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KDM4C regulates cathepsin L-mediated histone H3 N-terminal tail clipping through grainyhead-like 2 (GRHL2) methylation in breast cancer. This link between the cellular redox state and chromatin remodeling might represent a therapeutic target in KDM4C-amplified tumors.

To better understand the etiology of frailty, the authors perform a large genetic study. They identified 45 additional variants and implicated MET, CHST9, ILRUN, APOE, CGREF1 and PPP6C as potential causal genes, linking frailty to immune regulation, metabolism and cellular signaling.

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.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Type 1 polyketides are a major class of natural products with diverse bioactivities but are mostly identified via bioactivity-guided purification which is limited to relatively abundant compounds. Here, the authors present Seq2PKS, a machine learning algorithm that predicts the chemical structures derived from Type 1 polyketide synthases and use it to discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamideactiphenol.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

Analysis of genomic data from 25 distantly related plant species shows signatures of selection on the same gene families and functions that repeatedly contributed to local adaptation to climate.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

Deep-learning models for the automated measurement of retinal-vessel calibre in retinal photographs perform comparably to or better than expert graders in associations of measurements of retinal-vessel calibre with cardiovascular risk factors.

Extracellular vesicles have been implicated in the transmission of pathogens from the arthropod to the human host. Here the authors show that tick-derived extracellular vesicles play a role in feeding and modulate the outcome of bacterial infection.

Tool making has been considered to be an attribute of the genus Homo; this paper reports 3.3-million-year-old stone tools and the early timing of these tools provides evidence that the making and use of stone tools by hominins occurred before the evolution of our own genus.

A genome-wide association study suggests 41 previously unreported loci on top of the 23 known loci that influence the disease risk for lumbar disc herniations. Many of these loci harbour genes implicated in disc structure and inflammation, as well as genes related to the nervous system and nerve function.

Surface melt water from the Greenland ice sheet can become trapped in firn, delaying its journey to the sea. Radar and ice-core observations provide direct evidence of a perennial aquifer in the firn layer in southern Greenland that represents a potentially significant contribution to the Greenland mass budget.

Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Breaking down the endothelial barrier is a hallmark of systemic inflammatory response syndrome. Here the authors show that palmitoylation, a post-translational modification of proteins, plays a critical role in altering endothelial function during inflammation, and suggest the targeting of palmitoyl acyltransferase DHHC21 as potential disease therapy.

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.

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.

microbeMASST is a tool to associate known and unknown metabolites to microbial producers leveraging untargeted metabolomics data.

Cheung, Zhang et al. examine the association between secondhand smoke exposure and changes in the retinal vasculature among children aged 6 to 8, in a population-based cohort study. Children exposed to secondhand smoke have wider retinal arteriolar and venular calibers compared to those in smoke-free homes.

The authors pooled resources to identify best practices and develop a new standardized protocol for estimating functional connectivity in rats with magnetic resonance imaging.

The precision of base editing is enhanced with an engineered version of the APOBEC3A deaminase.

The giant planet KELT-9b has a dayside temperature of about 4,600 K, which is sufficiently high to dissociate molecules and to evaporate its atmosphere, owing to its hot stellar host.

A single therapeutic base edit of the BCL11A enhancer in human HSPCs can ameliorate cellular defects associated with sickle cell disease and β-thalassemia in vitro and efficiently induce fetal hemoglobin expression upon engraftment in mice in vivo.

It has been traditionally assumed that the heat released during a single enzymatic catalytic event does not perturb the enzyme in any way; however, here single-molecule fluorescence correlation spectroscopy is used to show that, for enzymes that catalyse chemical reactions with large reaction enthalpies, the heat released at the protein's active site during catalysis transiently displaces the protein's centre-of-mass, essentially giving rise to a recoil effect that propels the enzyme.

Sabeti et al. build on their This paper builds on previous work of detecting selection on human genes, using the many more markers available in the Phase II HapMap project. Three examples of apparent population-specific selection based on geographic area are described, and how these may relate to human biology is discussed.

The largest meta-analysis of GWASs of hepcidin and sTfR identified 43 genomic loci, of which 15 new. Mendelian randomisation revealed associations of systemic iron status and iron-related loci with selected health outcomes across multiple domains.