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  • 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
  • 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
  • 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
    • Patricia L. Foster
  • 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
  • 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
  • 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
  • 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
  • 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
    • Michael Wigler
  • 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
  • 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
  • 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
    • Peter M. Visscher
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
    • Teri A. Manolio