Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.

Chromosomes are shaped by an interplay between loop extrusion and compartmentalization. Two new studies demonstrate that bromodomain and extraterminal domain (BET) proteins contribute to both processes, with BRD4 facilitating one process and surprisingly inhibiting the other.

Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active

Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related

DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis. Although DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the

Typical genotyping workflows map reads to a reference genome before identifying genetic variants. Generating such alignments introduces reference biases and comes with substantial computational burden. Furthermore, short-read lengths limit the ability to characterize repetitive genomic regions, which are particularly challenging for fast k-mer-based genotypers. In the present study, we propose a new

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from

Overload of proteasomal clearance triggers formation of a large protein inclusion called the aggresome, which shares similarities with protein aggregates seen in neurodegenerative diseases such as Huntington’s. A new study uncovers how centrosome and centriolar satellite components facilitate stepwise assembly of aggresomes.

Biomolecular condensation has emerged as a fundamental mechanism for cellular organization, but less is known about the regulation of condensate subcellular location and size. A new study reports that membrane tethering of protein and RNA directly influences the assembly, size and material properties of ribonucleic condensates.

Skeletal muscle has long been recognized as an inhospitable site for disseminated tumour cells (DTCs). Yet its antimetastatic nature has eluded a thorough mechanistic examination. Here, we show that DTCs traffic to and persist within skeletal muscle in mice and in humans, which raises the question of how this tissue suppresses colonization. Results from mouse and organotypic culture models along with

Epithelial–mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E–M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance

Biomolecular condensates organize biochemistry, yet little is known about how cells control the position and scale of these structures. In cells, condensates often appear as relatively small assemblies that do not coarsen into a single droplet despite their propensity to fuse. Here, we report that ribonucleoprotein condensates of the glutamine-rich protein Whi3 interact with the endoplasmic reticulum

Germline–soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours

Protein degradation is critical to maintaining cellular homeostasis, and perturbation of the ubiquitin proteasome system leads to the accumulation of protein aggregates. These aggregates are either directed towards autophagy for destruction or sequestered into an inclusion, termed the aggresome, at the centrosome. Utilizing high-resolution quantitative analysis, here, we define aggresome assembly at

Andrew Robinson reviews five of the week’s best science picks.

Rare and common genetic variants associated with schizophrenia.

The United States should learn from its mistakes on decarbonization.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the

After a two-week trial, Feng “Franklin” Tao was convicted on 4 of 8 charges — but a judge is reviewing the case.

Rapa Nui has fewer than 10,000 residents but is on the receiving end of carbon monoxide from continents thousands of kilometres away.

A double-blinded dilemma.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P?

CBASS and Pycsar are anti-phage defense systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation1,2. Phages use multiple strategies to defeat host CRISPR and restriction-modification systems3–10, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that

Science, Volume 376, Issue 6589, April 2022.

Science, Volume 376, Issue 6589, April 2022.

Science, Volume 376, Issue 6589, April 2022.

Science, Volume 376, Issue 6589, April 2022.

Science, Volume 376, Issue 6589, April 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 16, April 2022.

SignificanceCHARGE syndrome is a complex developmental disorder caused by mutations in CHD7 (chromodomain helicase DNA-binding protein-7). We identified Caenorhabditis elegans chd-7 in a screen for suppressors of dauer formation, an alternative larval stage that develops under harsh environmental conditions. We found chd-7 regulates tumor growth factor-β (TGF-β) signaling pathways both for dauer diapause

SignificanceThe connecting cilium (CC) of the photoreceptor provides the only route for the trafficking of the outer segment (OS) proteins. Failure of OS protein transport causes degenerative photoreceptor diseases, including retinitis pigmentosa. We demonstrate that Tmem138, a protein linked to ciliopathy, is localized to the photoreceptor CC. Germline deletion of Tmem138 abolished OS morphogenesis

SignificanceMultiple human genetic diseases are caused by mutations in the maternally transmitted DNA of mitochondria, the powerhouses of the cell. It is important to study how these mutations arise and accumulate with age, especially because humans in many societies now choose to have children at an older age. However, this is difficult to accomplish in humans, particularly for female germline cells

SignificanceIt is increasingly recognized that chronic neuroinflammation is causally relevant to neurodegeneration. In Parkinson's disease (PD), α-synuclein pathology activates inflammatory signaling that disturbs parenchymal homeostasis and disrupts neuron-glia interactions. Herein, we report that the innate immune cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA-sensing pathway

SignificanceLand plants produce numerous terpenoids that regulate development and mediate environmental interactions. Thus, how typical plant terpene synthase (TPS) genes originated and evolved to create terpenoid diversity is of fundamental interest. By investigating TPSs from the genomes and transcriptomes of diverse taxa of green plants, it was demonstrated here that the ancestral TPS gene originated

SignificanceNovel approaches to promote killing of HIV-1-infected cells are necessary for elimination of the latent reservoir, the main barrier to a cure. Here, we utilized a diverse phage-display library to construct T cell receptor (TCR)-mimic antibodies to HIV-1 peptide-major histocompatibility complexes (pMHC). We show that single-chain diabody forms of these antibodies recognize distinct epitopes

SignificanceThe optic nerve conveys information from retinal ganglion cells (RGCs) to visual processing areas of the brain. Although this pathway normally cannot regenerate when injured nor in degenerative diseases such as glaucoma, this failure can be partially reversed by eliciting a controlled immune reaction in the eye. We show here that the chemokine SDF1 (stromal cell-derived factor 1) is an

SignificanceGenes encoding ribosomal RNA (rDNA) are organized into a repetitive array in eukaryotic genomes. The copy number of these genes often varies and is responsive to genetics and environment. Here, we show that variation in copy number at the rDNA locus is capable of altering replicative lifespan in yeast. These results indicate that considering rDNA copy number, and conditions that could potentially

SignificancePhosphatase and tensin homolog protein (PTEN) and fragile X mental retardation protein (FMRP) play a vital role in neuronal development and function. This work provides new evidence for the genetic interaction of Pten and Fmr1 in postnatal development of granule neurons and conserved mechanisms across evolution. The observed cellular phenotypic defects in Pten and Fmr1 knockout (KO) could

SignificanceCarotenoid pigments accumulate in specific patterns in vertebrate tissues and play important roles as colorants, chromophores, and hormone precursors. However, proteins that facilitate transportation of these lipophilic pigments within cells have not been identified. We provide evidence that Aster proteins are key components for this process and show that they bind the pigments with high

SignificanceUnderstanding how humans process time series data is more pressing now than ever amid a progressing pandemic. Current research draws on some fifty years of empirical evidence on laypeople's (in-)ability to extrapolate exponential growth. Yet even canonized evidence ought not to be trusted blindly. As a case in point, I review a seminal study that is still highly (even increasingly) cited

SignificanceAntibiotic exposure stands among the most used interventions to drive microbial communities away from undesired states. How the ecology of microbial communities shapes their recovery-e.g., posttreatment shifts toward Clostridioides difficile infections in the gut-after antibiotic exposure is poorly understood. We study community response to antibiotics using a model community that can reach

SignificanceScholars have identified that inequality is a notable detriment to well-being. Status-signaling luxury expenditure is taken as a symptom of the reduced well-being associated with income inequality. Despite evidence that status-signaling luxury expenditure is higher in unequal regions, it remains unclear who is affected by inequality. We use payroll and daily spending data from 683,677 individuals

SignificanceCancers and chronic infectious pathogens often evade immune-mediated elimination by suppressing T cell function via engaging inhibitory receptors expressed on T cells. The phospholipid lysophosphatidic acid (LPA) is often increased systemically from basal concentrations upon development of cancer and chronic infections. We previously showed that, at these elevated concentrations, LPA suppresses

SignificanceThe steroid hormone progesterone is highly involved in different physiological-pathophysiological processes, including bone formation and cancer progression. Understanding the working mechanisms, especially identifying the receptors of progesterone hormones, is of great value. In the present study, we identified GPR126 as a membrane receptor for both progesterone and 17-hydroxyprogesterone

SignificanceEstrogen receptor α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. We comprehensively searched for indicators of poor prognosis in ERα-positive breast cancer through the multiple databases, including interactome, transcriptome, and survival analysis, and identified FKBP52. We found that two immunophilins

SignificanceA variety of mechanisms safeguard the body from autoimmune reactions, yet how these processes cooperate is largely unclear. Using a range of mouse genetic models, we uncover a critical tolerogenic axis between the autoimmune regulator, AIRE, and the immune checkpoint molecule, PD-1. Their combined loss induced an early-onset lethal autoimmune syndrome driven by autoreactive CD4+ T cells

In this issue of Cell Stem Cell, Gómez-Salinero et?al. (2022) identify c-Maf as a driver for murine liver sinusoidal endothelial cell (LSEC) fate and function during liver development, homeostasis, and repair. Similarly, c-Maf defines human LSECs, and its overexpression specializes generic HUVECs into functional induced-LSECs, potentiating regenerative therapeutics.

Artificial thymic organoids (ATOs) allow the selective differentiation of chimeric antigen receptor (CAR)-transduced human iPSCs into CAR-T cells. In this issue of Cell Stem Cell, Wang et?al. now use ATOs to produce human CD19+ CAR-T cells that mimic conventional CAR-T cells and effectively control the progression of human CD19+ leukemia in an animal model.

Despite the surrounding controversy, quantitative sex-based differences exist in the human brain. In a recent issue of Nature, Kelava et?al. shed light on the mechanisms underlying increased brain volume and neuron density in males, while highlighting the importance of human PSC-derived organoids for studying human development.

In this issue of Cell Stem Cell, Reilly et?al. propose loss of LMNB1, the gene encoding lamin B1, often deleted in MDS/AML, as a novel genetic basis for the abnormal nuclear shape of neutrophils (known as acquired Pelger-Hu?t anomaly) and a cause of HSPC fate alterations promoting malignancy.

Du et?al. transplanted β cells derived from pluripotent stem cells in diabetic monkeys for the first time, as an intermediate stage toward clinical translation. They observed benefits unfolding over months but also observed immune rejection of the grafts by 5–6?months.