Project description:<p>The Human Connectome Project (HCP) has acquired vast amounts of data about the pattern of long-distance connections (wiring) in the brains of large numbers of healthy participants aged 22-35 using cutting-edge MRI and MEG neuroimaging, and extensive behavioral testing. Types of MR data collected included diffusion MRI (dMRI), resting-state functional MRI (r-fMRI), and structural MRI at both 3T and 7T, and task-evoked functional MRI (t-fMRI) at 3T. </p> <p>Following an extensive period of development and optimization of data acquisition and analysis methods, at Washington University in St. Louis we studied 1,206 participants comprising twins and their non-twin siblings. A subset of 184 twins was scanned again at the University of Minnesota using a 7T scanner. A different subset of 95 twins was studied at St. Louis University using combined resting state and/or task-activated MEG.</p> <p>We were able to collect genetic data on 1142 of our 1206 participants, including 149 pairs of genetically-confirmed monozygotic twins (298 participants) and 94 pairs of genetically-confirmed dizygotic twins (188 participants). Overall, there are 457 different families in the study, as determined by genetic analysis.</p> <p>Our rich set of imaging, behavioral and genetic data - available through the <a href="https://www.humanconnectome.org/data/">Human Connectome</a> database - will enable many types of analysis of brain circuitry, its relationship to behavior, and the contributions of genetic and environmental factors to brain circuits. </p>
Project description:The long non-coding RNA (lncRNA) Xist is a master regulator of X-chromosome inactivation in mammalian cells. Models for how Xist and other lncRNAs function depend on thermodynamically stable secondary and higher-order structures that RNAs can form in the context of a cell. Probing accessible RNA bases can provide data to build models of RNA conformation that provide insight into RNA function, molecular evolution, and modularity. To study the structure of Xist in cells, we built upon recent advances in RNA secondary structure mapping and modeling to develop Targeted Structure-Seq, which combines chemical probing of RNA structure in cells with target-specific massively parallel sequencing. By enriching for signals from the RNA of interest, Targeted Structure-Seq achieves high coverage of the target RNA with relatively few sequencing reads, thus providing a targeted and scalable approach to analyze RNA conformation in cells. We use this approach to probe the full-length Xist lncRNA to develop new models for functional elements within Xist, including the repeat A element in the 5'-end of Xist. This analysis also identified new structural elements in Xist that are evolutionarily conserved, including a new element proximal to the C repeats that is important for Xist function. Examination of dimethylsufate reactivity of Xist lncRNA and 18S rRNA in cells using targeted reverse transcription to determine reactivity, and comparisons with untreated control samples.
Project description:Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs
Project description:Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs
Project description:Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis, and there loci have been shown to be enriched in immune cell-specific enhancers, we add Synovial fibroblasts (FLS), the local stromal cells of joints to this analysis. We integrated ChIP-seq, Hi-C, Capture Hi-C, ATAC-seq and RNA-seq datasets from FLS , with genetic fine-mapping of RA loci. From this we identified putative casual variants, enhancers and genes for 30-60% of RA loci and demonstrated that FLS regulatory elements accounts for up to 24% of RA heritability. We also examined the effects of TNF stimulation on the chromatin landscape of FLS, and we found there are significant alterations in the organization of topologically associated domains, chromatin interactions and the expression of several putative causal genes.
Project description:The intrinsic complexity of quantitative traits was evident even before the molecular nature of the gene was understood. Yet we still lack a detailed molecular understanding of complex heritability. Here we alleviated statistical roadblocks to high-resolution genetic mapping by using an inbred population of diploid yeast with very low linkage disequilibrium and more individuals than segregating polymorphisms. We mapped over 18,000 quantitative trait loci, resolving more than 3,300 to single nucleotides. This allowed us to explore the molecular origins of complexity, hybrid vigor, pleiotropy, and gene ´ environment interactions and to rigorously estimate the distribution of fitness effects of natural genetic variation. Our results describe a comprehensive, high-resolution genotype-to-phenotype map and define general principles underlying the complexity of heredity.