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Polygenic scores aggregate the effects of common genetic variants and have been shown to underly certain rare diseases. Here, the authors conduct a large-scale association analysis of rare disease phenotypes and open-source polygenic scores and apply this information to rare variant interpretation and disease gene discovery

A trail-blazing astronomer, a climate revolutionary and a transplant pioneer are some of the people behind this year’s big stories.

Hybridization is an important evolutionary process. Here, the authors study isolated populations of the hybrid Italian sparrow and identify several novel and fully functional hybrid genomic combinations that arose independently in different islands.

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

The authors present a multiomics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits in Hispanic/Latino populations. They demonstrate how integrating GWAS with omics characterization can advance precision medicine.

Yersinia pestis, the causative agent of plague, is endemic in certain regions due to a stable transmission cycle between rodents and their fleas. Here, Pauling et al. provide evidence for vertical transmission of plague bacteria in fleas, from adults to eggs and through all subsequent life stages, suggesting this might contribute to Y. pestis persistence in the environment without plague activity in mammals.

Synaptic connections are critical for brain function but are hard to measure systematically. Here, authors present a method which uses rabies virus barcoding and single-cell RNAseq to parallelize monosynaptic network reconstruction from molecularly-profiled single cells.

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.

Emerging treatments for achondroplasia pose difficult choices for parents. Proponents say they are changing lives. Others fear they will feed stigma and erase identity.

Here, the authors ask how much regulatory activity DNA is expected to have in the absence of selection. In yeast and humans, they find that gene regulatory activity is common in evolutionarily naive DNA, suggesting that activity is not always indicative of function.

A proximity-dependent biotinylation technique defines the ___location of more than 4,000 proteins in a human cell, and almost 36,000 proximal interactions between proteins, including those at the interface of the mitochondria and ER.

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.

Prospective evaluation of a machine learning-based early warning system for sepsis, deployed at five hospitals, showed that healthcare providers interacted with the system at a high rate and that this interaction was associated with faster antibiotic ordering.

DNA methylation is an epigenetic mark involved in gene regulation. Here the authors investigate the extent to which genetics, sex and pregnancy influence genomic DNA methylation in mice, providing evidence of the stability of CpG methylation across generation and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.

In this prospective cohort study of Syrian refugee children living in Lebanon, authors identified that daily exposure to stressors was the factor most strongly associated with children’s mental health problems.

ABD957 is a potent and selective inhibitor of the ABHD17 family of depalmitoylases that disrupts N-Ras signaling in human acute myeloid leukemia cells and can synergize with MEK inhibition.

The ovarian tumour protease (OTU) family of deubiquitinating enzymes (DUBs) are biochemically well-characterised and of therapeutic interest, however, only a few tool compounds exist to study their cellular function and therapeutic potential. Here, the authors present a chemoproteomics fragment screening platform for identifying DUB-specific hit matter, which combines activity-based protein profiling with high-throughput optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs, and identify an enantioselective chloroacetamide-based covalent fragment for OTUD7B.

Soil macroporosity responds rapidly to climate variations and may induce wide-ranging changes in soil hydraulic conductivity by the end of the century.

Shoop et al. develop mitoARCUS, a mitochondria-targeted nuclease with high specificity, to correct a relatively common pathogenic mtDNA mutation, allowing for beneficial shifts in heteroplasmy while reducing nuclear off-target gene editing.

The hyper-arid climate of modern East Antarctica only arose in the late Miocene, millions of years after the interval of rapid ice-sheet expansion, according to meteoric beryllium-10 concentrations within the permafrost.

The analysis of essential genes in pathogens can be used to discover potential antimicrobial targets. Here, the authors use a machine learning model and chemogenomic analyses to generate genome-wide gene essentiality predictions for the fungal pathogen Candida albicans, define the function of three uncharacterized essential genes, and identify the target of a new antifungal compound.

Primary tumor presence and progression shape the systemic immune landscape and immune responses to pathogens in multiple murine tumor models.

A PROTAC termed P4B targeting BRAF V600E mutant has been developed, which displays enhanced inhibitory function in cell lines carrying BRAF mutations that impart resistance to conventional BRAF inhibitors.

Aregger et al. provide an approach to study genetic interactions in mammalian cells and describe genetic interaction maps that characterize genes involved in lipid metabolism. They identify the role of C12orf49, a previously uncharacterized gene, in regulating lipid uptake in human cells.

Scores of genes are implicated in obesity, but they cannot account for a family's predisposition to obesity. Are there other ways parents can influence their children?

Engineered switchgrass and poplar are better feedstocks for biofuel synthesis and yield more biomass in multi-year field trials.

In this study, Wits and Stanford researchers use short- and long-read DNA sequencing to profile the gut microbiome of women living in rural and urban South Africa and identify transitional composition, high inter-individual diversity, and many undescribed taxa.

A genome-wide association study for five cognitive phenotypes in a rural South African community suggests several variants associated with general cognition and ___domain-specific cognitive pathways in this cohort.

A review of computational tools for mapping networks from in vitro neuron morphology, facilitating topological analysis of cell organization.