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The genome of the gibbon, a tree-dwelling ape from Asia positioned between Old World monkeys and the great apes, is presented, providing insights into the evolutionary history of gibbon species and their accelerated karyotypes, as well as evidence for selection of genes such as those for forelimb development and connective tissue that may be important for locomotion through trees.

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).

An analysis of genomic, molecular and neuroanatomical traits across extant primates reveals early divergence in visual and olfactory systems of major primate lineages consistent with lineage-specific shifts in diel activity and dietary niche, providing support for a sensory ‘reallocation’ hypothesis.

A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

Tigers are an endangered species and therefore understanding their genetic architecture could aid conservation efforts. Here, the authors report the first genome sequence of the Amur tiger and, through close species comparative genomic analysis, provide insight into the genome organization, evolutionary divergence and diversity of big cats.

GDF8 and activin A are the dominant negative regulators of muscle mass in animal models. This two-part, randomized, placebo-controlled Phase 1 trial suggests that GDF8 and activin A are also the dominant negative regulators of muscle mass in humans.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Here the authors identify upstream open reading frames (uORFs), uORF1 and uORF2 in the Asian/American lineage and African uORF in the African lineage of Zika viruses, and show that uORF1 affects vimentin filaments and that the identified uORFs affect virus replication in neural cells.

The chromatin remodeling complex ATRX can promote gene expression, for example by binding G-quadruplexes (G4s) to prevent their negative effect on expression. Here the authors use a single-cell approach to show that only a subset of erythroid cells isolated from patients with ATRX mutations have reduced chromatin accessibility and alpha globin expression, suggesting a stochastic process.

As phase 1 of the Earth Microbiome Project, analysis of 16S ribosomal RNA sequences from more than 27,000 environmental samples delivers a global picture of the basic structure and drivers of microbial distribution.

Granulomatous/sarcoid-like lesions have been reported in patients treated with immune checkpoint inhibitors (ICIs). Here the authors report the occurrence of “nodal immune flare”, an apparent radiological cancer progression in the nodes characterized by the absence of cancer and the presence of non-caseating granulomas, in patients with non-small cell lung cancer following neoadjuvant ICI treatment.

ATRX, a chromatin remodelling factor, is mutated in cancers that maintain telomere length by alternative lengthening of telomeres (ALT). Here, the authors show that ectopic expression of ATRX triggers telomere shortening, ALT suppression and reduced replication fork stalling.

Tumour-infiltrating lymphocytes (TILs) can be suppressed by the tumour, but how this occurs is not clear. Here the authors show that the miR-200 family, which suppresses epithelial–mesenchymal transition, also targets tumour cell PD-L1 and thereby intratumoral immunosuppression and metastasis.

Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

The molecular determinants of lung cancer histologic subtypes are not well understood. Here the authors analyze lung cancers of mixed histology and find that histologic subtypes are associated with transcriptomic features rather than genomic profiles in most tumors.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.

The combination of neoadjuvant nivolumab, ipilimumab and chemotherapy showed promising efficacy in patients with resectable non-small cell lung cancer, with higher tumor immune cell infiltration and tertiary lymphoid structures after treatment compared with neoadjuvant nivolumab plus chemotherapy.

Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.

As techniques to sequence and map genomes and chromosomes improve, we should be able to learn more about our evolutionary history and what the genomes of our ancestors might have looked like. Three studies illustrate the potential of these approaches, comparing the genomes of 15 primate species with those of species from four non-primate orders to try and work out which are the ancestral mammalian genes.

Peter Donnelly and colleagues report a genome-wide association study for Barrett's esophagus, a common premalignant condition associated with stomach acid reflux and predisposing to esophageal adenocarcinoma. They identify two loci associated with susceptibility to Barrett's esophagus.

High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

George, Ellis et al. develop an explainable artificial intelligence model to predict 30-day emergency department admission in patients with cancer undergoing treatment. The authors describe an approach to monitor the model after deployment, which provides ongoing readouts of data consistency and model behavior.

Douglas Higgs and colleagues report a high-throughput approach, called Capture-C, to analyze interactions between cis regulatory elements. Using Capture-C, the authors interrogated hundreds of specific interactions at high resolution in a single experiment.

Claire Patterson et al. present the design and development of AZD0466, a drug-dendrimer conjugate, and use preclinical and mathematical models to determine the optimal release rate of the drug from the dendrimer carrier for maximal therapeutic index in terms of anti-tumour efficacy and cardiovascular tolerability. This study identifies this promising dual Bcl-2/Bcl-x_L inhibitor for progression to clinical development.