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3-Hydroxypropionic acid (3HP) is a top Department of Energy value-added chemical and precursor to bioplastics, yet cost-effective microbial bioproduction remains elusive. Here the authors establish efficient 3HP production in an acid tolerant yeast and validate its financially viability.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

This study shows that Alteromonas is a key driver of phosphorus recycling in the ocean and that its alkaline phosphatases are multifunctional—with different families coexisting in one genome by adopting distinct functions and secretion strategies.

Li et al. reveal projection neuron-type-specific dynamics that coordinate corticothalamic communication during reach-to-consume behavior in mice.

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.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Here, the authors report an exome-wide association study for multi-organ imaging traits by leveraging recent bioinformatic tools such as AlphaMissense. The identified signals elucidate the genetic effects from rare variants on human organs and their connections to complex diseases

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.

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Brain structural traits are highly heritable and have been linked to disease. Here the authors have used gene expression data to perform a transcriptome-wide association study on 211 brain structural traits, discovering 273 associated genes.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Solubility prediction is a longstanding challenge in the chemical sciences. Here, authors use deep learning to predict organic solubility and extrapolate to new solutes with accuracy approaching the limit of experimental variability.

_{Household survey data is vital to health and development. The study describes and maps data quality in 35 African countries, finding that data quality varies and worsens with distance from towns, indicating a need for investment in data collection.}

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.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

The traditional structural transformation narrative emphasizes intersectoral labour reallocation out of agriculture. This study presents ten stylized facts about how employment and compensation evolve within agrifood value chains amid structural transformation, offering insights into post-farmgate dynamics and gender pay inequality.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

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.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

The study introduces scFFPE-ATAC, a high-throughput single-cell chromatin accessibility profiling method enabling profiling from clinically archived formalin-fixed paraffin-embedded (FFPE) tissues, unlocking retrospective epigenetic insights across cancer and human diseases.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

The molecular basis for the enrollment of X family DNA polymerases in non-homologous end joining (NHEJ) is unclear. Here the authors elucidate the structure of Pol λ within the DNA-PK long-range complex and Pol μ in association with Ku70/80 and characterize the interaction between the BRCT domains of Pol λ and μ with Ku70/80.

Rechargeable zinc batteries are hindered by sluggish ion transport and unstable interfaces. Here, the authors design a zwitterionic gel-ligand-channel where molecular crowding promotes ion liberation, enabling fast ion migration and interfacial kinetics even at −60 °C.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The high-quality T2T genome serves provides a resource, revealing the evolutionary link between olfactory receptor genes and head shape adaptation in Neijiang pigs.

A large perturbation model that integrates diverse laboratory experiments is presented to predict biological responses to chemical or genetic perturbations and support various biological discovery tasks.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo.

Fixation of CO₂ in organic molecules is an area of great interest due to the implications in sustainable chemistry. Here, the authors show a visible light-mediated hydrocarboxylation of ketimines with atmospheric CO₂ to afford a number of α,α–diaryl α-amino acid derivatives.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

FAN1 is a structure-specific nuclease that plays a major role in eliminating highly cytotoxic interstrand DNA crosslinks. Here, Zhao et al. present several crystal structures of FAN1 in complex with DNA substrates and biochemical analyses that establish how FAN1 functions to resolve interstrand DNA crosslinks.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.