Reviews & Analysis

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.

A study uses single-cell RNA sequencing to profile human papillomavirus (HPV)-positive and -negative oropharyngeal squamous cell carcinoma, revealing considerable diversity within and between tumors. Within HPV-positive tumors, subsets of malignant cells are found with undetectable HPV expression and decreased HPV-related phenotypes, which may influence prognosis and response to therapy.

A GWAS meta-analysis, combined with tracing the parental transmitted and non-transmitted alleles in parent–offspring pairs, enabled us to distinguish the effects of maternal and fetal genomes on gestational duration and their links with birth weight. The identified genes are more likely to be differentially expressed during labor and show signs of antagonistic pleiotropy with fetal genome effects on birth weight.

Transposable elements (TEs) are transcriptionally activated in cancer and can generate chimeric TE–gene transcripts that are tumor specific. Our pan-cancer study reveals that these transcripts are a source of tumor-specific antigens that are shared across tumor types, bind to HLA and are presented on the extracellular surface of cancer cells appended to membrane-bound proteins.

Telomere length is an important determinant of cellular aging and disease risk, but the genetics of telomere length control in humans is unclear. A genome-wide CRISPR screen has now identified a central role for thymidine nucleotide metabolism in the regulation of telomere length, which has implications for the diagnosis and treatment of disease.

A new study deciphers the origin and evolution of childhood neuroblastoma using genome sequencing data, mathematical models and statistical inference, showing how neuroblastoma evolution is an accurate predictor of outcome.

How histone modifications are reprogrammed through germline development in plants is poorly understood. We found that H3K27me3 and H3K4me3 are extensively reprogrammed throughout the development of Arabidopsis male gametophyte. This reprogramming leads to widespread chromatin bivalency and selective removal of H3K27me3 marks from key developmental regulators in sperm.