Inferring neural signalling directionality from undirected structural connectomes, bioRxiv, 2019-03-11
Neural information flow is inherently directional. To date, investigation of directional communication in the human structural connectome has been precluded by the inability of non-invasive neuroimaging methods to resolve axonal directionality. Here, we demonstrate that decentralized measures of network communication, applied to the undirected topology and geometry of brain networks, can predict putative directions of large-scale neural signalling. We propose the concept of send-receive communication asymmetry to characterize cortical regions as senders, receivers or neutral, based on differences between their incoming and outgoing communication efficiencies. Our results reveal a send-receive cortical hierarchy that recapitulates established organizational gradients differentiating sensory-motor and multimodal areas. We find that send-receive asymmetries are significantly associated with the directionality of effective connectivity derived from spectral dynamic causal modeling. Finally, using fruit fly, mouse and macaque connectomes, we provide further evidence suggesting that directionality of neural signalling is significantly encoded in the undirected architecture of nervous systems.
biorxiv neuroscience 0-100-users 2019Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes, bioRxiv, 2019-03-11
AbstractMulti-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools for variant interpretation typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,996,125 MNVs across the genome with constituent variants falling within 2 bp distance of one another, of which 31,510 exist within the same codon, including 405 predicted to result in gain of a nonsense mutation, 1,818 predicted to rescue a nonsense mutation event that would otherwise be caused by one of the constituent variants, and 16,481 additional variants predicted to alter protein sequences. We show that the distribution of MNVs is highly non-uniform across the genome, and that this non-uniformity can be largely explained by a variety of known mutational mechanisms, such as CpG deamination, replication error by polymerase zeta, or polymerase slippage at repeat junctions. We also provide an estimate of the dinucleotide mutation rate caused by polymerase zeta. Finally, we show that differential CpG methylation drives MNV differences across functional categories. Our results demonstrate the importance of incorporating haplotype-aware annotation for accurate functional interpretation of genetic variation, and refine our understanding of genome-wide mutational mechanisms of MNVs.
biorxiv genomics 0-100-users 2019Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells, bioRxiv, 2019-03-11
SummaryIntermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes including signal transduction and gene expression patterns arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here we quantified over 100 metabolic features, mostly from 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.
biorxiv cancer-biology 0-100-users 2019Variation of immune cell responses in humans reveals sex-specific coordinated signaling across cell types, bioRxiv, 2019-03-09
Assessing the health and competence of the immune system is central to evaluating vaccination responses, autoimmune conditions, cancer prognosis and treatment. With an increasing number of studies examining immune dysregulation, there is a growing need for a curated reference of variation in immune parameters in healthy individuals. We used mass cytometry (CyTOF) to profile blood from 86 humans in response to 15 ex vivo immune stimuli. We present reference ranges for cell-specific immune markers and highlight differences that appear across sex and age. We identified modules of immune features that suggests there exists and underlying structure to the immune system based on signaling pathway responses across cell types. We observed increased MAPK signaling in inflammatory pathways in innate immune cells and greater overall coordination of immune cell responses in women. In contrast, men exhibited stronger STAT1 and TBK1 responses. These reference data are publicly available as a resource for immune profiling studies.
biorxiv immunology 0-100-users 2019A rapid and simple method for assessing and representing genome sequence relatedness, bioRxiv, 2019-03-08
AbstractCoherent genomic groups are frequently used as a proxy for bacterial species delineation through computation of overall genome relatedness indices (OGRI). Average nucleotide identity (ANI) is a widely employed method for estimating relatedness between genomic sequences. However, pairwise comparisons of genome sequences based on ANI is relatively computationally intensive and therefore precludes analyses of large datasets composed of thousand genome sequences.In this work we evaluated an alternative OGRI based on k-mers counts to study prokaryotic species delimitation. A dataset containing more than 3,500 Pseudomonas genome sequences was successfully classified in few hours with the same precision as ANI. A new visualization method based on zoomable circle packing was employed for assessing relationships between among the 350 cliques generated. Amendment of databases with these Pseudomonas cliques greatly improved the classification of metagenomic read sets with k-mers-based classifier.The developed workflow was integrated in the user-friendly KI-S tool that is available at the following address <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsiris.angers.inra.frgalaxypub-cfbp>httpsiris.angers.inra.frgalaxypub-cfbp<jatsext-link>.
biorxiv genomics 0-100-users 2019Mapping Histone Modifications in Low Cell Number and Single Cells Using Antibody-guided Chromatin Tagmentation (ACT-seq), bioRxiv, 2019-03-08
ABSTRACTModern next-generation sequencing-based methods have empowered researchers to assay the epigenetic states of individual cells. Existing techniques for profiling epigenetic marks in single cells often require the use and optimization of time-intensive procedures such as drop fluidics, chromatin fragmentation, and end repair. Here we describe ACT-seq, a novel and streamlined method for mapping genome-wide distributions of histone tail modifications, histone variants, and chromatin-binding proteins in a small number of or single cells. ACT-seq utilizes a fusion of Tn5 transposase to Protein A that is targeted to chromatin by a specific antibody, allowing chromatin fragmentation and sequence tag insertion specifically at genomic sites presenting the relevant antigen. The Tn5 transposase enables the use of an index multiplexing strategy (iACT-seq), which enables construction of thousands of single-cell libraries in one day by a single researcher without the need for drop-based fluidics or visual sorting. We conclude that ACT-seq present an attractive alternative to existing techniques for mapping epigenetic marks in single cells.
biorxiv genomics 0-100-users 2019