Reviews & Analysis

As we age, our cells acquire DNA mutations, resulting in cell-to-cell genomic heterogeneity. We characterized the landscape of mitochondrial DNA (mtDNA) heterogeneity in healthy human cells. Our observations provide deeper insight into the frequency of new mitochondrial mutations and the mechanisms that propagate low-level mutations in mtDNA over a lifetime.

Nearly 50% of the sequence of mammalian genomes is derived from mobile elements that inserted into the genome over millions of years of evolution. A recent mobile element insertion, found only in some individuals with European genetic ancestry, contributes to decreased skin pigmentation and increased sunburn frequency and skin cancer risk.

We present a multi-omic map of the human kidney in health and disease, using single-cell RNA, single-nuclei RNA, single-nuclei assay for transposase-accessible chromatin sequencing, spot-based and single-cell spatial transcriptomics. This comprehensive approach enables an in-depth understanding of the microenvironments in the diseased kidney.

This Review explores the challenges and strategies for developing gapless telomere-to-telomere genome assemblies to enhance our understanding of genome organization and improve crops through genome-assisted breeding or gene editing.

Genetic constraint identifies genes under selection against loss-of-function, but existing methods are inaccurate for shorter genes. A new study overcomes this key limitation to ascribe more confident predictions to all human protein-coding genes.

Identifying substrates of metabolic gene products is important to understand their function in physiology and disease. We developed GeneMAP, a multiomics platform for predicting metabolic gene functions using models of gene expression. We experimentally validated a top-scoring gene–metabolite association, thereby revealing a role for SLC25A48 in mitochondrial choline import.

The African BioGenome Project (AfricaBP) Open Institute for Genomics and Bioinformatics established a series of regional workshops in 2023 to exchange knowledge and overcome barriers, which could serve as a model for other scientific communities.

Infant genetic research is currently underexplored but, as highlighted in this Perspective, has the potential to impact basic science and affect educational policy, public health and clinical practice.

Idiopathic pulmonary fibrosis (IPF), a deadly lung disease of unclear etiology, lacks sufficient therapeutic options. We extensively mapped the spatial transcriptomes of patient lungs and made translational comparisons with a mouse model of lung fibrosis, providing insights into disease mechanisms and the utility of the animal model for drug discovery.

The impact of transposable elements (TEs) on gene regulatory networks and how they are governed remain poorly understood. A new study identifies a role for LINE1, a specific subset of TEs, in the long-range regulation of gene expression, particularly during embryonic development.

Relentless accumulation of somatic mutations renders mismatch repair (MMR)-deficient cancers immunogenic. The evolutionary strategies that these hypermutator tumors use to drive immune evasion remain unknown. We identify repetitive homopolymer sequences in MMR genes as genetic ON/OFF switches, which vary mutation rate and bias during tumor evolution to fuel intratumor heterogeneity.

Comprehensive dissection of the transcriptional basis of basal-like differentiation of pancreatic ductal adenocarcinoma (PDAC) revealed MED12 as a core regulator of this abnormal identity. Mechanistic studies demonstrate that MED12 cooperates with the basal-like master regulator transcription factor ΔNp63 by bridging it with the critical Mediator co-activator complex.

This Review discusses emerging technologies and insights from mitochondrial DNA variant profiling obtained by single-cell multi-omics, demonstrating how the powerhouse of the cell may record clonal lineages and contribute to disease heterogeneity.

We identify an elite haplotype of the transcription factor gene OsGATA8 in rice that is associated with enhanced nitrogen uptake and a higher proportion of productive tillers. Revealing how OsGATA8 regulates nitrogen use efficiency (NUE) enables insights into coordination of nitrogen uptake and productive tiller formation to achieve high NUE in rice.

Kaiser et al. propose a nuanced and inclusive definition of genetic discrimination that reflects its multifaceted impact. This adaptive definition is intended to remain relevant in the face of an evolving social context and advancing genomic science.

Microbats utilize ultrasonic echolocation to navigate and locate prey, whereas megabats primarily perceive human-audible sound in daily life. High-quality genomes and single-cell atlases of auditory cortices from microbat and megabat species identify parvalbumin-positive inhibitory neurons and the complexin-1 gene to be crucial in mammalian ultrasound perception.

Genotype × environment interactions are a key mechanism underlying human phenotypic variation and contribute to our understanding of the genetic architecture of human traits, with possible applications in personalized medicine.

We used high-throughput transposon screens to examine the responses of generalist and host-adapted Salmonella enterica serovars to 25 stress conditions that recapitulate key stages of human infection. We identified and characterized numerous typhoid-specific gene networks, revealing a role for specific pseudogenes in shaping bacterial fitness outcomes.

Our study explored cell-specific functional consequences and clonal expansions of mosaic structural variants in distinct hematopoietic stem and progenitor cells by utilizing advanced single-cell sequencing techniques. Our single-cell multi-omics approach paves the way for future studies to focus on the roles of somatic structural variants in aging and disease.

Trinucleotide repeat expansions, notably CAG repeats translated into toxic polyglutamine-containing proteins, are the leading cause of spinocerebellar ataxia (SCA). New work points to a GGC repeat expansion that encodes a polyglycine-containing protein as a cause of SCA4, highlighting polyglycine disorders as an emerging human genetic disease class.