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Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, the authors show that the pathogenesis of limb reduction in an Esco2 cohesinopathy mouse model of Roberts syndrome has an underlying vascular etiology that is mediated by p53-signaling, sharing commonality with thalidomide embryopathy.

Cancer mutational signatures have been associated with defects in genome maintenance pathways. Here the authors, by using a worm germline mutagenesis model defective of human orthologue BRCA-1, identify polymerase theta-mediated end-joining (TMEJ) as causing the BRCAness mutational signature.

The use of automated tools to reconstruct lipid metabolic pathways is not warranted in plants. Here, the authors construct Plant Lipid Module for Arabidopsis rosette using constraint-based modeling, demonstrate its integration in other plant metabolic models, and use it to dissect the genetic architecture of lipid metabolism.

The classification of psychiatric disorders in the DSM has been influential in neuroscience research but has also been subject to criticism. In this Viewpoint, six leaders in the field discuss whether the latest version, DSM-5, as well as the dimensional approach provided by the RDoC, will move psychiatry research forward.

Yurii Aulchenko and colleagues report a variance components–based method, GRAMMAR-Gamma, for genome-wide association studies including a large number of individuals and genetic markers. They demonstrate, using simulations as well as human and Arabidopsis thaliana data sets, that their method provides unbiased estimates of SNP effect and increases computational efficiency, which may facilitate analysis of human whole-genome resequencing studies.

This paper describes the use of paired Cas9 nickases to edit the mammalian genome with no detectable off-target effects.

CREST is a dual-recorder single-cell lineage tracing method for spatiotemporal mapping of the mouse brain.

The human genome still contains numerous uncharacterized genes. Here, the authors identify a fast evolving Factor associated with Metabolism and Energy (FAME) that is associated with altered body weight, energy expenditure, and metabolism and study its function in knockout mouse models.

SELECTIV is an efficient method for tissue-specific AAV-mediated transgene expression in mice mediated by AAV receptor overexpression.

Previous versions of photoactivatable Cre recombinase (PA-Cre) suffered from unintentional recombination in dark conditions. Here, the authors develop an improved version of PA-Cre, called PA-Cre 3.0, which shows reduced leakiness and improved efficiency upon activation, and make mouse lines that express PA-Cre 3.0 conditionally.

Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.

Developmental genes are frequently controlled by multiple enhancers sharing similar specificities, so deletions of such regulatory elements often fail to reveal their full function. Here the authors use the Pitx1 testbed locus to characterize the regulatory and cellular identity alterations following the deletion in vivo of one of its enhancers.

The mechanisms by which animals distinguish between harsh and gentle touch are unclear. UsingCaenorhabditis elegansas a model system, the authors identify neural circuits and touch-sensitive ion channels that are required for harsh touch sensation.

The domestic dog is an important model organism for our understanding of cancer and other diseases. Here the authors conduct a genome-wide association study across multiple breeds and identify novel loci significantly associated with several complex diseases and morphological traits.

Two conditional transgenic mouse lines based on CRISPRa and CRISPRi enable epigenome editing in vivo.

Humanized mouse models are useful for studies of human hematopoiesis and immunity. Li et al. report an improved model that harbors lymph nodes and therefore permits investigation of local human adaptive immune processes in secondary lymphoid tissue.

Individuals with Down Syndrome have hematopoietic abnormalities including high risk of leukaemia. Here the authors show that transcriptional silencing of one chromosome 21 by XIST effectively corrects cell function and development to prevent excessive production of megakaryocytes and erythroids, shown during hematopoietic differentiation of human iPSCs in culture.

This Resource describes genetic tools for microbial eukaryotes, providing a roadmap for developing genetically tractable organisms.

Embryonic stem cells undergo CRISPR–Cas9-mediated editing and are then used to reconstitute forebrain regions in mouse chimeras via neural blastocyst complementation.

Qiong Wang and colleagues introduce the AdipoChaser mouse, an in vivo tool to track the formation and turnover of adipocytes. They use this inducible mature adipocyte lineage-tracing system to monitor adipogenesis and follow the formation of white and beige adipocytes under different conditions: high-fat diet, cold exposure and β-adrenergic stimulation. The system produced some interesting findings on in vivo adipogenesis, including that beige adipocytes differentiate de novo from specialized precursors rather than by transdifferentiation of mature white adipocytes.

This Review presents arguments for and against each of two main models for the genetic basis of complex traits. It concludes that the infinitesimal model is essentially correct, but that rare, large-effect alleles also make an essential contribution to disease risk.

The African turquoise killifish is an extremely short-lived vertebrate that has emerged as an excellent model for aging research. Here, Harel et al describe how to successfully engineer its genome using CRISPR/Cas9 editing or Tol2-based transgenesis.

Crispr/Cas technology is a quick and efficient method of modifying the genomes of a range of organisms. Here the Jaenisch laboratory provides a protocol for CRISPR/Cas-mediated genome modification of mice.

Recurrent, reciprocal genomic disorders due to non-allelic homologous recombination (NAHR) are a major cause of human disease. The authors developed a CRISPR/Cas9 genome engineering method that directly targets segmental duplications and efficiently mimics the NAHR-mediated mechanism of microdeletion and microduplication that occurs in vivo using 16p11.2 and 15q13.3 as proof-of-principle models.

Heterologous TRP channels can be used to stimulate or ablate neurons in response to their chemical or thermal agonists in zebrafish larvae, providing a set of tools orthogonal to optogenetic manipulation.

The theoretical principles of adaptive evolution are being put to the test in a growing range of species and populations, particularly with new sequencing technologies and high-throughput experimental methods making headway in this area.

During cell reprogramming and direct cell fate conversion, changes in somatic and pluripotent cell fates do not require the passage through a hierarchy of distinct cell fates that are proposed to occur during normal development and are consistent with the original Waddington model. Instead, a 'flat epigenetic disc' model might explain cell fate transitions during these processes.