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A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

A genome-wide association study highlights a variant in DOCK2, which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Here, the authors perform cross-trait analyses of respiratory and cardiometabolic diseases, rheumatoid arthritis, and smoking and identify negative genetic correlations between respiratory and cardiometabolic diseases in individuals of East Asian ancestry, in opposition from the positive association in European ancestry individuals.

Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

Using biobank data from over 250,000 participants, the authors present a detailed picture of regional and individual variation in the tripartite ancestral structure of modern Japanese populations and demonstrate its impact on elevated body mass index.

Seishi Ogawa and colleagues report the results of a large-scale sequencing study of adult T cell leukemia/lymphoma. They find recurrent alterations enriched for T cell receptor/NF-κB signaling, T cell trafficking and other T cell pathways and highlight targets for the development of new therapeutics for this intractable cancer.

Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.

Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and young adults. Here, the authors conduct a genome-wide association study for IGCTs, identify a risk locus at BAK1, and characterize its functional consequences.

Genome-wide analyses in BioBank Japan, UK Biobank and FinnGen identify ~5,000 new loci associated with 220 human traits. Statistical decomposition of matrices of phenome-wide summary statistics further highlights variants underpinning diseases across populations.

Bicyclic peptides exhibit improved metabolic stabilities, membrane permeabilities, and target specificities over their linear and mono-cyclic counterparts, however, efficient bicyclization remains challenging. Here, the authors develop a one-pot tandem chemoenzymatic bicyclization by combination of penicillin-binding protein-type thioesterase-mediated head-to-tail macrolactamization and copper(I)-catalyzed azide–alkyne cycloaddition.

Certain cyanobacteria use an alternative biotin biosynthetic pathway that replaces BioA with the dehydrogenase BioU, a suicide enzyme that catalyzes its reaction via conjugation to Lys124 and loses the amino group of this residue in the process.

The conditions to induce human hepatic progenitor cells from other cell types are unclear. Here, the authors reprogram human endothelial cells to hepatic progenitor cells by expressing FOXA3, HNF1A and HNF6, capable of giving rise to hepatocytes and cholangiocytes that reconstitute damaged liver tissues on transplantation.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Sequencing of the MHC region in the Japanese population provides insight into population-specific allelic and structural variability. These data enable discovery and fine-mapping of genotype–phenotype associations across 52 phenotypes.

Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.

Penicillin-binding protein-type thiosterases are recently discovered trans-acting enzymes constructing macrocycles during non-ribosomal peptide biosynthesis. Now, their synthetic potential is explored and a protein crystal structure provides insights into their unusual stereochemical requirement.

A fast in vitro model of the formation of bone-like nodules, enabled by the retinoic-acid-mediated induction of the osteogenic differentiation of patient-derived induced pluripotent stem cells, recapitulates the osteogenesis-imperfecta phenotype.

Private enterprises offer preimplantation genetic testing with polygenic scores to select embryos with ‘desirable’ potential. In silico simulations using biobank resources show that the selected embryo would rely substantially on the choice of polygenic score method and randomness in score construction, which raises ethical concerns.

Genome sequencing of fractionated T-, B- and natural killer cells from patients with chronic active Epstein–Barr virus (EBV) infection sheds light on the nature of the EBV-infected progenitor and suggests a link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

Vzb22, an amino-group carrier protein from Streptomyces, is required for biosynthesis of the noncanonical amino acid DADH, a biosynthetic precursor of vazabitide A and related azabicyclohexane natural products.

Viral vectors with intense and long-lasting transgene expression are essential for manipulating and imaging of neuronal activity in the primate brain. Here, the authors created a mosaic vector composed of capsid proteins derived from AAV1 and AAV2 that exhibits improved transgene expression and neuronal specificity.

Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

Kenichi Yamamoto et al. report a genetic analysis of mitochondrial DNA (mtDNA) and a phenome-wide association study in Japanese individuals from the BioBank Japan Project. They describe the genetic landscape of the mitochondria and identify pleiotropic mtDNA variants associated with 5 late-onset complex traits.

Kazuhiko Yamamoto and colleagues report an association of two SNPs in CD244 with increased risk of rheumatoid arthritis. These variants promote increased expression of CD244 in luciferase reporter assays.

In this paper, the authors investigated the high light stress response in Synechocystis sp. PCC6803 and revealed two key mutations in hik26 and slr1916 using whole genome sequencing and reverse engineering. Here, the high light tolerant strain exhibited no growth inhibition in conditions up to 9000 μmol m⁻² s⁻¹, which had no effect on excitation-energy flow and instead showed an increase in isiA expression.

Mimasu et al. report a rat full-length structure of kynurenine 3-monooxygenase (KMO) in its membrane-embedded form, complexed with two inhibitors. They find that the dimeric interface of KMO is critical for its activity. This study provides insights into the drug development strategies that target KMO, an important regulator of tryptophan metabolism.