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A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Leukemia cells resistant to CD123-targeted therapies are susceptible to a trifunctional NK cell engager.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

A study describes the release of clinical-grade whole-genome sequence data for 245,388 diverse participants by the All of Us Research Program and characterizes the properties of the dataset.

Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease.

Applications of laser-plasma accelerated protons in fundamental, applied and medical sciences crucially depend on the creation of stable collimated beams with high repetition rates. Here the authors demonstrate the generation of multi-MeV protons at 5 Hz, with low (degree-level) proton beam divergence from a laser pulse focused onto a water sheet target, potentially mitigating the need for beam capturing techniques.

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

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Many African countries have reported relatively low numbers of COVID-19 cases but the true scale of the epidemic is unclear. Here, the authors conduct a population-based survey in a province of Cameroon and estimate 29% seroprevlance, >300 fold higher than the nationwide attack rate implied by case counts.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Results from the phase 2/3 clinical trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease reveal no beneficial effects on cognitive measures despite a significant reduction in amyloid plaques and other key biomarkers in those treated with gantenerumab.

Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.

Direct in situ high-resolution X-ray radiography and tomography observations now reveal instability and metastability domains in cellular solidification of colloidal suspensions and the transition to the stable phase. These results provide important insight into the study of morphological instabilities and could prove significant in the design of various types of nanostructure.

Multiple transcriptome approaches, including single-cell sequencing, demonstrate that escape from X chromosome inactivation is widespread and occasionally variable between cells, chromosomes, and tissues, resulting in sex-biased expression of at least 60 genes and potentially contributing to sex-specific differences in health and disease.

GATK-gCNV uses a probabilistic model and inference framework to discover rare copy number variants (CNVs) from sequencing read-depth information. This algorithm is used to generate a reference catalog of rare coding CNVs in exome sequencing data from UK Biobank.

Synergistic cancer therapies SMAC mimetic compounds synergize with oncolytic viruses and other innate immune stimuli to promote tumor cell death.

In a new study including 200 families who experienced perinatal death, adding genomic analyses to standard autopsies improved the identification of underlying pathogenic causes and informed genetic counseling.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery.

Autism is a highly heritable neurodevelopmental disorder, and yet few specific susceptibility genes have been identified to date. A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms is now described in a common set of 1,031 multiplex autism families. The linkage regions identified provide targets for rare variation screening whereas the discovery of a single novel association, SEMA5A, demonstrates the action of common variants.

Paul Thompson and colleagues report a genome-wide association study for hippocampal, intracranial and total brain volume. They identify a locus at 12q24 associated with hippocampal volume and a locus at 12q14 associated with intracranial volume.

Immune cell engagers — antibody-based molecules engineered to direct immune effector cells to recognize and kill cancer cells — represent a rapidly expanding approach in cancer therapy. Here, the authors bring us up to date with the targets, challenges and opportunities for harnessing the anticancer activities of T cells, natural killer cells and myeloid cells with immune cell engagers.