Reviews & Analysis

Saccharomyces cerevisiaehas become an important model organism in the field of evolutionary genomics. Comparative genomic analysis of laboratory, wild and domesticated yeast populations is generating insights into how new species form and how populations adapt to their environments.

To unlock the potential of epigenetic variation for crop improvement, it will be crucial to understand how epigenetic variation is established and how it is stably inherited across generations. Springer and Schmitz review these challenges, the different sources of epigenetic variation in plants, and how epigenome profiling and engineering could help to improve crops.

The authors review the concept of synthetic lethality — when the perturbation of one of two genes alone is viable, but the perturbation of both genes simultaneously results in the loss of viability — from model organisms to human cancers, and discuss how genetic interactions can be exploited for the identification of new drug targets in cancer.

Technical errors can hamper the interpretation of next-generation sequencing (NGS) data, which poses a major challenge for the clinical application of this technology. This Review discusses how reference standards circumvent this issue by calibrating NGS measurements and evaluating diagnostic performance of NGS-based genetic tests.

Network propagation is based on the principle that genes underlying similar phenotypes are more likely to interact with each other. It is proving to be a powerful approach for extracting biological information from molecular networks that is relevant to human disease.

Epigenome-wide association studies (EWAS) are potentially powerful approaches for identifying transcriptional regulatory perturbations (particularly DNA methylation) that associate with phenotypes of interest. In this Opinion article, Lappalainen and Greally provide their views on how to maximize the interpretability and biological insights from these associations, such as by hypothesis-driven consideration of cellular phenotypes, characterizing the roles of transcription factors, dissecting directions of causality and moving towards multi-omics profiling.

Genetic variation of the human Y chromosome plays a key part in studies of human evolution, population history, genealogy, forensics and male medical genetics. This Review outlines how next-generation sequencing has contributed to recent progress in these fields.

A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.

A full understanding of chromatin in diverse cellular processes requires the consideration of its dynamics, but most standard chromatin assays provide only a static snapshot. This Review describes various emerging methods for probing chromatin dynamics across a wide range of temporal and spatial scales, and discusses the resulting biological insights.

Polyploidy occurs frequently but is usually detrimental to survival; thus, few polyploids survive in the long term. Here, evidence linking the short-term evolutionary success of polyploids to environmental upheaval is reviewed and possible longer-term evolutionary benefits of polyploidy are discussed.

Three-dimensional genome organization can shape gene expression by facilitating interactions between regulatory elements. The authors review the process of X-chromosome inactivation with a focus on chromatin organization and subnuclear localization of the active and inactive X chromosomes, as well as the potential roles of long non-coding RNAs.

Multicellular organisms rely on a complex interplay between diverse cell types, but how multicellularity evolved from unicellular ancestors has long been a debated research question. In this Review, the authors describe how comparative and functional genomics have provided valuable insights into the transition between unicellularity and multicellularity, including how various molecular networks have been adopted for multicellular life.

Next-generation sequencing technologies have enabled the comprehensive characterization of human and mouse genomes, including at the transcriptional level. This article reviews the degree of conservation of human and mouse transcriptomes, along with the challenges of identifying when the mouse is a suitable model of human physiology.

As the genetic and phenotypic heterogeneities among cells become more appreciated, there is increasing demand for technologies that facilitate high-throughput and high-efficiency single-cell 'omic' analyses in miniaturized and automated formats. This Review discusses the diverse microfluidic methodologies — with a primary focus on valve-, droplet- and nanowell-based platforms — for characterization of the genomes, epigenomes, transcriptomes and proteomes of single cells, and addresses technical considerations and future opportunities.

The abundance and heterogeneity of mutations in cancer create challenges for understanding their effects, but such functional characterization will be crucial for optimizing clinical care. In this Review, the authors discuss diverse computational tools and systems biology experimental strategies for elucidating the functional effects of cancer mutations, including consequences on gene regulation, protein structure and local and global perturbations of molecular interaction networks.

The past decade has seen tremendous progress in understanding the genetic architecture of coronary artery disease (CAD). Khera and Kathiresan review research efforts that have improved our understanding of the genetic drivers of CAD, and discuss the promises and challenges of integrating genetic information into routine clinical practice.

Next-generation sequencing has facilitated the study of how transposable elements and retroviruses select their diverse genomic sites of integration, and revealed integration site preferences that range from specific nucleotide sequences to particular chromatin states. The authors review the various mechanisms of integration site selection in eukaryotes, as well as the molecular and cellular determinants that guide this process.

Advances in genetics and genomics have transformed the field of organ transplantation. Here, the authors review the role of genetic dissimilarities between donor and recipient in transplant tolerance and rejection, and how the identification of genetic variants that predict adverse transplant outcomes can be used for personalized medicine.

Various large studies have provided unprecedented insights into the genetics of autism spectrum disorders (ASDs). This Review discusses the challenges and opportunities of translating genetic and biological insights into clinical progress for ASDs, in areas including genetic testing, ASD classification, genetic counselling, comorbidities and therapeutics.

Although it has been known for decades that RNA is subjected to numerous covalent modifications, there has been a recent surge in interest driven by sequencing-based transcriptome-wide detection methods and the realization that RNA modifications have important roles in diverse biological processes. This Review describes the range of detection strategies for RNA modifications, their particular strengths and limitations, and how responsible and complementary application of these techniques will be required to ensure the quality and interpretability of the rapidly accumulating data sets.