Project description:Although genome-wide association study is an important tool for linking genetic variation to common complex diseases, it remains difficult to identify the causal variants underlying susceptibility loci. Recent work demonstrated mapping chromatin accessibility across different individuals can be a powerful method for interpreting genetic variant function, existing assays to measure chromatin landscapes (e.g., DNaseI-seq) are labor intensive and require very large numbers of cells preventing their application in real-world settings. This project aims to assess the ability of a novel assay for chromatin accessibility, ATAC-seq, to detect chromatin structure variation among individuals. We will apply ATAC-seq in 24 GBR HapMap lymphoblastoid cell lines (LCLs), which are a model system for studying the function of human genetic variation. We will also employ a novel approach to molecular quantitative trait locus identification which utilizes both population quantitative trait locus and allele-specific signatures, and gives increased mapping power in small sample sizes.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Project description:GABAB receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic GBR function is the gating of ion channels. However, where stable GBR-effector channel signaling units are formed in the biosynthetic pathway has remained unclear. Here we show that the vesicular protein synaptotagmin-11 (Syt11) binds the auxiliary GBR subunit KCTD16 and Cav2.2 channels. This enables Syt11 to recruit GBR/Cav2.2 channel complexes to post-Golgi vesicles that transport the pre-assembled signaling complexes in axons and dendrites. Bimolecular fluorescence complementation experiments reveal that GBR/Syt11 complexes are delivered to synaptic sites. Furthermore, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Syt11-deficient neurons exhibit reduced glutamatergic synaptic transmission and impaired GBR-mediated presynaptic inhibition, thus highlighting a key role for Syt11 in the transport and stable expression of functional GBR/Cav2.2 complexes at synapses.
