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Holt et al. describe an anti-HIV strategy in which human hematopoietic stem/progenitor cells are modified with zinc-finger nucleases to knock out the viral co-receptor CCR5. Transplantation of these cells into mice confers resistance to HIV, as shown by higher human T-cell counts and lower viral loads compared with animals that received unmodified cells.

Mutations in ATP8b1 are found in certain individuals susceptible to pneumonia. Ray et al. now report that bacterial pneumonia is associated with elevated levels of the phospholipid cardiolipin in airway fluids, that ATP8b1 is a cardiolipin importer and that excessive cardiolipin in the lung contributes to impaired lung function. The findings suggest that ATP8b1 might be a new therapeutic target for the treatment of pneumonia.

Genome-wide data from ancient and modern individuals in Remote Oceania indicate population replacement but language continuity over the past 2,500 years. Papuan migrations led to almost complete genetic replacement of in situ East Asian-derived populations, but not replacement of Austronesian languages.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Joyce, Pascual et al. identify luminal progenitors as likely cells-of-origin in BRCA2-mutant breast cancer, exhibiting dysregulated proteostasis and translation, which may be therapeutically targeted via mTORC1 inhibition.

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.

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.

Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy.

The global genetic diversity of cassava and related Manihot species is revealed by sequencing of 53 cultivated and wild accessions and genotyping of 268 African cassavas, providing a vital resource for breeding.

To date, treatment strategies for heart failure have focused on the symptomatic stage of disease, often after irreversible remodeling and functional impairment have occurred. Early identification of cardiac dysfunction would allow implementation of early intervention strategies to delay the progression or to prevent the onset of heart failure altogether. This Review highlights the utility of a staged approach for patients with predisposing risk factors, which uses serological biomarkers followed by noninvasive imaging techniques.

M-current is conveyed by voltage-sensitive KCNQ channels, which are enriched in GABAergic neurons and are activated by anticonvulsants such as retigabine. Here the authors show that GABA directly activates KCNQ3, at the residue required for its anticonvulsant activity.

Bracher et al. compare 15 forecasting models of COVID-19 cases and deaths in Germany and Poland between January and mid-April 2021. Many, though not all, models outperform a simple baseline model up to four weeks ahead, with ensemble methods showing very good relative performance.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

We present a protocol for long-term intravital imaging of mouse mammary tissue while maintaining tissue access using a skin flap and an imaging chamber. Strategies are provided for single-cell imaging, photomanipulation and multiplexed analysis.

Aberrant increased dopaminergic function results in impaired value-based decision making. Here the authors report pathway-specific effects of VTA activation on distinct aspects of flexible value-based decisions in rats.

Ubiquitylation of H2B is associated with transcription and regulation of chromatin structure. Here, the authors perform an unbiased screen to identify the role of chromatin modifications on ubiquitylation of H2BK120 and characterize the crosstalk between H2BK120ub and H2A modifications and variants.

Richard Gilbertson and colleagues report an in vivo screen of 84 candidate oncogenes and 39 candidate tumor-suppressor genes in ependymoma mouse models. The validated targets are involved in vesicle trafficking, DNA modification and cholesterol biosynthesis.

Linda Holmfeldt, Lei Wei et al. report whole-genome and exome sequencing of 40 childhood hypodiploid acute lymphoblastic leukemias.

Combining the kinase inhibitor sorafenib with allogeneic stem cell transplantation boosts immune responses against a subtype of acute myelogenous leukemia, suggesting potential clinical benefit.

The APOE4 allele is the leading risk factor for late-onset Alzheimer’s disease, but how it might contribute to the disease is not clear. Here the authors show that a mouse expressing the human APOE4 allele displays hyperactivity in the entorhinal cortex due to a decreased inhibitory tone, which may in part explain accelerated Alzheimer’s pathology in APOE4 carriers.

Studies of honest signaling have found an inconsistent relationship between carotenoid coloration and individual quality. Here, Weaver et al. compare dietary and biochemically converted carotenoid coloration using meta-analyses and show that converted carotenoids drive relationships with quality measures.

IL-7R activation drives early B cell development, but the signalling is unclear. Here the authors show PLCγ is involved in IL-7R-induced mTOR activation via a DAG/PKC-dependent pathway, and that double deficiency of the two PLCγ isoforms arrests B cell development at the pre-pro-B stage in mice.

Munji et al. analyzed the transcriptomes of endothelial cells from multiple organs and in neural tissue of neurological disease models. They identified a blood–brain barrier dysfunction module in seizure, multiple sclerosis, stroke and brain trauma.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

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.

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

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

This Resource presents an atlas classifying the age-related changes in human hematopoietic stem and progenitor cells from gestation through aging.

A machine learning model that uses longitudinal ctDNA metrics robustly predicts survival in two phase 3 trials of patients with metastatic NSCLC, which may improve therapy selection and risk stratification.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Tumour hypoxia reduces the efficacy of radiotherapy. Starting from a drug screen, here the authors demonstrate that the anti-malarial, atovaquone, reduces the oxygen consumption rate of cancer cells by inhibition of mitochondrial complex III and sensitises to radiotherapy by reducing tumour hypoxia.

The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process.

During transformation via Agrobacterium tumefaciens, sequence composition of T-DNA (that is, DNA repeats) affects T-DNA concatenation in Arabidopsis. In addition, loss of specific DNA repair proteins dramatically decreases T-DNA concatenation levels. This study showcases the potential of T-DNA concatenation as a tool to enhance gene editing.

Branconi et al. report on an experimental approach to investigate the ecological and social drivers of cooperative breeding in clownfish. Experiments were performed on a wild population in Papua New Guinea and indicate that clownfish non-breeding strategies can be understood using economic bargaining theory and cooperative breeding theory.

Sequencing the nuclear genomes of Guillardia theta and Bigelowiella natans, transitional forms in the endosymbiotic acquisition of photosynthesis by engulfment of certain eukaryotic algae, reveals unprecedented alternative splicing for a single-celled organism (B. natans) and extensive genetic and biochemical mosaicism, shedding light on why nucleomorphs persist in these species but not other algae.

VAMP7 is a SNARE protein involved in the fusion of endosomes and lysosomes with various cellular membranes. The longin domain of VAMP7 forms autoinhibitory interactions that prevent VAMP7 SNARE assembly. New structural and functional data reveal how the regulatory protein Varp, a known VAMP7 binding partner, kinetically inhibits SNARE complex formation.

Robert Graham and colleagues carried out a GWAS meta-analysis for Parkinson's disease (PD) and report 17 new risk loci. Their analyses support a key role for autophagy and lysosomal biology in PD risk.