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Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

This protocol provides structure-guided capsid library approaches to evolve new adeno-associated viral vectors for enhanced CNS gene delivery with altered tissue tropism, higher transduction efficiency and the ability to evade pre-existing humoral immunity.

The paralogs cytidine diphosphate diacylglycerol synthase 1 and 2 form a potentially targetable synthetic lethal relationship in mesenchymal-like cancers that involves disruption of lipid metabolism.

Gonzalez et al. use a viral evolutionary approach to generate cross-species compatible AAV (ccAAVs) vectors. They describe a highly potent new variant, AAV.cc47, with enhanced transduction efficiency over AAV serotype 9 and show its efficacy in different mouse models, pigs and non-human primates.

Bats account for 20 per cent of all mammals, these are the only mammals with powered flight, and are among the few animals that echolocate. Here, Seim et al. sequence the genome of the long-lived (>40 years) Brandt’s bat, Myotis brandtiiand provide clues to its evolution, longevity and other traits.

The control of flagellar synthesis and function in the Lyme spirochete Borrelia burgdorferi is poorly understood, as this pathogen lacks the typical flagellar sigma factor and transcriptional regulators. Here, the authors identify a broadly conserved structural flagellar component that modulates flagellar assembly and is important for cell division, motility and virulence.

Genome assemblies of 13 domesticated and wild rice relatives reveal salient features of genome evolution across the genus Oryza, especially rapid species diversification and turnover of transposons. This study also releases a complete long-read assembly of IR 8 ‘Miracle Rice’.

A variant telomerase template demonstrates that human telomeres can tolerate significant degeneracy and remain functional. Once incorporated by telomerase, variant sequences can influence telomere length dynamics.

Argonaute proteins are key effectors in the microRNA pathway. Here, the authors show that the conserved peptidase DPF-3 regulates Argonautes in C. elegans, and that loss of dpf-3 restores function and fitness in animals lacking the microRNA Argonaute ALG-1.

The authors present a characterization of complex X-linked lncRNA loci with sex- and allele-specific epigenetic signatures that serve as a platform for the largest chromatin structures in mammals, thereby elucidating diverse phenotypes and combinatorial effects on autosomes.

Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.

McGavern and colleagues identified a CD8⁺ T cell population that expresses GZMK in ʽtau-richʼ brains, where it may play a protective role against neurodegeneration.

The origins and antiquity of the people of Europe has been much debated. Here, the authors sequence 3.7 Mb of the Y chromosome in over 300 Europeans and Middle Easterners and show a recent, continent-wide and male-specific expansion dating back to the Bronze Age.

Tryptophan depletion in melanoma cells after prolonged treatment with interferon-γ (IFNγ) results in ribosomal frameshifting and the production of aberrant peptides that can be presented to T cells and induce an immune response.

Discrete hippocampal cell types differentially regulate behavior. Here authors show that parvalbumin and somatostatin interneurons differentially innervate and regulate pyramidal cell projections, providing a potential circuit mechanism underlying hippocampal control of behavior.

Damaged linearized mtDNA needs to be removed from the cell for mitochondrial genome stability. Here the authors shed light into the identity of the machinery responsible for rapidly degrading linearized DNA, implicating the role of mtDNA replication factors.

The appearance of a new intron that splits an exon without disrupting the corresponding peptide sequence is a rare event in vertebrate genomes. Hellstenet al.demonstrate that, under certain circumstances, a functional intron can be produced in a single step by segmental genomic duplication.

Accurate and actionable biomarkers that integrate diverse molecular, functional and clinical information hold great promise in precision medicine. Here, the authors develop SIMMS, a method for pathway-based cross-disease biomarker discovery.

Cancer genetics has benefited from the advent of next generation sequencing, yet a comparison of sequencing and analysis techniques is lacking. Here, the authors sequence a normal-tumour pair and perform data analysis at multiple institutes and highlight some of the pitfalls associated with the different methods.

Replication stress induces STING-TRPV2 dissociation to promote Ca²⁺ release from the ER for fork protection; however, the precise mechanism remains unclear. Here, the authors identify TCAF1 as a fork protection factor that facilitates STING-TRPV2 dissociation, thereby enabling Ca²⁺ release.

Tryptophan depletion, which occurs in tumours, results in in-frame translation across tryptophan-encoding codons by phenylalanine substitution.

David Page and colleagues report the sequence of the chicken W sex chromosome and compare ancestral W-linked genes across bird species. They find that the W chromosome did not acquire genes expressed exclusively in reproductive tissue, but retained genes through selection to maintain appropriate dosage levels of broadly expressed genes.

Shi et al. present a hybrid dependency map based on machine-learning analysis of gene essentiality data from the DEPMAP database, translated to data from TCGA. This application can be used to visualize other gene essentiality data.

Julia Jehn et al. report a phylogenetic analysis and expression studies of PIWI genes in 11 mollusk species. They find that PIWI genes and piRNAs are expressed in both the germline and soma, as in arthropods, suggesting that somatic expression of the piRNA system represents the ancestral state in animals.

Here, Li et al. show that functional redundancy, which has not previously been quantified at the proteome level, can arise when different microbes play similar roles in the gut microbiome, revealing that proteomes are nested among gut microbes, favoring high functional redundancy.

Analysis of a large ancient genome dataset shows that genetic risk for multiple sclerosis rose in steppe pastoralists, providing insight into how genetic ancestry from the Neolithic and Bronze Age has shaped modern immune responses.

Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion.

Hoelzl et al. employ multi-omics to catalog genes escaping X chromosome inactivation across major organs throughout the mouse lifespan, revealing that aging promotes reactivation of the Barr body at distal chromosome regions.

Genetic variation is key to species evolution. Here the authors sequence two phenotypically distinct populations of the ant Cardiocondyla obscurior, and find accumulations of transposable elements correlating with genetic variation that may have a role in differentiation, adaptation and speciation.

Metagenome sequencing can now distinguish closely related microbes using long reads and haplotype phasing.

Developmental nicotine exposure increased cortical dendritic complexity, levels of Ash2l and Mef2c (components of a histone methyltransferase complex), and H3MeK4 trimethylation at promoters of genes involved in synapse maintenance. Knockdown and overexpression experiments in utero showed that Ash2l and Mef2c regulate nicotine-mediated dendritic remodeling and changes in passive avoidance behavior.

Transplantation of mouse-induced pluripotent stem cells (iPSCs), but not of iPSC-derived terminally differentiated cells, triggers a T-cell-dependent immune response. Here the authors show that iPSC-derived endothelial cells are accepted by self-tolerance mechanisms similar to autologous endothelial cells.

Transcriptomic profiling using a newly-developed cre-inducible method to biotinylate wild-type and mutant MeCP2 protein highlights the cellular heterogeneity of transcriptional changes in rodent models of Rett Syndrome, including cell-type- and subcellular compartment-specific differences in male brains and X-linked mosaicism in female brains.

Seasonal malaria chemoprevention provides substantial benefit for young children, but resistance to used drugs will likely develop. Here, Chotsiri et al. evaluate the use of dihydroartemisinin-piperaquine as a regimen in 179 children, and population-based simulations suggest that small children would benefit from a higher and extended dosage.

A new phylogenomic tree for butterflies is constructed using 391 genes from 2,300 species, representing 92% of genera. It suggests that butterflies originated around 100 million years ago in what is now the Americas and originally fed on Fabaceae.

Re-exposure to a high-fat diet in mice led to emergency myelopoiesis and increased neutrophils in the blood, which infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis.

Phylogeographical genomic analysis of Neisseria gonorrhoeae uncovers its recent emergence and current distribution into two distinct lineages that are differentially associated with antibiotic resistance and sexual networks.

A fusion of RNA-binding proteins (RBPs) to a poly(U) polymerase allows the tagging of endogenous RNAs bound by the RBPs with a U-tail that can be used to identify the bound RNA by sequencing. RNA tagging is suited to discover RNA-protein networks in vivo.

Several COVID-19 vaccines have received emergency approval, but durability of protection is unclear. Here, the authors describe correlates of protection (CoP) for the Ad26.COV2.S vaccine in rhesus macaques and report that CoP predict the protection observed 6 months post vaccination.

The One Thousand Plant Transcriptomes Initiative provides a robust phylogenomic framework for examining green plant evolution that comprises the transcriptomes and genomes of diverse species of green plants.