Striking Departures from Polygenic Architecture in the Tails of Complex Traits.

Understanding the genetic architecture of human traits is of key biological, medical and evolutionary importance. Despite much progress, little is known about how genetic architecture varies across the trait continuum and, in particular, if it differs in the tails of complex traits, where disease often occurs. Here, applying a novel approach based on polygenic scores, we reveal striking departures from polygenic architecture across 148 quantitative trait tails, consistent with distinct concentrations of high-impact rare alleles in one or both tails of most of the traits.

Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.

Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC.

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder.

Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia.

Quantitative mapping of proteasome interactomes and substrates using ProteasomeID.

Proteasomes are essential molecular machines responsible for the degradation of proteins in eukaryotic cells. Altered proteasome activity has been linked to neurodegeneration, auto-immune disorders and cancer. Despite the relevance for human disease and drug development, no method currently exists to monitor proteasome composition and interactions in vivo in animal models.