studies. Here, the authors present the Developmental Mouse Brain Common Coordinate Framework, a 3D multimodal atlas from embryonic to adult ages for cell type mapping through brain development.

Accurate cell type annotation is a major challenge in single-cell and spatial omics. Here, authors present a user-friendly platform providing robust automatic annotation and enhanced biological interpretation of single-cell and spatial populations in health and disease.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Payton et al. develop small-molecule inhibitors of kinesin KIF18A able to selectively kill cancer cells with high chromosomal instability and demonstrate that the inhibitors are therapeutically beneficial in cancer patient-derived in vivo models.

The Type VI Secretory System (T6SS) is used by some bacteria to kill non-kin competitors. Here, McNally and colleagues combine mathematical modelling, experiments withVibrio choleraand phylogenetic analysis to show that by eliminating nearby non-kin the T6SS may also favour cooperation among kin.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

Malaria chemoprevention is used for young children, but resistance mutations raise concerns on efficacy. In this analysis of trials across Africa, the authors show that prevention treatment protects >42 days against susceptible parasites but <12 days against highly resistant strains highlighting the importance of genomic surveillance for chemoprevention strategies.

The authors developed an optimized rabies tracing system for generating brain-wide monosynaptic input connectomes, and applied it in mouse visual cortex to reveal topographically organized subnetworks co-defined by visual areas, layers and cell classes.