• Opinion |

    Advances in genome sequencing, editing and synthetic biology have enhanced the feasibility of large-scale genome engineering, termed genome writing. In this Opinion article, Chari and Church discuss the strengths and limitations of diverse strategies for genome writing, including extensively modifying existing genomes versus synthesizing genomesde novo, and they provide future visions for writing large genomes.

    • Raj Chari
    •  & George M. Church
  • Opinion |

    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.

    • Tuuli Lappalainen
    •  & John M. Greally
  • Opinion |

    Mutation is the source of genetic diversity on which natural selection acts, therefore understanding the rates of mutations is crucial for understanding evolutionary trajectories. In this Opinion article, the authors discuss how emerging experimental mutation-rate data from genome-wide sequencing studies, combined with population-genetic theory, can provide unifying explanations for the diversity in mutation rates between species and across genomic locations.

    • Michael Lynch
    • , Matthew S. Ackerman
    • , Jean-Francois Gout
    • , Hongan Long
    • , Way Sung
    • , W. Kelley Thomas
    •  & Patricia L. Foster
  • Opinion |

    Formal representations of Waddington's epigenetic landscape represent cell fate decisions as smooth, continuous events in which cells follow predetermined trajectories. Here, the authors provide an alternative interpretation and posit that fate decisions are discontinuous, stochastic events within cell lineages.

    • Naomi Moris
    • , Cristina Pina
    •  & Alfonso Martinez Arias
  • Opinion |

    In this Opinion article, the authors discuss important questions relating to the study ofde novo genes. They discuss the challenges of identifying de novogenes, understanding how they originate and why they spread, and propose that antagonistic evolution may have a key role in their evolution.

    • Aoife McLysaght
    •  & Laurence D. Hurst
  • Opinion |

    Transposable elements are key drivers of evolutionary innovation across many species. This Opinion article proposes evolutionary scenarios in which transposable elements have acted on innate immunity loci to generate adaptive immune systems and discusses striking parallels between the evolution of different adaptive immune systems: CRISPR–Cas in bacteria and archaea, and V(D)J recombination in vertebrates.

    • Eugene V. Koonin
    •  & Mart Krupovic
  • Opinion |

    In this Opinion article, the authors highlight the potential of genome engineering for the study of evolution and focus on microbial systems. They discuss the prospects and problems of the emerging field of evolutionary genome engineering, and pinpoint how a combination of genome engineering and laboratory evolution can shed light on evolutionary forces.

    • Csaba Pál
    • , Balázs Papp
    •  & György Pósfai
  • Opinion |

    In the past few years, there have been rapid advances in the identification of the genetic components of autism spectrum disorders, particularly in the form ofde novomutations. Here, the authors review these developments in light of genetic models for autism spectrum disorders.

    • Michael Ronemus
    • , Ivan Iossifov
    • , Dan Levy
    •  & Michael Wigler
  • Opinion |

    Next-generation sequencing for variant identification is now becoming widespread, although pipelines have not yet been optimized. In this Perspective article, the authors discuss ways to minimize erroneous variant calls, in particular, by using replicates.

    • Kimberly Robasky
    • , Nathan E. Lewis
    •  & George M. Church
  • Opinion |

    The authors discuss strategies and challenges of population-based studies of epigenetic variation. Such studies should contribute to our understanding of the contribution of epigenetic factors to human disease, but need to be performed and interpreted with consideration of their limitations.

    • Jonathan Mill
    •  & Bastiaan T. Heijmans
  • Opinion |

    The data from genome-wide association studies can be applied to genotype data to predict the phenotype of a complex trait. Here the authors discuss the potential pitfalls of such analyses and the inherent limitations of the method.

    • Naomi R. Wray
    • , Jian Yang
    • , Ben J. Hayes
    • , Alkes L. Price
    • , Michael E. Goddard
    •  & Peter M. Visscher
  • Opinion |

    The concepts of orthology and paralogy are fundamental to comparative genomics and are also frequently used for the functional annotation of uncharacterized genes. However, assumptions regarding function have recently been challenged, and the implications of assigning genes as orthologues or paralogues are far from straightforward.

    • Toni Gabaldón
    •  & Eugene V. Koonin
  • Opinion |

    Clinical sequencing tests that focus on genes linked to specific diseases or phenotypes are increasingly widely being used. This article discusses how disease-targeting tests retain several advantages despite moves towards the clinical application of whole-genome or exome sequencing.

    • Heidi L. Rehm
  • Opinion |

    In this Opinion article, the authors discuss models that could explain the evolution of stress-induced mutagenesis in bacteria. They include a new model that argues that genetic drift could have a role in the evolution of low-fidelity DNA polymerases.

    • R. Craig MacLean
    • , Clara Torres-Barceló
    •  & Richard Moxon
  • Opinion |

    Recent measurements of the human mutation rate using next-generation sequencing have revealed a value of approximately half of that previously derived from fossil calibration. Here, the authors discuss the implications of this revised mutation rate in relation to our understanding of human evolution.

    • Aylwyn Scally
    •  & Richard Durbin
  • Opinion |

    The author discusses the advantages and challenges of 'cellular phenotyping' and the way in which this integrated analysis of cellular phenotypes is likely to advance our understanding of the genetic and long-term environmental influences on complex traits.

    • Emmanouil T. Dermitzakis
  • Opinion |

    Meta-analyses that use data from several genome-wide association studies are revealing more disease-associated genetic variants, but how can the privacy of study participants be protected when data are shared? This article considers ways to evaluate the risk of loss of privacy.

    • David W. Craig
    • , Robert M. Goor
    • , Zhenyuan Wang
    • , Justin Paschall
    • , Jim Ostell
    • , Michael Feolo
    • , Stephen T. Sherry
    •  & Teri A. Manolio
  • Opinion |

    This Opinion article argues that capturing phase information in human genomics studies is crucial for important aims such as understanding how genotype contributes to phenotypes. existing approaches for phasing will need to be improved in order to meet this goal.

    • Ryan Tewhey
    • , Vikas Bansal
    • , Ali Torkamani
    • , Eric J. Topol
    •  & Nicholas J. Schork
  • Opinion |

    Chronic stress is increasingly implicated as a contributing factor in common diseases, including cancer, cardiovascular disease and diabetes. This Opinion article brings together evidence supporting the idea that stress can induce epigenetic changes that alter cell behaviour and thereby lead to disease.

    • Sarah E. Johnstone
    •  & Stephen B. Baylin
  • Opinion |

    Identity by descent (IBD) — the probability that two alleles descended from a common ancestor — is used in fundamental applications such as gene mapping and estimating heritability. The authors offer a solution to the confusion between IBD and identity by state (IBS) that is caused by the common practice of using dense SNPs to estimate IBD.

    • Joseph E. Powell
    • , Peter M. Visscher
    •  & Michael E. Goddard
  • Opinion |

    Batch effects can lead to incorrect biological conclusions but are not widely considered. The authors show that batch effects are relevant to a range of high-throughput 'omics' data sets and are crucial to address. They also explain how batch effects can be mitigated.

    • Jeffrey T. Leek
    • , Robert B. Scharpf
    • , Héctor Corrada Bravo
    • , David Simcha
    • , Benjamin Langmead
    • , W. Evan Johnson
    • , Donald Geman
    • , Keith Baggerly
    •  & Rafael A. Irizarry
  • Opinion |

    Recent evidence indicates that gene bookmarking — the combination of mitotic retention of transcription factors at promoters, histone modifications and DNA methylation — is a novel epigenetic mechanism that sustains cellular identity after mitosis. This Opinion article discusses the importance of bookmarking in biological control and disease.

    • Sayyed K. Zaidi
    • , Daniel W. Young
    • , Martin A. Montecino
    • , Jane B. Lian
    • , Andre J. van Wijnen
    • , Janet L. Stein
    •  & Gary S. Stein
  • Opinion |

    Increasing evidence suggests functional similarities between promoters and insulators. The authors propose that these findings unify existing models of insulator function, provide new directions for understanding how insulators work and suggest that insulators have evolved from promoters.

    • Jesse R. Raab
    •  & Rohinton T. Kamakaka
  • Opinion |

    Results from genome-wide association studies support the view that qualitative disorders can be interpreted as being the extremes of quantitative dimensions. Research on quantitative traits could have far-reaching implications for the diagnosis, treatment and prevention of the problematic extremes of these traits.

    • Robert Plomin
    • , Claire M. A. Haworth
    •  & Oliver S. P. Davis
  • Opinion |

    DNA methylation is a somatically heritable epigenetic mark that must be faithfully maintained through cell division. This re-examination of the evidence relating to how DNA methylation is maintained leads the authors to propose a revised model for this important biological process.

    • Peter A. Jones
    •  & Gangning Liang
  • Opinion |

    The authors argue that ancient whole-genome duplications might be linked to major ecological upheavals and extinction. When established, polyploidy might lead to increased vigour, species diversity and phenotypic novelties, and could therefore contribute to the evolutionary success of a lineage.

    • Yves Van de Peer
    • , Steven Maere
    •  & Axel Meyer
  • Opinion |

    Genome-wide association studies have identified many cancer susceptibility alleles, but much heritable risk for this complex heterogeneous disease remains unexplained. Mouse model studies are yielding evidence that integrated analysis of genetic and genomic data might prove a fruitful strategy to meet this challenge.

    • David Quigley
    •  & Allan Balmain
  • Opinion |

    The mitochondrion and plastid are derived from bacterial endosymbionts that were transformed over time into organelles. Here the authors posit an explanation for how the eukaryotic hosts controlled the evolution of these organelles through the establishment of protein-sorting systems.

    • Jeferson Gross
    •  & Debashish Bhattacharya
  • Opinion |

    Comparisons between species are essential for evo–devo research, but are there benefits in focusing on organisms in which sophisticated analytical tools are available? The author of this Perspective discusses this question, and also proposes further integration of evo–devo with other areas of evolutionary research.

    • Ralf J. Sommer
  • Opinion |

    The success of genome wide association (GWA) studies raises the hope that disease-associated markers will be useful in predicting disease risk. However, the metrics used to report effect sizes in GWA studies are not useful for determining the accuracy of genetic profiles.

    • Peter Kraft
    • , Sholom Wacholder
    • , Marilyn C. Cornelis
    • , Frank B. Hu
    • , Richard B. Hayes
    • , Gilles Thomas
    • , Robert Hoover
    • , David J. Hunter
    •  & Stephen Chanock
  • Opinion |

    In mammals, errors in synapsis are associated with impaired meiosis, which is male-biased and is associated with reduced fertility. The recent discovery that asynapsed chromosome segments are transcriptionally silenced has provided fresh insight into the connection between asynapsis and meiotic impairment.

    • Paul S. Burgoyne
    • , Shantha K. Mahadevaiah
    •  & James M. A. Turner
  • Opinion |

    Gene regulatory networks (GRNs) are hierarchically connected sub-circuits composed of genes and thecis-regulatory sequences on which they act. The authors propose that evolutionary alterations in morphology depend on the position in the GRN hierarchy at which regulatory change occurs.

    • Douglas H. Erwin
    •  & Eric H. Davidson
  • Opinion |

    Several models exist to explain the architecture of complex disease traits — each with its limitations. In this Perspective article it is proposed instead that human traits are canalized, and that their perturbation by genetic or environmental differences exposes genetic variation, leading to increased disease risk.

    • Greg Gibson
  • Opinion |

    Selectionists and neutralists invoke different theories to explain the emergence of evolutionary innovation. Our recent understanding of molecular phenotypes makes it possible to reconcile these two views by proposing that neutral variants prepare the ground for adaptive mutations to occur.

    • Andreas Wagner
  • Opinion |

    Current approaches for dissecting complex traits largely ignore epiallelic variation. To overcome this limitation the authors propose a quantitative approach to identifying the dynamic interplay between DNA sequence, chromatin and environmental contributions to the phenotype, across generations and developmental time points.

    • Frank Johannes
    • , Vincent Colot
    •  & Ritsert C. Jansen
  • Opinion |

    How did the complex regulatory networks that control eukaryotic gene expression evolve? This article explores evidence that transposable elements played an important part by providing thecis and transcomponents of these networks.

    • Cédric Feschotte
  • Opinion |

    The ability to evolve — evolvability — is important in determining the course of evolution. But does evolvability itself evolve, and how should we even agree on a definition of evolvability?

    • Massimo Pigliucci
  • Opinion |

    Evo–devo is now a mature field encompassing a wide range of research areas. The author offers his assessment of its main theoretical implications and challenges for the immediate future.

    • Gerd B. Müller
  • Opinion |

    Copy number variation constitutes a major source of inter-individual genetic variation that could explain variable disease penetrance and variation in the phenotypic expression of aneuploidies, and could be an important factor in the aetiology of complex traits. Therefore, systematic exploration of both single nucleotide and copy number variation will be key to identifying the genomic contributors to polygenic traits and diseases.

    • Jacques S. Beckmann
    • , Xavier Estivill
    •  & Stylianos E. Antonarakis
  • Opinion |

    The prevailing view is that planar cell polarity is the outcome of one genetic pathway. On the basis of their observations in genetically mosaic adult flies, the authors challenge this assumption and discuss potentially far-reaching implications of their model.

    • Peter A. Lawrence
    • , Gary Struhl
    •  & José Casal
  • Opinion |

    Some structures, such as mammalian forelimbs and bird wings, are obviously homologous, but the basis of this is often elusive as the developmental genes involved are not homologous. The author argues that it is instead the gene regulatory networks that are homologous.

    • Günter P. Wagner
  • Opinion |

    Evo–devo has inherited its model organisms from developmental biology. New models must now be chosen to study important phenomena that the original models do not represent. The authors discuss the best criteria for choosing new models.

    • Ronald A. Jenner
    •  & Matthew A. Wills
  • Opinion |

    Standardization and mass production have been invaluable in biological software, but what about accommodating the specific needs of different experiments? The authors propose a method for generating such customized software infrastructures from existing parts.

    • Morris A. Swertz
    •  & Ritsert C. Jansen
  • Opinion |

    This article argues that recombination has a far more important role in the evolution of plant genomes than is currently appreciated, and that genome-wide patterns of recombination might explain some intriguing differences between plant and animal genomes.

    • Brandon S. Gaut
    • , Stephen I. Wright
    • , Carène Rizzon
    • , Jan Dvorak
    •  & Lorinda K. Anderson