Reviews & Analysis

Although clear genetic connections to ALS were first established three decades ago, there has been negligible progress in the development of disease-modifying treatments for this disease. Despite tremendous unmet need, industry has often been largely baffled by a disease seemingly designed to thwart current effective drug development approaches. In the largest genetic study of ALS to date, van Rheenen and colleagues use sophisticated analyses to gain novel insights into its pathogenesis.

The human endometrium exhibits complex signaling cascades mediated by spatial–temporal cellular interactions. Understanding the normal endometrial microenvironment is the first step towards understanding diseases of endometrial dysfunction.

Oncogene amplification is a major driver of tumorigenesis; yet, the mechanisms generating amplification are only partially understood. New research reports on the identification of a new focal amplification pattern termed ‘seismic amplification’ that is hypothesized to originate from recombination between extrachromosomal DNA circles.

How somatic and germline mutations interact in cancer remains largely unexplored. A study of 17,152 patients with cancer suggests that the relative contribution of pathogenic germline mutations is governed by lineage and penetrance.

A new study shows that re-expressing PKD genes early in the course of the disease can fully reverse polycystic kidney disease in mice. These results reveal an unexpected ability of the kidney to regenerate following genetic rescue of polycystin function.

The genomes of cells across human tissues are riddled by changes to their DNA^1–3. Many of these mutations do not alter the properties of a cell, and are neutral passengers. However, a small proportion can change a cell’s fitness, and increase or decrease the progeny that originate from the mutated cell⁴. How many of these alterations under positive selection (drivers) exist in total is unknown. Whether the current list of drivers is almost complete, or whether large proportions of positively selected drivers in the human genome remain undetected is yet to be determined.

Mutational signatures can shed light onto mechanisms of carcinogenesis and reveal the mutagenic impact of novel and established environmental risk factors. A new study examines the mutational spectra of esophageal squamous cell cancer together with exposure information in regions of high and low incidence of the disease, and demonstrates both the limitations and potential of mutational signature analyses.

Heterogeneity in brain tumors has been viewed through many lenses—from microscopes and experimental models to ‘omic’ analysis at the tissue and single-cell levels. Two studies now characterize patterns of DNA methylation and gene expression in single cells to reveal epigenomic underpinnings of cellular heterogeneity and plasticity in exquisite detail, including mechanistic insight into cellular transitions between stem-like and differentiated-like states.

Metastable epialleles refer to loci with variable methylation states among individuals without underlying genetic differences. Although these loci have generally been assumed to be vulnerable to environmental influence, a new study reports their remarkable metastable epigenetic robustness toward a range of physiological, chemical and dietary disruptions in mammals.

Genome-wide association studies have identified genetic variants in maternal and fetal genomes associated with early-life growth traits but have been limited by the paucity of large-scale family-based cohorts that would enable the resolution of informative transmissions between parents and their offspring. A new study uses extensive pedigree data from the Icelandic population to identify genetic effects on birth weight that differ according to parental origin and to demarcate distinct contributions from the maternal intrauterine environment and offspring genetics on fetal growth.

R-loops—nucleic acid structures composed of an RNA:DNA hybrid and displaced single-stranded DNA—are abundant in the genome and may impair progression of the replication fork, thus leading to accumulation of DNA damage and genome instability. A new study demonstrates that SWI/SNF chromatin-remodeling complexes are instrumental in resolving such R-loop-mediated transcription–replication conflicts, highlighting the importance of these chromatin remodelers in R-loop homeostasis and the maintenance of genome integrity.

The UK Biobank Exome Sequencing Consortium aims to sequence all the exomes of approximately 500,000 UK Biobank participants. This Perspective describes the results from approximately 200,000 exomes and discusses the lessons learned from this UK Biobank–biopharmaceutical company collaboration.

Genome editing with CRISPR–Cas9 is beginning to be used clinically; promising results to date inspire hope for broad medical impact and mindfulness about safety. A new study shows that when Cas9 cuts its target, a fraction of the time, the target chromosome experiences a breakage process known as chromothripsis, thus prompting efforts to understand the potential negative consequences of this phenomenon and ways to mitigate them.

Single-cell and bulk transcriptomics of adult human microglia from a population of individuals reveals activated states across several brain disorders and maps Alzheimer’s disease variants to microglia-enriched genes.

Numerous statistical models have been used to analyze single-cell RNA sequencing data. This Perspective proposes that a Poisson measurement model is sufficient and suitably flexible for this task, and its use would resolve current controversies.

This Perspective on crop genomics discusses the promises of new technologies and approaches to help minimize food insecurity and to lay the foundation for sustainable agricultural systems needed to feed the world.

Recent technologies allow experimental manipulation of chromatin conformation. This Perspective discusses the insights obtained from gain-of-function studies that engineer the three-dimensional genome.

RNA is dynamic and can fold into multiple alternative conformations. A new study shows that cells control mRNA translation by regulating the stoichiometry of alternative RNA structures formed from extremely conserved sequences of 5′ untranslated regions and that this control may contribute to embryonic development.

Neurological, cognitive and genetic sciences share a longstanding interest in studying the relationship between the shape of the human skull and of the brain. However, the downstream biological genetic underpinnings of such interactions, if they exist, remain largely unknown. A new genetic study now reports on a set of genes that may be involved in substantially shaping the profile of our face and the physical shape of our brain, but not so much its capabilities.

The nucleosome remodeling and deacetylase (NuRD) complex is a chromatin modifier with a key role in the switch from fetal to adult hemoglobin. In a new study, Vinjamur et al. identify a fetal hemoglobin repressor, ZNF410, which does not directly bind the γ-globin promoter but acts through highly specific regulation of CHD4, a protein subunit of the NuRD complex, thus presenting a potential approach for therapeutic reactivation of fetal hemoglobin.