Reviews & Analysis

High-throughput sequencing technology is enabling the structures of RNA to be determined on an unprecedented scale, providing insights into the relationship between the structures adopted by RNAs and the functions they perform in the cell.

Eukaryotic cells must regulate not only their nuclear genomes but also the intimate functional interplay with organelle genomes, such as those in mitochondria and plastids. This Review discusses the functional and evolutionary implications of cellular genomes being partitioned between the nucleus and organelles, including the translocation of genes and gene products, chimeric enzyme complexes and insights into molecular co-evolution.

Cornelia de Lange syndrome is a genetic disorder affecting multiple organ systems that exhibits great phenotypic heterogeneity. This Consensus Statement summarizes recommendations for the diagnosis and management of patients with Cornelia de Lange syndrome.

High-throughput sequencing technologies have enabled comparative analysis of large numbers of diverse bacterial genomes. Such studies are providing insights into the genomic changes that accompany changes in host specificity, with possible implications for controlling transmission of pathogenic bacteria.

Various types of observational studies can provide statistical associations between factors, such as between an environmental exposure and a disease state. This Review discusses the various genetics-focused statistical methodologies that can move beyond mere associations to identify (or refute) various mechanisms of causality, with implications for responsibly managing risk factors in health care and the behavioural and social sciences.

Genomic technologies are helping researchers to understand the natural genetic variation that exists in wild and cultivated rice populations. Harnessing this genetic variation will be key to developing Green Super Rice varieties with high yield and low environmental costs.

Fine-mapping is the process by which a trait-associated region from a genome-wide association study (GWAS) is analysed to identify the particular genetic variants that are likely to causally influence the examined trait. This Review discusses the diverse statistical approaches to fine-mapping and their foundations, strengths and limitations, including integration of trans-ethnic human population data and functional annotations.

Virtually all studies depend on annotations, maps of the genome that catalogue gene loci and the sequences of their transcripts. This Review discusses the state of currently available long non-coding RNA annotations and the impact of emerging technologies such as long-read sequencing.

Polygenic risk profiling can lead to actionable outcomes for individuals at high risk of developing a subset of common adult-onset polygenic diseases. The authors review recent studies that have demonstrated the utility of polygenic risk scores for disease risk stratification and their potential impact on early disease detection, prevention, therapeutic intervention and life planning.

RNA is controlled at various stages of transcription and processing to achieve appropriate gene regulation. Whereas much research has focused on the cytoplasmic control of RNA levels, this Review discusses our emerging appreciation of the importance of nuclear RNA regulation, including the molecular machinery involved in nuclear RNA decay, how functional RNAs bypass degradation and roles for nuclear RNA decay in physiology and disease.

The authors review the changes in life history traits brought forth by the Industrial Revolution and the evidence for antagonistic pleiotropic effects, whereby genetic variants associated with higher fitness in the past now predispose to diseases such as cancer and coronary artery disease.

Variation in the composition of translation complexes may serve as a means to regulate gene expression. How translation of select transcripts is achieved by specialized components and the role of this form of dynamic control of gene expression in disease are reviewed.

Parallels are increasingly being drawn between prion diseases and other aggregate-mediated neurodegenerative disorders. While prion diseases are a distinct subclass of protein misfolding disorders (PMDs), a better understanding of shared mechanisms is likely to benefit treatment of all PMDs.

Recent studies show that structural variation can alter the genome architecture, leading to changes in the regulation of gene expression that cause disease. The authors review the role of genetic structural variation in disease and the pathogenic potential of changes to the 3D genome.

Next-generation sequencing technologies have enabled the comparison of editomes from multiple individuals and from multiple species. The results have changed our understanding of the extent and distribution of A-to-I editing and its role in evolution and disease.

Biomarkers of ageing based on DNA methylation data enable accurate age estimates for any tissue across the entire life course. Horvath and Raj review the development of these ‘epigenetic clocks’ and how they link to biological ageing.

Although the field of functional genomics is increasingly adopting genome-scale approaches, a comprehensive understanding of gene functions requires the parallel development of deep phenotyping platforms. This Review discusses strategies for broad-based mouse phenomics, applied both to gene knockout collections and to diverse strains harbouring natural genetic variation. The authors discuss technical challenges, analysis pipelines and insights into human disease genetics.

Various genomics-related fields are increasingly taking advantage of long-read sequencing and long-range mapping technologies, but making sense of the data requires new analysis strategies. This Review discusses bioinformatics tools that have been devised to handle the numerous characteristic features of these long-range data types, with applications in genome assembly, genetic variant detection, haplotype phasing, transcriptomics and epigenomics.

Despite the remarkable throughput of next-generation sequencing technologies, standard techniques are limited by the difficulty in distinguishing sequencing errors from genuine low-frequency DNA variants within heterogeneous cellular or molecular populations. This Review discusses sequencing methodologies and bioinformatic strategies that have been devised for the reliable detection of rare mutations and describes various important applications in diverse fields including cancer, ageing and metagenomics.

Fruit flavour is a complex phenotype that has been adversely affected by human intervention. Recent progress in defining the chemistry of consumer preferences and the availability of high-quality genome sequences are providing a foundation for defining the genetics underlying this trait and could be used for flavour improvement.