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Patterns of amino acid conservation have been used to guide the interpretation of the disease-causing potential of genetic variants in patients; now, an appreciable fraction of pathogenic alleles are shown to be fixed in the genomes of other species, suggesting that the genomic context has an important role in allele pathogenicity.

Ivona Aksentijevich and colleagues identify heterozygous loss-of-function mutations in TNFAIP3 (encoding A20) in six unrelated families with early-onset systemic inflammation. Affected individuals exhibit increased expression of NF-κB–mediated proinflammatory cytokines, consistent with the established role of A20 as a potent inhibitor of the NF-κB signaling pathway.

Ton, Keitley et al. provide a morphological and molecular atlas of rabbit development. Comparative studies reveal that combining rabbit and mouse atlases can serve as a model for dissecting early primate development.

Data on the richness and composition of the skin microbiome from 2,349 individual amphibians, representing 205 species across a broad geographic range, is compared with local biotic and abiotic environmental factors.

This protocol describes SHIMS 2.0, a method to generate accurate reference sequences from structurally complex genomic regions in a cost-effective, high-throughput manner.

H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.

Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD.

PfLPLAT1 has important roles in the phospholipid synthesis pathway of Plasmodium falciparum, particularly phosphatidic acid as an essential substance for cytostome internalization. Its dysfunction leads to cell cycle arrest and death of parasites.

Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

An analysis of the finished sequence of human chromosome 12 representing 4.5% of the human genome determines that chromosome 12 hosts a number of genes mutated in specific cancers, as well as movement disorders and potentially Alzheimer's disease.

Rett syndrome is caused by mutation of the MECP2 gene that codes for a protein that binds methylated DNA; this study reveals that MeCP2 affects the expression of long genes, which often serve neuronal functions.

Whole-genome sequencing and comparative genomic analysis of immune-related genes of Cercocebus atys and Macaca mulatta identify candidate genes, such as ICAM2 and TLR4, that may explain the AIDS resistance of C. atys.

A collection of 1,406 high-quality, immunoprecipitation- and immunoblotting-grade monoclonal antibodies to 737 human transcription factors is made available as a community resource, along with all validation data.

Rare truncating mutations in the p53-inducible protein phosphatase PPM1D are shown to be associated with predisposition to breast cancer and ovarian cancer; notably, all of the mutations are mosaic in white blood cells but are not present in tumours, and probably have a gain-of-function effect.

A C-SWAT acceptor library allows the user to easily insert any tag of choice after yeast ORFs by swapping it for the acceptor module.

Zhu et al. discover that in human brain there is widespread anatomic distribution of low-frequency somatic, mosaic L1 insertions, using deep whole-genome sequencing of neuronal and glial fractions and machine-learning analysis.

The observations that introns are acquired in bursts and that exons are often nucleosome-sized can be explained by the generation of introns from DNA transposons, which insert between nucleosomes.

David Reich, Shamil Sunyaev and colleagues report an analysis of the per-genome accumulation of nonsynonymous substitutions across diverse pairs of human populations. They find no evidence for a higher load of deleterious mutations in non-Africans than in West Africans and show that the observed patterns are not likely to reflect changes in natural selection.

In vivo and in vitro studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors.

Eli Stahl, Robert Plenge and colleagues report the application of a polygenic analysis, using a Bayesian inference framework, to rheumatoid arthritis GWAS datasets. They find that polygenic risk scores are associated with rheumatoid arthritis case-control status and estimate the total variance explained by common variants in these GWAS. They show comparable estimates for applications to GWAS for celiac disease, myocardial infarction and coronary artery disease and type 2 diabetes.

Although multiple reaction monitoring (MRM) mass spectrometry holds considerable promise for quantifying candidate protein biomarkers in blood, transferability of MRM assays between laboratories has never been shown. Addona et al. assess the reproducibility, dynamic range and limits of detection and quantification of MRM across multiple sites.

Mutations in a small noncoding gene called RNU4-2 are responsible for one of the most common neurodevelopmental disorders that is mediated by a single gene.

The popularity ofCaenorhabditis elegans as a model organism is paralleled by the range of resources that are available to worm researchers. This Review provides a guide to existing C. elegansresources, and highlights areas for future development.

Richard O'Connell and colleagues report the genomes and transcriptomes of two Colletotrichum plant fungal pathogens. C. higginsianum infects Arabidopsis thaliana, and C. graminicola infects maize (Zea mays); comparative genomics in both species lead to molecular insights into the transition from biotrophic to necrotrophic life stages.

Sunetra Das et al. combine genetic and immunohistochemistry data to characterize mutation and expression profiles of canine osteosarcoma and its association with clinical outcomes. Their results provide further insight into the pathogenesis and potential future therapeutic targets for osteosarcoma.

Data-driven disease progression models are computational tools that infer long-term disease timelines from short-term biomarker data and may provide insights into disease processes. In this Review, Young, Oxtoby et al. provide an overview of such models, with a focus on how they have been used in the context of neurodegenerative diseases, notably Alzheimer disease.

Vivianna Van Deerlin and colleagues report that common variants at 7p21 are associated with a subtype of frontotemporal lobar degeneration marked by TDP-43 inclusions. They further show that the risk alleles are associated with elevated brain expression of TMEM106B, which resides at the peak of association on 7p21.

Matched Annotation from NCBI and EMBL-EBI (MANE) delivers joint transcript sets from Ensembl/GENCODE and RefSeq for standardizing variant reporting in clinical genomics and research.