News & Views in 2023

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.

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.

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.

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.

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.

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.

Quantifying whether different populations share similar effect sizes of common causal variants is vital to understand the genetic basis of disease and build better prediction models. A new study proposes a method leveraging admixture to estimate the correlation of causal genetic variants and finds they are largely similar across ancestry backgrounds.

Current risk assessment and treatment strategies for venous thromboembolism (VTE) consider genetic factors only in a limited way. New work shows a more pervasive role of common variants in VTE risk, inspiring genetic predictors that surpass and complement individual clinical risk factors and monogenic thrombophilia testing.

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 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.

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.

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.