Review Articles in 2016

In this article, the author reviews the current understanding of the genetic basis for Down syndrome phenotypes, including congenital heart defects, Alzheimer disease and leukaemia. The potential for Down syndrome therapies is discussed in light of recent progress in the field.

Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling.

Many genetic studies focus on germline-inherited genomic variation. However, there is increasing realization that mutations occurring during our lifetime are so frequent and pervasive that, in all likelihood, no two of our cells are truly genetically identical. In this Review, the authors describe the detection, molecular nature and dynamics of this under-appreciated post-zygotic variation, and discuss the implications for normal human physiology and disease.

A wealth of data is emerging from diverse studies of epigenomics, including genome-scale profiles of DNA methylation, histone modifications and higher-order chromatin features. In this Review, the authors discuss how, despite all this information, many challenges remain for inferring and proving the physiological and pathological functions of chromatin states. They describe the degrees of 'functionality' that are revealed by different experimental approaches, the value of integrative strategies and visions for the future.

Genome-wide mapping, mathematical models and functional genetic analyses suggest that distinct molecular interactions at replication initiation sites underlie the regulation of DNA replication in metazoans. In this Review, the authors discuss recent insights into these DNA–protein interactions, and the genetic and epigenetic features of mammalian replication origins.

Transposable elements (TEs) are widely known for their deleterious consequences of selfish propagation and mutagenesis. However, as described in this Review, TEs also provide hosts with rich, beneficial gene-regulatory machinery in the form of regulatory DNA elements and TE-derived gene products. The authors highlight the diverse regulatory contributions of TEs to organismal physiology and pathology, provide a framework for responsibly assigning functional roles to TEs and offer visions for the future.

With the increasing availability of microbial whole genomes, researchers are beginning to carry out genome-wide association studies (GWAS) in bacteria, viruses and protozoa. In this Review, the authors discuss the specific challenges and considerations associated with the application of GWAS methods to microorganisms and consider the future of microbial GWAS in the light of lessons learned from human studies.

Investigating the genetic basis of complex traits and diseases using individual-level genetic data from genome-wide association studies is often hampered by privacy concerns and logistical considerations. Here, the authors review recent statistical methods that leverage summary association data, which are widely available and can circumvent these issues.

To characterize the genetic underpinnings of speciation, genome scans can identify genomic regions that differ between divergent populations of wild organisms. In this Review, Wolf and Ellegren describe the methodological details of these approaches and how genomic islands of differentiation should be interpreted cautiously in the search for 'speciation genes'. They also discuss methodological best practice that takes into consideration genomic differentiation occurring through speciation-independent evolutionary processes.

In this article, the authors review the current understanding of the molecular mechanisms underlying cell type identity and discuss how new phenotypic features of cell types evolve. They explain how evolutionary lineage differs from developmental lineage and highlight how an evolutionary view of cell type identity can facilitate research in comparative cell biology.

MicroRNAs (miRNAs) have emerged as crucial components of gene-regulatory networks, in which they act alone or cooperatively to regulate gene expression. Here, the authors provide a systems-biological view of miRNA function and how disruption of miRNA networks can lead to malignancy.

Loss-of-function (LOF) approaches are powerful experimental tools for characterizing gene functions. However, emerging discrepancies when genes are investigated using different tools or organisms has triggered debate about how such LOF results should be biologically interpreted. In this Review, experts from varied fields discuss how understanding the underlying features of each LOF approach can provide explanations for different experimental outcomes and can guide their optimal and reliable application.

A genome sequence is only useful once the information encoded in it can be deciphered. In this Review, Mudge and Harrow describe the latest approaches to higher eukaryote gene annotation, including making the best use of complex transcriptome data sets, integrating evidence for functionality and extending annotations to encompass regulatory features.

In this Review, the author discusses current knowledge on the paramutations that occur in maize and contrasts these behaviours with potentially parallel examples in metazoans. He highlights the key role of small RNAs (sRNAs) in diverse paramutation mechanisms across eukaryotes and considers the evolutionary importance of these regulatory systems.

In this article the authors review current knowledge on chromatin architecture and the molecular mechanisms that underlie it. They discuss how three-dimensional (3D) organization of chromatin relates to gene expression, development and disease, and consider its effect on genome evolution.

Circular RNAs (circRNAs) are pervasively expressed in eukaryotic genomes, representing the major transcript isoform for many genes. In this article, the authors review sources of experimental and bioinformatic biases that complicate the accurate discovery of circRNAs and discuss statistical approaches used by published algorithms to address these biases.

Studies have demonstrated that paternal traits acquired in response to environmental conditions can be inherited by the offspring, sometimes persisting for multiple generations. In this Review, the authors discuss the accumulating evidence of a major role for sperm RNAs and RNA modifications in the inheritance of acquired traits and the mechanisms that may underlie this.

Recent drug discovery efforts in cancer have focused on epigenetic marks, such as DNA methylation and histone modifications. The authors discuss existing therapeutics that target the cancer epigenome, the role of epigenetic marks as biomarkers of drug response and emerging strategies that combine epigenetic drugs with other cancer therapies.

Numerous long non-coding RNAs (lncRNAs) have emerged as having important and mechanistically diverse roles in gene regulation. However, for most lncRNAs, evolution is rapid and functions remain uncharacterized. This Review describes how comparative genomics and transcriptomics can provide broad insights into the functional importance and evolutionary trajectories of lncRNAs across species, and offers guidance for cross-species studies of lncRNAs.

In early germline development, extra-embryonic signals trigger a regulatory network that induces the specification and subsequent epigenetic reprogramming of primordial germ cells, the precursors of sperm and eggs. Here, the authors review germline specification and reprogramming in humans, and discuss the crucial mechanistic differences between these processes in humans and mice.