High order expression dependencies finely resolve cryptic states and subtypes in single cell data.

Single cells are typically typed by clustering into discrete locations in reduced dimensional transcriptome space. Here we introduce Stator, a data-driven method that identifies cell (sub)types and states without relying on cells' local proximity in transcriptome space. Stator labels the same single cell multiply, not just by type and subtype, but also by state such as activation, maturity or cell cycle sub-phase, through deriving higher-order gene expression dependencies from a sparse gene-by-cell expression matrix.

Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans.

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest.

The histone chaperone SPT2 regulates chromatin structure and function in Metazoa.

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response.

Comparison of T-cell receptor diversity of people with myalgic encephalomyelitis versus controls.

Objective: Myalgic Encephalomyelitis (ME; sometimes referred to as Chronic Fatigue Syndrome) is a chronic disease without laboratory test, detailed aetiological understanding or effective therapy. Its symptoms are diverse, but it is distinguished from other fatiguing illnesses by the experience of post-exertional malaise, the worsening of symptoms even after minor physical or mental exertion. Its frequent onset after infection suggests autoimmune involvement or that it arises from abnormal T-cell activation.

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study.

Background: People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.

Human genetics seen through an evolutionary lens.

Most DNA bases crucial for species perpetuation are marked by a dearth of sequence change among species related over long evolutionary time. Recently, Christmas et al. and Sullivan et al.

An ependymal cell census identifies heterogeneous and ongoing cell maturation in the adult mouse spinal cord that changes dynamically on injury.

The adult spinal cord stem cell potential resides within the ependymal cell population and declines with age. Ependymal cells are, however, heterogeneous, and the biological diversity this represents and how it changes with age remain unknown. Here, we present a single-cell transcriptomic census of spinal cord ependymal cells from adult and aged mice, identifying not only all known ependymal cell subtypes but also immature as well as mature cell states.

, a new member of the / transcriptional co-regulator family.

Motivation: Disrupted gene expression causes an intractable congenital diarrhoea in infants. However, this gene's molecular mechanism is unknown and no homologous proteins have been reported.

Results: Our detailed evolutionary analysis of PERCC1 sequence reveals it to be a previously unappreciated member of the YAP/TAZ/FAM181 family of homologous transcriptional regulators.

OAF: a new member of the BRICHOS family.

Summary: The 10 known BRICHOS domain-containing proteins in humans have been linked to an unusually long list of pathologies, including cancer, obesity and two amyloid-like diseases. BRICHOS domains themselves have been described as intramolecular chaperones that act to prevent amyloid-like aggregation of their proteins' mature polypeptides. Using structural comparison of coevolution-based AlphaFold models and sequence conservation, we identified the Out at First (OAF) protein as a new member of the BRICHOS family in humans.

DecodeME: community recruitment for a large genetics study of myalgic encephalomyelitis / chronic fatigue syndrome.

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy.

Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression.

Aims: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterize the transcriptome of the human foetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart.

Refining the domain architecture model of the replication origin firing factor Treslin/TICRR.

Faithful genome duplication requires appropriately controlled replication origin firing. The metazoan origin firing regulation hub Treslin/TICRR and its yeast orthologue Sld3 share the Sld3-Treslin domain and the adjacent TopBP1/Dpb11 interaction domain. We report a revised domain architecture model of Treslin/TICRR.

Citrullination Was Introduced into Animals by Horizontal Gene Transfer from Cyanobacteria.

Protein posttranslational modifications add great sophistication to biological systems. Citrullination, a key regulatory mechanism in human physiology and pathophysiology, is enigmatic from an evolutionary perspective. Although the citrullinating enzymes peptidylarginine deiminases (PADIs) are ubiquitous across vertebrates, they are absent from yeast, worms, and flies.

Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction.

Traditional sequence analysis algorithms fail to identify distant homologies when they lie beyond a detection horizon. In this review, we discuss how co-evolution-based contact and distance prediction methods are pushing back this homology detection horizon, thereby yielding new functional insights and experimentally testable hypotheses. Based on correlated substitutions, these methods divine three-dimensional constraints among amino acids in protein sequences that were previously devoid of all annotated domains and repeats.

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present, and drives mortality, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units.

Ageing compromises mouse thymus function and remodels epithelial cell differentiation.

Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear.

Genetic risk factors of ME/CFS: a critical review.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of ∼0.2-0.

Genetics Needs Non-geneticists.

Answering genetics' big data questions often needs an interdisciplinary team whose members freely share their diverse expertise in analysis, statistics, and computation. Sharing requires mutual trust and open acknowledgement of strengths and weaknesses, including those of established geneticists. Only then will newcomers to genetics contribute far beyond their entry-level expectations.

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated.