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Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

The Omicron variant is partially attenuated, likely because it fails to efficiently infect lung cells. Here, Hoffmann et. al. show that this defect can be lost during Omicron evolution as demonstrated for the subvariant BA.5 that robustly infects lung cells in vitro and in vivo.

Here, in a longitudinal case study, Weigang et al. demonstrate that evolution of SARS-CoV-2 within a persistently infected immunosuppressed patient can result in the emergence of novel variants with reduced sensitivity to antibody neutralization.

Human transplantation with allogeneic donor organs results in non-matching of MHC and differential presentation of T cell antigens. Here the authors show that in a lung transplanted SARS-CoV-2 infected patient T cell responses generated from the host may not be able to recognise infected cells within the graft and this may contribute to virus persistence.

Late-stage functionalization of complex drug molecules is challenging. To address this problem, a discovery platform based on geometric deep learning and high-throughput experimentation was developed. The computational model predicts binary reaction outcome, reaction yield and regioselectivity with low error margins, enabling the functionalization of complex molecules without de novo synthesis.

NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Antibodies against SARS-CoV-2 can be used to treat infections but there is a risk of driving viral resistance to antibodies. Here the authors characterise SARS-CoV-2 escape mutants from an immunocompromised patient treated with anti-SARS-CoV-2 antibodies using mouse protection studies and structural prediction.

In situ cryoEM and modelling of the Campylobacter jejuni flagellar motor characterize the periplasmic scaffold and the structural basis for increased torque generation.

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.

Expression of TMPRSS2—a protease that activates SARS-CoV-2 for entry into cells—renders SARS-CoV-2 insensitive to chloroquine.

The A.27 SARS-CoV-2 lineage spread globally in 2021 but did not become dominant. Here, the authors show that A.27 shares some mutations in the spike gene that are present in variants of concern, but lacks the D614G mutation, indicating independent evolution of immune escape properties.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

Vaccines against SARS-CoV-2 have changed the course of the COVID-19 pandemics, but waning immunity necessitates repeated immunization. Authors here show that immunity declines faster following two doses of vector-based vaccine compared to a first dose of vector-based vaccine followed by boosting with an mRNA vaccine, but application of an mRNA vaccine as a third dose minimises the difference between the two groups.

Patients with different small round cell sarcoma (SRCS) often receive the same treatment regimen but for some SRCS subtypes, response to chemotherapy is poor and targeted treatment options are limited. Here, the authors establish a biobank of paediatric patient-derived SRCS tumoroids and perform drug screening, identifying MCL inhibition as a potential therapeutic strategy in CIC::DUX4 sarcomas.

SARS-CoV-2 Omicron lineage BA.2.86 has over 30 mutations compared to the parental BA.2 lineage. Here Bdeir and colleagues apply reverse mutational scanning to determine which among these mutations present in Omicron BA.2.86 are epitopes linked to immune escape from antibody recognition.

The function of DNMT1 (DNA methyltransferase 1) in these subsets of immature, migrating cortical inhibitory interneurons is not fully understood. This study shows that DNMT1 regulates cortical development by orchestrating the migration of postmitotic SST+ interneurons and their signaling to cortical progenitors, with implications for proper cortical architecture and function.

In a large single-arm phase 2 trial, the anti-PD-1 inhibitor tislelizumab combined with the next-generation BTK inhibitor zanubrutinib had an overall response rate of 58.3% and was well tolerated in patients with Richter’s transformation.

Medulloblastoma in children is a difficult cancer to treat and the immune response to this tumour is not fully understood. Here the authors characterise and validate T cell epitopes from these cancers using an immunopeptidomics approach, comparing different molecular subtypes.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Bernhard Radlwimmer and colleagues report whole-genome bisulfite sequencing of 13 Burkitt lymphomas and nine follicular lymphomas. They find that both types of germinal center B cell lymphomas show global hypomethylation compared to normal germinal center B cell precursors and identify regions of differential methylation that correlate with somatic mutations and differential gene expression.

Chromosomal instability (CIN) is a common feature of colorectal cancer cells and several mechanisms have been suggested for CIN generation. Bastians and colleagues find that increased microtubule plus-end stability can be triggered by AURKA overexpression and is associated with abnormal spindles and lagging chromosomes in colorectal cancer cells.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Microdeletions of chromosome 16p11.2 can cause autism, but the pathogenic mechanisms remain unclear. Here the authors show that in a 16p11.2 mouse model, mGluR5 synaptic plasticity and protein synthesis are altered and that a modulator of mGluR5 reverses the cognitive deficits.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

A base-editing approach optimized to target the retina shows high editing rates in a mouse model of Stargardt disease, as well as in nonhuman primates and ex vivo human retinal explants, paving the way for potential clinical applications.

Taniguchi et al. structurally analyse nuclear pore complex architecture in situ during differentiation, which is associated with mechanical constraints on the nuclear envelope. They link nuclear pore complex elasticity to nuclear envelope integrity in differentiation.

Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.