Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNM) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense de novo mutations (DNMs) (0.101 vs. 0.031, empirical P=0.01, BH-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01×10−5, corrected P =2.1×10−3). Genes with DNMs overlapped with genes implicated in autism (e.g. AUTS2, CDH8, MECP2) and intellectual disability (ID) (e.g. HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes which function in the epigenetic regulation of brain development and cognition could have a central role in the susceptibility to, pathogenesis, and treatment of mental disorders.

Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33 mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33 brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33 microglia in the same brain suggest that there is little spreading of TGF-β activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-β provide localized and selective activation of TGF-β.

BackgroundThe availability of various high-throughput experimental and computational methods allows biologists to rapidly infer functional relationships between genes. It is often necessary to evaluate these predictions computationally, a task that requires a reference database for functional relatedness. One such reference is the Gene Ontology (GO). A number of groups have suggested that the semantic similarity of the GO annotations of genes can serve as a proxy for functional relatedness. Here we evaluate a simple measure of semantic similarity, term overlap (TO).ResultsWe computed the TO for randomly selected gene pairs from the mouse genome. For comparison, we implemented six previously reported semantic similarity measures that share the feature of using computation of probabilities of terms to infer information content, in addition to three vector based approaches and a normalized version of the TO measure. We find that the overlap measure is highly correlated with the others but differs in detail. TO is at least as good a predictor of sequence similarity as the other measures. We further show that term overlap may avoid some problems that affect the probability-based measures. Term overlap is also much faster to compute than the information content-based measures.ConclusionOur experiments suggest that term overlap can serve as a simple and fast alternative to other approaches which use explicit information content estimation or require complex pre-calculations, while also avoiding problems that some other measures may encounter.

Highlights d Cell-surface IR translocates to the nucleus and associates with promoters genome-wide d IR interaction with DNA is mediated by coregulator HCF-1 and transcription factors d IR associates with Pol II and regulates gene expression d Target genes are characteristic of insulin functions in physiology and disease