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To understand the contribution of variants to transcript expression regulation, long-read transcriptome data are generated from the GTEx resource, and a new software package to perform allele-specific analysis is developed.

This study describes structures of the transcription factor brachyury revealing the mechanism of DNA recognition. They identify fragments using X-ray fragment screening and optimize these into potent ligands with potential as cancer therapeutics.

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.

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.

Some cancer cells that become tolerant to a drug remain resistant even after its withdrawal, yet these cells eventually become sensitive to the drug again. The underlying molecular mechanism is unusual.

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.

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-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.

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

Chemical probes are urgently needed to functionally annotate hitherto-untargeted kinases and stimulate new drug discovery efforts to address unmet medical needs. The size of the human kinome combined with the high cost associated with probe generation severely limits access to new probes. We propose a large-scale public-private partnership as a new approach that offers economies of scale, minimized redundancy and sharing of risk and cost.

Genome-wide analyses of ancient DNA from individuals from California and Mexico shed light on the spread of Mexican ancestry to California and how it correlates with linguistic flow.

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.

RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.

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.

Joint analysis of new and previously published sequencing data for primary and metastatic prostate cancers identifies new candidate driver mutations and provides insights into disease progression and potential drug targets.

The safety and efficacy of ribonucleoproteins for genome editing can be enhanced by formulations of lipid nanoparticles optimized for enhanced stability, delivery efficiency and editing potency of the protein complexes.

The protein Hsp90 is a target of promising anticancer drugs. An analysis of the components of Hsp90 complexes in tumours reveals a path that may lead to predictive assays of drug sensitivity in cancer patients.

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.

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.

ATP-competitive inhibitors compete with the Hsp90 cochaperone Cdc37 for the ATP site in kinases, depriving kinases of access to protein quality control machinery and promoting their degradation. Thus, in addition to inhibiting the catalytic activity of kinases, ATP-competitive inhibitors can reduce the number of active kinases in a cell by promoting their degradation.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Directly sequencing RNA strands through a nanopore retains the full length of the transcript and allows for analysis of polyA tail length, transcript haplotypes and base modifications.

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.

Analysis of ancient human DNA from the Swahili coast reveals that predominantly African female ancestors and Asian male ancestors formed families after around ad 1000 and lived in elite communities in coastal stone towns.

A large-scale study sheds light on the extraordinary molecular-recognition skills of the chaperone HSP90, which allow this protein to interact selectively with hundreds of other proteins of diverse function.

Chemical probes reveal Hsp90 to be a key molecule for the control of apoptosis in small-cell lung cancer—with important implications for Hsp90 biology and cancer treatment.

Phosphoinositide 3-OH kinases (PI(3)Ks) are important lipid signaling enzymes and exciting drug targets for a number of human diseases. The first, much anticipated crystal structure of the delta isoform of PI(3)K provides surprising new insights into the selectivity of inhibitors for this versus other PI(3)K isoforms and facilitates the design of improved drugs.

Chemoproteomic studies have revealed that a Wnt-pathway inhibitor, CCT251545, is a potent and selective small-molecule chemical probe that inhibits the Mediator complex–associated protein kinases CDK8 and CDK19 through a type 1 binding mode and modulates the growth of Wnt-dependent tumors.

Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.

Two studies highlight the role of the heat shock response in initiating and maintaining cancer.

A recent landmark analysis compared genome-wide mutations and associated 'omics' features for 3,281 tumours across 12 human cancer types. There is a clear need for objective target assessment and prioritization by the drug discovery community to make the best use of such vast amounts of data.

A combination of chemical and genetic approaches has established a proof of concept in mouse models—with strong mechanistic underpinning—indicating that targeting the aberrantly recruited histone methyltransferase activity of DOT1L has therapeutic potential in aggressive leukemias driven by MLL fusion genes.