Reviews & Analysis

Matched single-cell transcriptomic and epigenomic profiles obtained from human scalp reveal gene regulatory maps of diverse cell types in the hair follicle niche. Integrating these data with existing genome-wide association studies enabled prioritization of cell types, genes, and causal variants implicated in the pathobiology of androgenetic alopecia, eczema, and other complex traits.

How the chromatin states of transposable elements (TEs) are controlled in development and disease is unclear. We present CARGO-BioID, a CRISPR-based proteomic approach to identify TE-associated proteins, and reveal an interplay between RNA N6-methyladenosine (m⁶A) and DNA methylation that is crucial for regulating TE activation and human embryonic stem cell (hESC) fate.

The three-dimensional organization of mammalian chromosomes can regulate transcription. Whether transcription itself influences genome structure has remained a source of debate. Using sensitive genome-wide readouts, two recent studies describe the involvement of transcription on genome architecture by different mechanisms.

Identifying the ways that a study sample is not representative is essential for maximizing the generalizability of findings to the population. A new method proposes discerning non-representativeness in large-scale genetic studies by comparing the genotypes of closely related participants.

Single large-scale mitochondrial DNA deletions cause a spectrum of disease with differing severities and tissue expressivity. Quantification of single-cell deletion levels with multi-modal cellular readouts provides insights into hematopoietic cell fate and disease manifestation.

Cross-ancestry genome-wide association meta-analyses of neuroimaging genetics data from European and East Asian populations identified 339 genetic variant–hippocampal volumetric trait associations (23 new). Further cross-ancestry analyses revealed similar genetic effects on hippocampal volumetric traits between ancestries, with improved fine-mapping precision and predictive accuracy of polygenic scores in the under-represented East Asian population.

Genome-wide association studies (GWAS) of type 2 diabetes have identified few loci connected to muscle biology. A GWAS of post-glucose-challenge measures of insulin has now identified loci related to insulin resistance and GLUT4 regulation in skeletal muscle, illustrating the benefit of studying dynamic glycemic measures.

An extra copy of a chromosome region that includes four genes encoding interferon receptors contributes to immune dysregulation, heart malformations, developmental delays, cognitive deficits and craniofacial abnormalities in a mouse model of Down syndrome.

Meta-analysis of genome-wide association studies of spontaneous coronary artery dissection (SCAD), an important cause of myocardial infarction, identified 11 risk loci that involve genes related to artery integrity and tissue-mediated coagulation. Evidence supports SCAD as a genetically distinct condition from atherosclerotic coronary artery disease.

Two studies describe kinase fusion proteins (KFPs) that regulate the perception and deception of wheat pathogens. These highlight the emergence of KFPs as plant immune regulators and emphasize the importance of crop wild relatives as a reservoir for resistance breeding and global food security.

Tumors develop mechanisms to escape immune destruction. A systematic analysis of large genome sequencing datasets shows that one in four tumors develop genetic immune escape and its prevalence is remarkably similar between primary and metastatic tumors, suggesting that immune escape is an early event during tumor evolution.

Single-cell RNA-sequencing analysis combined with host genetic data for a Japanese population reveals the dysfunction of innate immune cells, particularly non-classical monocytes, in individuals with severe COVID-19, as well as enrichment of host genetic risk factors for severe COVID-19 in monocytes and dendritic cells.

We introduce scEC&T-seq, a new single-cell sequencing method that enables parallel profiling of extrachromosomal circular DNA and mRNAs in single cells. Using scEC&T-seq, we characterized all types of circular DNA elements in single human cancer cells and profiled the intercellular heterogeneity and structural dynamics of cancer-specific extrachromosomal DNA.

Aberrant RNA splicing events resulting from DNA variations are common causes of genetic disorders. Two studies published in Nature Genetics independently describe methods to decipher DNA-variant-associated aberrant splicing using high-throughput RNA sequencing data.

A new method infers huge gene trees and tests the tree branches for phenotypic associations. This improves power to map the effects of rare variants that are missing from genotype arrays and imputation panels.

Liability scores for chronic obstructive pulmonary disease obtained from our deep learning model improve genetic association discovery and risk prediction. We trained our model using full spirograms and noisy medical record labels obtained from self-reporting and hospital diagnostic codes, and demonstrated that the machine-learning-based phenotyping approach can be generalized to diseases that lack expert-defined annotations.

We developed a machine learning model to quantify cardiac fibrosis (which is associated with cardiovascular disease) using cardiac MRI data from 41,505 UK Biobank participants. In the subsequent large-scale GWAS of cardiac fibrosis, we identified 11 independent genomic loci, 9 of which were implicated in in vitro cardiac fibroblast activation.

Reconstructing phylogenetic trees from large collections of genome sequences is a computationally challenging task. We developed MAPLE, a method for performing phylogenetic inference on large numbers of closely related genomes, which might be useful when studying the evolution and spread of SARS-CoV-2 and of infectious pathogens in future pandemics.

Genome assembly of nine wild species and two domesticated accessions of tomato generated a super-pangenome for the tomato clade. Comparative analyses revealed the landscape of structural variations in wild and cultivated tomatoes and led to the discovery of a wild tomato gene that has the potential for yield increase in modern breeding.

Specific chromatin features, especially histone H3 lysine 27 acetylation, are widely used to identify active enhancers, yet current methods are imprecise. New work suggests that histone H2B N terminus multisite lysine acetylation (H2BNTac) is a notable signature of active enhancers and could substantially improve enhancer prediction.