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Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.

In this immunological ancillary study of the PREVAC trial, the authors show that approved Ebola virus vaccines induce memory T-cell responses that persist during the five year follow-up after initial vaccination.

Luis Pérez-Jurado, Stephen Chanock and colleagues detect clonal chromosomal abnormalities in peripheral blood or buccal samples from individuals in the general population. They show that the frequency of such events increases with age and is associated with elevated risk of developing subsequent hematological cancers.

Ganguli et al. show that CDKN2A loss in Barrett’s esophagus prevents esophageal adenocarcinoma initiation by counterselecting subsequent TP53 loss and report context-dependent effects of 9p21 gene co-deletions on disease progression.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.

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.

A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

The NLRP3 inflammasome is primarily known for producing inflammatory cytokines and inducing pyroptosis. Stuart and colleagues identify an additional role for NLRP3 in driving down the pH of phagosomes.

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.

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.

Soils combat climate change by storing carbon but lose considerable amounts of carbon into downstream waters. Here a general process for how microbes transform carbon across soil-to-stream to impact its persistence in the natural environment is demonstrated.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

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.

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.

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.

Analyses of real-world evidence from digital clinical practice data provide important insights for healthcare decision makers. Here, authors test reproducibility of 150 peer-reviewed studies, reporting strong reproducibility, which could be further improved through more complete reporting in future original studies

Hyper-IgE syndrome is an autosomal dominant immunodeficiency that has been linked to mutations in stat3. This paper shows that stat3 mutant subjects fail to generate T_H17 cells, which may account for their susceptibility to recurrent infections.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

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.

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.

Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.

A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types.

Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.

The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

A multi-ancestry genome-wide association study of prostate cancer performed in 156,319 cases and 788,443 controls identifies 187 novel risk variants associated with the disease. Genetic risk scores associated with overall risk, and risk of aggressive disease in men of African ancestry.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

The largest whole-exome sequencing study of sporadic congenital hydrocephalus identities mutations associated with disrupted fetal neuro-gliogenesis as the primary pathophysiological event in a significant number of cases.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

Single-cell- and metagenomics-based study reveals two members of the candidate genus ‘Entotheonella’, symbionts of the marine sponge Theonella swinhoei; distinct biosynthetic gene clusters that account for most of the bioactive polyketides and peptides known from T. swinhoei are shown to be attributable to a single member of the T. swinhoei Y microbiome.

Jaako et al. discover a conserved tier of translational control that dynamically couples ribosome assembly and recycling. This mechanism is corrupted in an inherited bone marrow failure disorder associated with an increased risk of blood cancer.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

A consortium reports the tripling of the number of genetic markers in Phase II of the International HapMap Project. This map of human genetic variation will continue to revolutionize discovery of susceptibility loci in common genetic diseases, and study of genes under selection in humans.

Vivianna Van Deerlin and colleagues report that common variants at 7p21 are associated with a subtype of frontotemporal lobar degeneration marked by TDP-43 inclusions. They further show that the risk alleles are associated with elevated brain expression of TMEM106B, which resides at the peak of association on 7p21.

Autophagy, which is believed to be an Atg7- and Atg3-dependent process, is known to be involved in animal development. Baehrecke and colleagues show that autophagy drives the controlled degradation of the developing Drosophila midgut. Interestingly, this process is Atg7- and Atg3-independent, and instead requires the E1-activating enzyme Uba1 for programmed reduction of cell size in the midgut.