Review Articles

The authors review the history of, and recent progress towards, mapping genes for type 2 diabetes mellitus (T2D), discuss the consequent implications for disease genetic architecture and propose open and interactive sharing of data by an integrated T2D web portal as a new research paradigm to hasten clinical translation of genetic discoveries.

Marine vertebrates are key contributors to global biodiversity and human food supply. In this Review, the authors discuss how comparative genomics studies in marine vertebrates have provided insight into major evolutionary transitions between the land and sea, as well as intra-species adaptation to diverse types of aquatic environments. They also highlight applications in species management and conservation.

Cancer immunotherapies are promising strategies for cancer treatment. However, their optimized use will require a comprehensive understanding of the diverse cell types, antigens and genetic variants (both germline and somatic) that comprise the tumour–immune system interface. This Review discusses various bioinformatics tools that process multi-level omics data for insights into tumour–immune cell interactions.

Computer simulation of next-generation sequencing data can be extremely useful for assessing and validating biological models, benchmarking sequence analysis tools or gaining an understanding of specific data sets. Here, the authors review the functionality, requirements and applications of 23 currently available simulation tools and provide a guide for the selection of the most appropriate one.

The degree of genetic diversity differs greatly among species and across genomic loci within genomes. The wide ranges in genetic diversity have important implications, including for evolution, conservation and management of wild and domesticated species. In this Review, the authors discuss how genome-scale sequencing strategies are providing insight into the varied determinants of genetic variation both among species and across genomic regions.

Advances in transcriptomics and analysis have identified thousands of previously unknown non-canonical splicing events. In this Review, the authors discuss the mechanisms and functions of these events and their roles in a variety of diseases. They explain how non-canonical splicing mechanisms can be targeted or exploited for therapeutic strategies.

Advances in DNA sequencing technologies have led to vast increases in the diversity of sequencing-based applications and in the amount of data generated. This Review discusses the current state-of-the-art technologies in both short-read and long-read DNA sequencing, their underlying mechanisms, relative strengths and limitations, and emerging applications.

The authors review recent studies into the heritable basis of population epigenomic variation and discuss important challenges when interpreting results from these genetic studies in different species to highlight the state of knowledge regarding how genetic variation can influence differences in chromatin states between individuals.

Common diseases have complex aetiology involving the interplay of genetic susceptibility and environmental risk factors. Here, the authors describe methods for building and evaluating models for the prediction of disease risk based on information from genetic testing and environmental factors, and use case studies to illustrate the potential of such models in the prevention of diseases.

Gene loss is emerging as a pervasive source of genetic variation. The authors review the mechanisms by which gene loss has influenced evolution of different species and discuss insights from comparative population genomics studies of gene loss. Further, they highlight future directions for the study of gene losses and their relevance in evolutionary biology and biomedicine.

Applying CRISPR–Cas9 genome editing technologies in safe and reliable ways requires a firm appreciation of the specificity of target-site recognition and cleavage. In this Review the authors discuss various approaches for characterizing off-target effects of CRISPR–Cas9 genome editing, how mechanistic knowledge can drive the engineering of more-specific nucleases, and the implications for research and therapeutic applications.

Empirical evidence supporting the competitive endogenous RNA (ceRNA) hypothesis is accumulating, but studies that model transcriptome-wide binding site abundance suggest that physiological expression changes of most individual transcripts do not compromise microRNA (miRNA) activity. This Review aims to critically evaluate the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions.

RNA sequencing (RNA-seq) is a powerful approach for comprehensive analyses of transcriptomes. This Review describes the widespread potential applications of RNA-seq in clinical medicine, such as detecting disease-associated mutations and gene expression disruptions, as well as characteristic non-coding RNAs, circulating extracellular RNAs or pathogen RNAs. The authors also highlight the challenges in adopting RNA-seq routinely into clinical practice.

In this Review, the author discusses the extent to which adaptive convergence in protein function is caused by convergent or parallel changes at the amino acid level, and addresses questions about the repeatability and predictability of molecular evolution.

Disruption to the epigenome is increasingly appreciated as a major contributor to the development of cancer. The authors discuss how conceptualizing genes affecting the epigenome as epigenetic modulators, epigenetic modifiers or epigenetic mediators provides a valuable framework for understanding diverse aspects of the causes and consequences of epigenome alteration in cancer.

In this Review, the authors highlight the potential for efficacy genetics to drive drug development and guide treatment options. They argue for the integration of routine pharmacogenetic screening into clinical development and propose strategies for identifying efficacy loci for marketed drugs.

The observation that many, if not all, functional enhancers generate non-coding enhancer RNAs (eRNAs) has raised critical questions regarding the potential biological roles of the enhancer transcription process and, indeed, of eRNAs. This article reviews fundamental insights into the inter-regulation of enhancers and promoters and discusses unresolved questions regarding the functional role of enhancers as transcription units in genome regulation.

Recent studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based and in DNA replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and the tremendous plasticity and dynamic nature of our genome.

Genome-wide approaches have advanced the study into mechanisms triggering autoimmunity. This Review illustrates how this has been achieved for twelve common autoimmune diseases, and discusses recent functional genomics approaches that have the potential to help define key immune molecular traits, cell types and cell states.

RNA-guided endonucleases have the potential to revolutionize the engineering of synthetic gene drives, which may be particularly useful for the control of vector-borne diseases. Here, the authors review different types of engineered gene drives and their potential applications, as well as considerations regarding the safety and regulation of gene drives for the manipulation of wild populations.