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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.

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.

Petrels are wide-ranging, highly threatened seabirds that often ingest plastic. This study used tracking data for 7,137 petrels of 77 species to map global exposure risk and compare regions, species, and populations. The results show higher exposure risk for threatened species and stress the need for international cooperation to tackle marine litter.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Germinal centers are typically divided into dark and light zones. Clark and colleagues identify ‘gray zone’ cyclin B1⁺ B cell clusters as sites of ongoing cell proliferation, and these cells are distinct from dark zone B cells that undergo AID-dependent somatic hypermutation. This separation of function safeguards B cells undergoing DNA replication against potential mutagenic events that could result in neoplastic transformation.

Zinc finger design is facilitated with a deep-learning model.

Designing improved catalysts is predicated on understanding how they work. Now, by positioning three ruthenium centres in a macrocyclic framework, a remarkable acceleration of catalytic water oxidation has been achieved. Detailed mechanistic studies revealed that the catalyst operates through the ‘water nucleophilic attack’ pathway—similar to the natural oxygen-evolving cluster of photosystem II.

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.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

While the two individual half-reactions involved in visible-light-driven water splitting are well studied, producing H₂ and O₂ simultaneously on a single particle remains challenging. Here, the authors achieve this by decorating CdS nanorods with both Pt nanoparticles and molecular Ru complexes to catalyse the evolution of H₂ and O₂, respectively.

How signals through the pre–B cell antigen receptor (pre-BCR) and IL-7 receptor (IL-7R) coordinate population expansion of pre-B cells with subsequent recombination of the immunoglobulin κ-chain locus is unclear. Clark and colleagues show that pre-BCR signaling via the Ras-MEK-Erk pathway poises pre–B cells to undergo differentiation after escaping IL-7R signaling.

Herpes simplex viruses cause a variety of diseases, from cold sores to encephalitis. Here, Martinez-Martin et al. show that the viral protein gG binds to cell surface glycosaminoglycans and induces chemokine receptor clustering, enhancing chemokine function and thus modulating the immune response.

Mandal and colleagues report how the chromatin modulator BRWD1 mediates extensive changes in 3D chromatin topology during B cell development by converting static to dynamic cohesin.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Here it is shown that telomere dysfunction drives metabolic and mitochondrial compromise. Mice with dysfunctional telomeres activate p53, which in turn represses PGC-1α and PGC-1β, master regulators of metabolic and mitochondrial processes. This results in reduced mitochondrial mass, mitochondrial dysfunction and reduced ATP generation, impaired gluconeogenesis, cariomyopathy and increased reactive oxygen species. This telomere–p53–PGC pathway shows how telomere dysfunction may compromise organ function and contribute to age-related disorders.

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.

V(D)J recombination is developmentally regulated and occurs at restricted sites within the genome. Clark and colleagues show that the histone reader BRWD1 is required for precise positioning of nucleosomes and targeting of RAG recombinase proteins within the Igk locus.

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.

Aromatic amino acids in proteins support ligand binding and protein stability. To parse the physiocochemical roles of aromatic interactions, here Galles, Infield and co-authors identify pyrrolysine-based aminoacyl-tRNA synthetases that enable the encoding of fluorinated phenylalanine amino acids.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

The transcription factor STAT5 commonly activates gene transcription. Clark and colleagues show that tetrameric STAT5, induced by high concentrations of interleukin 7, can repress gene expression by recruitment of the histone methyltransferase Ezh2.

Savage and colleagues identify a population of CD4⁺ T cells within the endogenous repertoire that exhibit hallmarks of overt self-reactivity, spontaneously adopt a follicular helper T cell phenotype and are enriched in non-lymphoid organs following sustained T_reg cell depletion.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

In a cross-cultural study of eight diverse societies, House et al. provide evidence that links societal variation in prosociality to the development of a universal psychology for responding to social norms.

Pre-B cells undergo a transition checkpoint needed for developmental progression. Mandal and colleagues show that the CXCL12–CXCR4 signaling axis orchestrates late B cell lymphopoiesis by suppressing Myc and cyclin D genes and promoting Rag-mediated recombination of immunoglobulin light-chain genes.

Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.

B-1a B cells are innate-like cells with biased reactivity to bacteria and self-antigens. Here the authors show that reduced interleukin-7 in developing fetal liver-derived pro-B cells induces premature immunoglobulin κ rearrangement, alleviating the requirement for a pre-BCR selection stage and allowing the generation of autoreactive B1-a B cells.

The neural mechanisms underlying the beneficial effects of behavioural training in combination with transcranial direct current stimulation (tDCS) are not well understood. Here, the authors combine cognitive training with tDCS, showing a modulation of prefrontal white and grey matter microstructure, and increased prefrontal functional connectivity.

Intrarenal B cells are indicative of poor prognosis in human renal allografts. Here the authors use single cell RNA sequencing to examine how intrarenal B cells contribute to renal rejection and find a population of innate B cells reactive to renal-specific or inflammation-associated antigens.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

It remains difficult to distinguish cognate APC–T cell interactions in human tissue sections. Clark and colleagues have developed an imaging–machine-learning pipeline that uses deep convolutional and tuned neural networks to identify the combination of distance and cell-shape features that can discriminate between bystander human APC–T cell interactions and cognate interactions in situ.

Combining parallel genome-wide association studies from both host plant (Arabidopsis thaliana) and insect herbivore (Pieris rapae) perspectives, plus a comparative analysis across diverse butterfly/plant systems, the authors identify core genes involved in herbivory.

Clinicians face a rapidly evolving set of challenges and opportunities for generating insights into the health of patients from microbiome analysis. Here, the authors summarize the major decision points confronting new entrants to the field or for those designing new projects in microbiome research.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Despite their extensive use, the absolute dating of tree-ring chronologies has not hitherto been independently validated at the global scale. Here, the identification of distinct ¹⁴C excursions in 484 individual tree rings, enable the authors to confirm the dating of 44 dendrochronologies from five continents.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

1000 Genomes imputation can increase the power of genome-wide association studies to detect genetic variants associated with human traits and diseases. Here, the authors develop a method to integrate and analyse low-coverage sequence data and SNP array data, and show that it improves imputation performance.

A hallmark of systemic lupus erythematosus is the production of type I interferons in response to immunocomplexes containing self DNA from dead cells and DNA-specific IgG. Sanjuan and colleagues find that IgE specific for self DNA also exacerbates this disease.