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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).

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

Amino-acid sequence comparison and tertiary structure modelling suggest a structure for type I DNA methyltransferases and an evolutionary link to type II DNA methyltransferases.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

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.

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.

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.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Levels of circulating thyrotropin and free thyroxine reflect thyroid function, however, their genetic underpinnings remain poorly understood. Taylor et al. take advantage of whole-genome sequence data from cohorts within the UK10K project to identify novel variants associated with these traits.

Although wireless optogenetic technologies enable brain circuit investigation in freely moving animals, existing devices have limited their full potential, requiring special power setups. Here, the authors report fully implantable optogenetic systems that allow intervention-free wireless charging and controls for operation in any environment.

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

Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3gene strongly associated with plasma triglyceride levels.

Isolated populations often have special genetic compositions that can be leveraged for genetic association studies. Here, Xue and colleagues generate and analyse 3,059 low-depth whole-genome sequences from eight European isolated populations and two matched general populations.

Chan et al. report that 3′ UTR splicing is widespread and enhanced across different cancer types and is associated with more advanced tumour progression.

Combinations of single-stranded DNA repair templates and small molecules markedly enhance genome editing.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.

Batista, Schief and colleagues use a series of germline-targeting immunogens in knock-in mice expressing heavy chain sequences derived from the HIV broadly neutralizing antibody 10E8 to characterize the requirements of 10E8 B cell precursors for entry and maturation in the germinal center.

Understanding the process of exciton fission, which occurs in certain organic materials, could lead to the development of more efficient photovoltaic devices. Here, an expression derived from first principles is used to accurately characterize the singlet fission rate of a wide array of materials, reproducing a transition from weak to strong coupling as a function of molecular separation.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Crystal structures of the CLC^F proton-coupled fluoride antiporter Eca in two conformations capture two rotamers of the gating glutamate and reveal simultaneous accessibility of F^– and H⁺ ions via separate pathways on opposite sides of the membrane.

The prevalence of cardiometabolic diseases (CMDs) is increasing rapidly across Africa. Here, the authors investigate autozygosity in CMD-associated traits in over 10,000 sub-Saharan African individuals, showing these traits are influenced by sex-specific inbreeding depression and environmental interactions.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Manju Kurian and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance. Their findings highlight a clinically recognizable form of dystonia and demonstrate a crucial role for KMT2B in the physiological control of voluntary movement.

Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

The histone H3K36 methyltransferase NSD3, which is associated with the common 8p11–12 chromosomal amplification, is an oncogenic driver in lung squamous cell carcinoma.

Indigenous-led structured decision-making workshops with local Indigenous people on Bundjalung Country in Australia identified and prioritized culturally significant species and determined Bundjalung-led actions for the management of these culturally significant entities.

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations.

Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.

The simultaneous high-pressure and high-temperature phase diagram of two MOFs, ZIF-4 and ZIF-62, is mapped. Crystalline, pressure- and temperature-amorphous, and liquid states are found, while melting temperature is found to decrease with pressure.

Carl Anderson, Jeffrey Barrett and colleagues use whole-genome sequencing and imputation to explore the genetic architecture of inflammatory bowel disease. They identify a low-frequency missense variant in ADCY7 that doubles risk of ulcerative colitis and detect a burden of very rare, damaging missense variants in known Crohn's disease risk genes.

The genome of a western lowland gorilla has been sequenced and analysed, completing the genome sequences of all great ape genera, and providing evidence for parallel accelerated evolution in chimpanzee, gorilla and human lineages at a number of loci.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.