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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.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

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.

Establishing generic carbohydrate sequencing methods is both a major scientific challenge and a strategic priority. Here the authors show a hybrid analytical approach integrating molecular spectroscopy and mass spectrometry to resolve carbohydrate isomerism, anomeric configuration, regiochemistry and stereochemistry.

The intermolecular amination of C–H bonds is an enabling transformation for the synthesis of nitrogen-containing molecules; however, developing catalysts for this class of reactions is very challenging. Now, an iron-based enzyme for this reaction has been engineered, demonstrating that a protein can confer a difficult new function upon an otherwise unreactive base metal.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.

This study employs a citizen science approach to identify and classify over 230,000 light sources in German city centers, suburbs and villages. The results underscore the pivotal role of citizen science in expanding knowledge of artificial light emissions and bolstering policymaking efforts to mitigate urban light pollution.

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Hofmann and colleagues describe the mechanism underlying the therapeutic benefit of combinatorial use of SOS1 and KRAS-G12C inhibitors in the context of KRAS-G12C mutant-driven lung and colorectal cancer.

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.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 (GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.

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

A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.

Schwann cells (SCs) can acquire a repair phenotype following nerve injury. Here, the authors show that stromal SCs in ganglioneuromas express nerve-repair genes. Importantly, neuroblastoma cells respond to repair-related SCs increasing neuronal differentiation and reducing proliferation via EGFL8.

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.

Whole-exome sequencing in a large autism study identifies over 100 autosomal genes that are likely to affect risk for the disorder; these genes, which show unusual evolutionary constraint against mutations, carry de novo loss-of-function mutations in over 5% of autistic subjects and many function in synaptic, transcriptional and chromatin-remodelling pathways.

Discovering disease genes on the X chromosome can be particularly challenging. Here, the authors use features of known disease genes and machine learning to predict genes that remain to be associated with disorders on this chromosome.

Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.

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.

Rauh et al. developed a selective MCL1 inhibitor that is efficacious in hematological and solid tumors and has the advantage of limited cardiotoxicity because of more rapid clearance of the drug in vivo.

Genome-wide ancient DNA data from individuals from the Middle Bronze Age to Iron Age documents large-scale movement of people from the European continent between 1300 and 800 bc that was probably responsible for spreading early Celtic languages to Britain.

The post-transcriptional 5-methylcytosine (m⁵C) modification occurs in a wide range of nuclear-encoded RNAs. Here the authors identify the mitochondrial tRNA-Met as a target for the m⁵C methyltransferase NSun3—found mutated in a mitochondrial disease patient—and link mitochondrial tRNA modifications with energy metabolism.

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.

Anna Köttgen and colleagues report genome-wide association studies for serum urate in over 140,000 individuals from the Global Urate Genetics Consortium (GUGC). They identify 18 loci newly associated with serum urate concentrations and confirm 10 known loci, characterize their associations with gout and include a network analysis suggesting a role for inhibins-activins pathways in regulating urate homeostasis.

Targeting oncogenic ALK activity in neuroblastoma is an attractive therapeutic strategy but success has been limited by resistance to ALK inhibitors. Here, the authors identify loss of miR-1304-5p as a driver of ALK inhibitor resistance via regulation of NRAS, and therapeutically target this axis with the addition of a farnesyltransferase inhibitor in preclinical models of neuroblastoma.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Glioblastoma is a highly aggressive, and also the most common, brain tumour type in adults. Here, the authors generate a nanoparticle encapsulating the TLR7/8 agonist, R848, which induces tumour regression in mice by reprogramming myeloid cells independently of T and NK cells.

Aiming for declining global temperatures can limit long-term climate risks compared with a mere stabilization of global warming, including sea-level rise and cryosphere changes.

This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.

Examination of archaeological pottery residues and modern genes suggest that environmental conditions, subsistence economics and pathogen exposure may explain selection for lactase persistence better than prehistoric consumption of milk.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Understanding the pathology and immunological response to SARS CoV2 infection in specific patient groups is essential for informing the scientific and clinical handling of infections within these patient populations. Here the authors characterise the adaptive immune response to SARS-CoV2 infection in people living with HIV.

Clinical and genetic evaluation of individuals with childhood-onset amyotrophic lateral sclerosis identifies a new monogenic cause for early-onset ALS and proposes a specific metabolic mechanism leading to motor neuron disease via sphingolipid excess.

Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

Analysing a global database of >40,000 tundra plant phenological observations monitored for up to 20 years, the authors show that community-level flowering has been contracting in response to recent warming, in contrast to findings from lower latitudes.

The European X-ray free-electron laser (EuXFEL) in Hamburg is the first XFEL with a megahertz repetition rate. Here the authors present the 2.9 Å structure of the large membrane protein complex Photosystem I from T. elongatus that was determined at the EuXFEL.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Conserved microbiome features across clinical and geographical variations may enable microbiome-based predictions of outcomes in CD19-targeted CAR-T cell immunotherapy

Asian soybean rust caused by Phakopsora pachyrhizi is an important plant pathogen, but an accurate genome assembly for this fungus has been lacking. This study sequenced three independent P. pachyrhizi isolates and generated reference quality assemblies and genome annotations, representing a critical step for further in-depth studies of this pathogen and the development of new methods of control.

Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder, characterized by chronic airway disease. Here, the authors identify mutations in the Multicilin gene, MCIDAS, and suggest that these mutations cause RGMC through disruption of multiciliated cell differentiation.