Review Articles in 2015

Genome engineering can be used to introduce targeted genetic changes to design and reprogramme organisms, to introduce new functionalities and to discover causal associations in evolving phenotypes. In this Review, the rationale, techniques and applications in genome engineering are described, outlining key advances, technological goals and challenges, as genome engineering approaches move towards massively parallel platforms.

Robustness of a phenotypic trait is characterized as lack of, or low, variance in that phenotype under a particular genetic or environmental perturbation. The authors review recent studies characterizing robustness, provide guidance in reporting robust features and insights into how variation propagates across biological systems.

The extent of horizontal gene transfer (HGT) is now becoming apparent. In this Review, the authors describe the mechanisms of HGT using examples from recent findings of HGT between prokaryotes and eukaryotes (including the human microbiome), and also between multicellular eukaryotes. They further describe the acquisition of novel traits via HGT in an evolutionary context.

The emergence of drug resistance is a major challenge for controlling diverse infectious diseases and cancer. In this Review, the authors discuss the mechanisms and evolutionary consequences of drug resistance. They highlight commonalities and distinctions across diverse pathogens and systems, and the implications for optimizing the current use and future development of drug therapies.

The study of the genetic basis of neurodevelopmental disorders and neurodegenerative diseases has progressed through recent large-scale association studies as well as the application of a range of high-throughput molecular methods. In this Review, the authors examine systems biology approaches and demonstrate how gene networks provide an organizing framework to integrate the analysis of large-scale genetic and molecular profiling data sets to characterize the genetic basis of phenotypes that affect the central nervous system.

MicroRNAs (miRNAs) repress gene expression both through initiating mRNA degradation and through translational repression. This Review describes how molecular studies and structural data are revealing key insights into both mechanisms of miRNA-mediated gene repression in animals, including their intricate interplay, and are posing new questions for future research.

The rate and mechanism of protein sequence evolution are fundamental questions in the field of molecular evolution. This Review examines theoretical models and empirical testing based on recent analyses of large-scale genomic data sets that have offered new insights into the determinants of the rate of protein evolution.

Directed evolution uses laboratory-based evolution to enhance the properties of biomolecules, primarily to generate proteins with optimized or novel activities. This Review discusses the diverse range of technologies for the directed evolution of proteins, particularly methods for generating diversity in the gene library and approaches for screening and selecting for variants with desired properties. The relative strengths and limitations of these approaches are highlighted to guide readers to appropriate strategies.

Sequencing genomes of ancient specimens, including human ancestors, can provide rich insights into evolutionary histories. However, ancient DNA samples are frequently degraded, damaged and contaminated with ancient and modern DNA from various sources. This Review describes the methodological and bioinformatic advances that allow these challenges to be overcome in order to process and sequence ancient samples for genome reconstruction, as well as recent progress in characterizing ancient epigenomes.

The analysis of whole-genome sequence data from both modern and ancient humans has provided evidence for archaic adaptive introgression. Here, the authors provide an overview of the statistical methods used and the supporting evidence for reported examples of archaic introgression, which may have driven the acquisition of beneficial variants that enabled adaptation and survival in new environments.

A large proportion of genetic variants in the human genome have been predicted to be deleterious. This Review examines the frequency and patterns of deleterious alleles in the human genome and considers recent studies with conflicting findings on whether the mutation load, or burden of deleterious alleles, differs across populations.

Machine learning methods are becoming increasingly important in the analysis of large-scale genomic, epigenomic, proteomic and metabolic data sets. In this Review, the authors consider the applications of supervised, semi-supervised and unsupervised machine learning methods to genetic and genomic studies. They provide general guidelines for the selection and application of algorithms that are best suited to particular study designs.

High-throughput DNA sequencing technologies are providing an ever-expanding wealth of genome sequence data, including detailed information on human genetic variation. However, such data typically lack haplotype information (that is, thecis-connectivity of variants along individual chromosomes). This Review describes diverse recent experimental methods by which genetic variants can be resolved into haplotypes, accompanying computational methods and important applications of these methods in genomics and biomedical science.

Arabidopsis thaliana, a member of the phenotypically diverse Brassicaceae family, has proved to be a key model organism for characterizing plant genome and morphological evolution. This Review outlines how recent comparative and functional genomic studies usingArabidopsisrelatives have further advanced our understanding of plant diversity and evolution.

CRISPR–Cas9 has been adopted as a powerful genome-editing technology in various species. By generating libraries of thousands of guide RNAs — which direct the Cas9 nuclease to chosen genomic loci — high-throughput genetic perturbations are now possible. This Review discusses the latest applications of CRISPR–Cas9 in mammalian functional genomics screens. It covers related genome-scale applications of Cas9 for either gene knockout or transcriptional modulation, and provides comparisons with complementary RNA interference (RNAi)-based approaches.

Before genome-wide association studies, linkage analysis was the primary approach used for genetic mapping of complex traits in humans. Now, with the widespread application of whole-genome sequencing (WGS), linkage analysis based on WGS data is emerging as a useful tool for the identification of susceptibility genes for human disease. This Review reiterates the main principles of linkage analysis and provides guidelines for performing linkage analysis on WGS data.

Host–pathogen interactions influence genetic diversity, and comparative genomic analyses are beginning to dissect genetic determinants involved in this process. This Review describes examples of such host–pathogen interactions and outline evolutionary approaches that are useful for identifying genomic regions associated with susceptibility to infection in mammals.

The rising human population and climate instability are putting unprecedented pressure on global agricultural practices. This Review describes the diverse mechanisms by which plants tolerate various stresses, such as flooding, drought, toxins, salinity and temperature extremes. The authors focus on how the genetic loci that underlie these survival and tolerance traits can be introgressed into current crops to improve yield stability.

The evolution of genes is influenced by regional variation in mutation rates (RViMR). Chromatin organization affects RViMR, although the correlation between chromatin state and mutation types and rates is complex. This Review describes recent research on RViMR and chromatin organization, and the emerging findings from investigations of both germline and somatic mutations.

Rett syndrome is a neurological disorder associated with mutations in the X-linked geneMECP2(methyl-CpG-binding protein 2). This Review details emerging insights into the link between the functions of MeCP2 and the pathogenesis of Rett syndrome.