Reviews & Analysis

Interacting proteins commonly perform similar functions. A protein interaction network analysis of genes linked to 1,002 human traits identifies molecular mechanisms that are shared across traits and so-called pleiotropic biological processes, whose disruption might affect many aspects of human biology.

Multi-omic profiling of lesions at autopsy reveals a plethora of resistance mechanisms present within individual patients with ovarian cancer. This highlights the extreme challenge faced in treating end-stage disease and underscores the need for new methods of early detection and intervention.

A meta-analysis of harmonized human brain RNA-seq datasets creates expression quantitative trait locus (eQTL) maps for multiple ancestries and brain regions, predicts cell-type-dependent eQTLs and produces gene networks. This prioritizes genes for multiple brain-related diseases, serving as a promising step toward the identification of central nervous system (CNS) drug targets.

Using laser-capture microdissection and whole-genome sequencing of individual crypts, we characterized the landscape of somatic mutations in human small intestinal epithelium. Mutational signatures of APOBEC mutagenesis were found frequently and are probably due to the activity of APOBEC1, which is expressed at high levels in the small intestine.

Using a series of mouse mutants, we found that the Sox2 promoter does not require CTCF–cohesin loops to interact with distal enhancers. Surprisingly, mice with varying numbers of CTCF motifs in different positions showed that some distal enhancers can bypass boundaries that are created by CTCF–cohesin loops to ensure robust Sox2 expression.

Current methods of chromatin analysis focus mainly on the most abundant cell types in a sample. We present a workflow that combines enrichment of rare cell types with high-resolution mapping of histone modifications, which enables us to study chromatin dynamics in rare stem and progenitor cell populations.

This Perspective article discusses Singapore’s efforts to implement a National Precision Medicine Strategy through the integration of genomic, clinical and lifestyle data of up to one million Singaporean individuals.

Endometriosis affects around 10% of individuals born with a uterus, yet we know remarkably little about its underlying biology. Our single-cell transcriptional profiling of endometrial-type epithelial and stromal cells is shedding light on the cells and processes that contribute to endometriosis, which opens up new avenues for diagnostics and therapeutics.

A high-throughput reporter gene assay for use in living tissues has been developed. The assay allows investigators to quantify, in parallel, the activities of reporter genes in each of the cell types that constitute a tissue.

A major challenge in human genetics is the prioritization of causal genes in common complex diseases. A genome-wide CRISPR screen for intracellular insulin content in a human β-cell line has now identified a new candidate gene for type 2 diabetes, demonstrating the utility of this screening approach in β-cells.

The cell types of the lung enable gas exchange and protect against infection. Our spatial atlas of the human lung and airways revealed 11 new cell types and mapped their anatomical locations. In particular, we defined the gland-associated immune niche (GAIN), which is involved in fighting respiratory infections.

It is well known that dietary composition affects lifespan, but whether the effects of diet are mediated through interactions with genetics is unknown. By careful tracking of genome-wide allele frequency in Drosophila, we identify hundreds of loci that affect longevity only in the context of a high-sugar diet.

CRISPR cell and gene therapy have been designed largely with respect to a single reference human genome. A new study reveals how human genetic diversity could lead to off-target effects and presents a new tool to identify these risks.

We profiled human DNA methylation for 987 GTEx samples across nine tissues and characterized how genetic regulation of the methylome, compared with the transcriptome, contributes to GWAS phenotypes. This resource contributes to our understanding of molecular regulatory mechanisms in human tissues and their effects on complex traits.

5-hydroxymethylcytosine (5hmC) accumulates in transcribed gene regions (called ‘gene bodies’) and near enhancers, but its biological role has remained mysterious. A new study demonstrates that 5hmC serves to counteract inappropriate, spurious intragenic transcription in airway smooth muscle cells and by doing so, this DNA base functions in the prevention of chronic inflammation in the lung and an asthma-like phenotype.

Previous genome-wide association studies of coronary artery disease (CAD) have discovered multiple susceptibility loci but have largely failed to uncover causal genes. A new study identifies hundreds of likely causal genes underlying the genetic risk for CAD.

For plants, the decision to germinate is a gamble on their subsequent survival. Xu et al. have now discovered a mechanism that determines the choice between germination and dormancy by regulating the level of ABA.

We developed a CRISPR-based functional assay for genetic sequence variants found in human disease, probing their effects on cell proliferation, survival, motility and any physiological or pathological process measurable by fluorescence-activated cell sorting (FACS). The assay accurately assessed variant pathogenicity, drug responsiveness or resistance and mechanistic role in disease, in vitro and in vivo.

K27M mutation of histone H3 has been identified as a driver event in diffuse midline glioma. Two studies used comprehensive multi-model single-cell genomic, epigenomic and chromatin structure analysis to characterize the cell of origin and find a distinct etiology of H3K27M between pontine and thalamic tumors, and show that pontine gliomas harbor more immature oligodendrocyte-precursor-like cells.

High-grade serous ovarian cancer, the most common form of the disease, is often fatal. This study investigated the genomic and immune characteristics of tumors from women who survived more than 10 years after their initial diagnosis, and compared them with short-term and moderate-term survivors.