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Genome sequencing and phylogenomic analysis show that the lungfish, not the coelacanth, is the closest living relative of tetrapods, that coelacanth protein-coding genes are more slowly evolving than those of tetrapods and lungfish, and that the genes and regulatory elements that underwent changes during the vertebrate transition to land reflect adaptation to a new environment.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Single cell genome sequencing approaches have identified somatic copy number variants (CNVs) in human neurons, but small sample sizes (<100 neurons) have limited the power to find recurrent patterns such as CNV hotspots in a single individual. Here, the authors develop an approach to map CNVs in 2097 neurons from a neurotypical individual, finding that >10% neurons contain at least one somatic CNV, and enabling deeper investigation of these events.

HLA peptidomic analysis identifies recurrent intracellular bacteria-derived peptides presented on HLA-I and HLA-II molecules in melanoma tumours, revealing how bacteria can modulate immune functions and responses to cancer therapies.

Rodin and Dou et al. characterized genome-wide somatic mutation in autistic and control brains, revealing that even unaffected individuals may possess dozens of brain somatic mutations and providing insight into the role of somatic mutation in autism.

The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

SpaGCN is a spatially resolved transcriptomics data analysis tool for identifying spatial domains and spatially variable genes using graph convolutional networks.

The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.

VirtualFlow, an open-source drug discovery platform, enables the efficient preparation and virtual screening of ultra-large ligand libraries to identify molecules that bind with high affinity to target proteins.

Brain genetic co-expression networks pinpoint specific, convergent synaptic pathways—rather than the complement system—through which genetic variation at the C4 locus imparts risk for schizophrenia.

An improved, fully re-annotated Aedes aegypti genome assembly (AaegL5) provides insights into the sex-determining M locus, chemosensory systems that help mosquitoes to hunt humans and loci involved in insecticide resistance and will help to generate intervention strategies to fight this deadly disease vector.

Gnirke et al. present a bead-based method for capturing sequences of interest in the human genome for massively parallel sequencing. Using long, biotinylated RNA probes to pull down PCR-amplified DNA fragments, they demonstrate sequencing of 2.5 Mbs of exons in 1,900 genes.

Girdhar et al. constructed chromosomal domains from prefrontal histone acetylation and methylation maps and discovered, in a large cohort of schizophrenia and bipolar brains, converging alignment by genetic risk, neuronal function and three-dimensional genomics.

David Weinstock and colleagues identify a triplication at chromosome 21q22 that is associated with development of B cell acute lymphoblastic leukemia (B-ALL) that causes B cell self renewal in vitro. They further demonstrate that this triplication leads to overexpression of the nucleosome remodeling protein HMGN1 and loss of H3K27me3, implicating these changes in B-ALL.

Single-molecule-based sequencing technology is applied to generate genome-wide maps of chromatin modifications in mammalian cells. Histone marks can discriminate genes that are active, poised for activation, or stably repressed and therefore reflect cell state and developmental potential.

A transcriptome-wide association study integrating genome-wide association data with expression data from brain, blood and adipose tissues identifies new candidate susceptibility genes for schizophrenia, providing a step toward understanding the underlying biology.

An iPSC-based three-dimensional model of the human blood–brain barrier reveals that NFAT and APOE dysregulation in pericyte-like mural cells contributes to cerebral amyloid angiopathy and can potentially be targeted to treat Alzheimer’s disease.

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 genome of the grey short-tailed opossum Monodelphis domestica has been sequenced and analyzed, giving a first peek at a marsupial's genetic code. Of particular interest are the genetics of the immune system, which has been studied as a model for humans, and of the X chromosome for historical reasons.

A reference genome sequence for threespine sticklebacks, and re-sequencing of 20 additional world-wide populations, reveals loci used repeatedly during vertebrate evolution; multiple chromosome inversions contribute to marine-freshwater divergence, and regulatory variants predominate over coding variants in this classic example of adaptive evolution in natural environments.

Linking epigenetic marks to clinical outcomes promises insight into the underlying processes. Here, the authors introduce a statistical approach to estimate associations between a phenotype and all epigenetic probes jointly, and to estimate the proportion of variation captured by epigenetic effects.

Caroline Fox and colleagues report results of a genome-wide association study to identify common variants associated with indices of renal function. They show that variants at UMOD, a gene previously implicated in rare monogenic forms of kidney disease, are associated with risk of chronic kidney disease in the general population.

A comprehensive analysis of brain somatic mosaicism across the neocortex demonstrates the origins and distribution patterns of cells within the human brain.

A deep learning model detects low frequency mosaic variants with improved accuracy.

Despite the growing number of X-ray crystal structures of membrane proteins, direct structural information about proteins in their native membrane environment remains scarce. Neutron diffraction, solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations are now used to investigate the structure and hydration of bilayer membranes containing S1–S4 voltage-sensing domains.

In geographic atrophy, a type of macular degeneration, retinal pigmented epithelium (RPE) cells die. This paper finds that DICER1, which processes miRNA precursors, is reduced in RPE from individuals with geographic atrophy. Cell death is not due to loss of miRNA processing, however; rather, the absence of DICER1 allows accumulation of pathological Alu repeat sequence RNAs. This work reveals a novel function of Dicer in degrading Alu RNAs.

In this work, the authors transcriptionally and genetically profile 443 caudate nucleus samples, including 154 with schizophrenia, highlighting new genes associated with schizophrenia risk, including the presynaptic DRD2 isoform.

Noncanonical open reading frames are shown to be essential for cancer cell function.