Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and adaptable set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploration. Whereas other methods provide an inflexible set of variant filters or prioritization methods, GEMINI allows researchers to compose complex queries based on sample genotypes, inheritance patterns, and both pre-installed and custom genome annotations. GEMINI also provides methods for ad hoc queries and data exploration, a simple programming interface for custom analyses that leverage the underlying database, and both command line and graphical tools for common analyses. We demonstrate GEMINI's utility for exploring variation in personal genomes and family based genetic studies, and illustrate its ability to scale to studies involving thousands of human samples. GEMINI is designed for reproducibility and flexibility and our goal is to provide researchers with a standard framework for medical genomics.

Studies of the adult Drosophila midgut have led to many insights in our understanding of cell-type diversity, stem cell regeneration, tissue homeostasis, and cell fate decision. Advances in single-cell RNA sequencing provide opportunities to identify new cell types and molecular features. We used single-cell RNA sequencing to characterize the transcriptome of midgut epithelial cells and identified 22 distinct clusters representing intestinal stem cells, enteroblasts, enteroendocrine cells (EEs), and enterocytes. This unbiased approach recovered most of the known intestinal stem cells/enteroblast and EE markers, highlighting the high quality of the dataset, and led to insights on intestinal stem cell biology, cell type-specific organelle features, the roles of new transcription factors in progenitors and regional variation along the gut, 5 additional EE gut hormones, EE hormonal expression diversity, and paracrine function of EEs. To facilitate mining of this rich dataset, we provide a web-based resource for visualization of gene expression in single cells. Altogether, our study provides a comprehensive resource for addressing functions of genes in the midgut epithelium.

The development of neural circuits relies on axon projections establishing diverse, yet well-defined, connections between areas of the nervous system. Each projection is formed by growth cones (GCs), subcellular specializations at the tips of growing axons, encompassing sets of molecules that control projection-specific growth, guidance, and target selection1. To investigate the set of molecules within native GCs forming specific connections, we developed GC Sorting and Subcellular RNA-Proteome Mapping, an approach that identifies and quantifies local transcriptomes and proteomes from labeled GCs of single projections in vivo. Using this approach on the developing callosal projection of the mouse cerebral cortex, we mapped molecular enrichments in trans-hemispheric GCs relative to their parent cell bodies, producing paired subcellular proteomes and transcriptomes from single neuron subtypes directly from the brain. These data provide generalizable proof-of-principle for this approach, and reveal novel GC molecular specializations, including accumulations of the growth-regulating kinase mTOR2, together withmRNAs containing mTOR-dependent motifs3,4. These findings illuminate therelationships of RNA and protein subcellular distributions in developing projectionneurons, and provide a new systems-level approach for discovery of subtype- and stage-specific molecular substrates of circuit wiring, miswiring, and potential for regeneration.

Summary Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the “necklace” subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically-relevant ligands including pheromones and fatty acids in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.