Review Articles in 2015

The authors review the history, prospects and challenges of using molecular clock dating to estimate the timescale for the Tree of Life in the genomics era, and trace the rise of the Bayesian molecular clock dating method as a framework for integrating information from different sources, such as fossils and genomes.

Long non-coding RNAs (lncRNAs) are a class of RNAs with great molecular and regulatory diversity. This Review discusses how, beyond their lack of protein-coding potential, some types of lncRNAs are known to exhibit features that are distinct from mRNAs, including their transcriptional regulation, localization, processing, biological capabilities and degradation. Such properties underlie many of the key cellular functions of lncRNAs.

The differentiation of sex chromosomes in vertebrates created a need for mechanisms that compensate for differences in dosage of gene expression between the sexes. The author reviews the diversity of these mechanisms, their effects on gene expression, and their origin and evolution across the major vertebrate groups.

Complex and intricate RNA splicing mechanisms are crucial for gene regulation and for maximizing proteomic diversity. This Review discusses how alterations to splicing mechanisms — such as mutations in pre-mRNAs, or mutations and dysregulation of core spliceosome proteins and other RNA-binding proteins — results in diverse molecular consequences and various diseases. Opportunities for therapeutic correction of these defects are also explored.

With biomedical datasets growing exponentially in size and number, efforts to increase their utility and availability are essential, but much work remains to maximize exploitability. This Review summarizes trends, developments and future perspectives in the rapidly advancing field of human genotype–phenotype databases.

The rapid accumulation and increasing quality of human DNA sequence-variation data brought about by advances in genome-scale sequencing present opportunities to investigate human evolution. The authors discuss the statistical methods and models that can be used to gain insight into the evolution of human populations from analyses of large-scale genomic data sets, as well as the challenges associated with these approaches.

The phenotypic heterogeneity of intellectual disability (ID) disorders has hampered studies of the underlying genetics, but major progress has been achieved by recent applications of next-generation sequencing. This Review discusses our latest understanding of ID genetics, including the identification ofde novoand inherited mutations of various types, strategies for assigning disease causality to the mutations, emerging pathological mechanisms and future research directions.

Many disease-associated genetic variants have been identified, but how genetic variation contributes to protection from disease is less well understood. In this Review, the authors discuss the identification and characterization of protective alleles and modifier variants, and the potential implications of these findings for disease prevention and drug development.

The recent rise in obesity and its associated diseases has sparked intensive research into the transcriptional control of metabolic processes, collectively termed energy homeostasis. The authors review our current understanding of transcriptional and epigenetic regulators of energy homeostasis and crosstalk between pathways, and provide insights into emerging developments and challenges in this field.

Various methodologies have been developed to characterize diverse features of chromatin, but understanding how epigenomic states contribute to cellular heterogeneity requires adoption of these techniques at the single-cell level. This article discusses the technological developments driving single-cell epigenomics, including the practical and bioinformatic challenges and emerging biological insights.

In diploid organisms, expression from only one allele is frequently observed. This Review focuses on the widespread random monoallelic expression (RME) of autosomal genes, highlighting both the mitotically stable form observed in bulk analyses of cell populations and the recently discovered dynamic form identified through single-cell studies. The article also addresses the implications of different experimental criteria for calling monoallelic expression and potential biological roles in disease manifestations.

The wealth of existing and emerging DNA-sequencing data provides an opportunity for a comprehensive understanding of human genetic variation, including the discovery of disease-causing variants. This Review describes how the limitations of current reference-genome assemblies confound the characterization of genetic variation and how this can be mitigated by important advances in algorithms and sequencing technology that facilitate thede novoassembly of genomes.

In this Review, the authors discuss the concept, and possible mechanisms, of non-genetic transgenerational inheritance. They outline the evidence to date that environmental factors can influence behaviour across generations in mammals through the modification of epigenetic marks and/or non-coding RNAs.

R loops form when a transcript hybridizes to a complementary DNA locus to result in an RNA–DNA hybrid and a displaced single DNA strand. Such structures can have detrimental cellular roles by causing genome instability. However, recent studies have provided detailed views of genome-wide R-loop occurrences and uncovered various apparently beneficial roles in gene regulation. This Review discusses our latest understanding of the contrasting functions of R loops and the implications for genome regulation and various diseases.

The plant circadian clock regulates many physiological processes, such as growth, flowering time, abiotic and biotic stress responses, and metabolism. In turn, many of these responses feed back to control the circadian clock. This Review describes the integration of circadian dynamics into the study of plant physiological processes and highlights the importance of incorporating circadian, spatial and temporal information into predictive models to improve crop breeding.

Ecological evolutionary developmental biology (Eco-Evo-Devo) is a relatively new field that integrates developmental biology and ecology into evolutionary theory. The authors review new research in this field relating to the roles of developmental plasticity and developmental symbiosis in evolution.

Combining experimental evolution with next-generation sequencing, the evolve and resequence (E&R) approach is a powerful method for dissecting the genomic changes underlying the adaptation of populations of laboratory organisms or molecules. This Review describes the E&R results from diverse systems and discusses the extent to which various features, including population genetics, experimental setups and reproduction modes, account for the distinct observed outcomes.

Mitochondrial DNA (mtDNA) mutations have been associated with numerous human diseases, from severe inherited disorders to common late-onset diseases. In this Review, the authors consider the origins of these mtDNA mutations in a single cell, their spread across populations and their contributions to disease risk.

Small interfering RNA (siRNA)-based drugs offer a promising approach to block the synthesis of disease-causing proteins, although their delivery has posed challenges. The authors review recent advances in siRNA therapeutics, including progress in overcoming delivery challenges, and clinical trials showing efficient and durable gene knockdown in the liver.

There is accumulating evidence that the genetic code is not fixed but instead varies across organisms and that decoding is influenced by genomic and physiological contexts. This Review describes the various types of non-standard decoding, including altered codon meanings and ribosomal frameshifting, and highlights their pervasiveness, classification and biological implications.