Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Identifying and modeling sources of reducing equivalents in the nitric oxide detoxification response of Escherichia coli

The important role of nitric oxide (NO) as a key mediator of macrophage cytotoxicity makes a comprehensive understanding of its metabolism in bacteria a valuable tool for investigating both bacterial pathogenesis and the workings of the immune system. The large set of reactions involving NO and other reactive nitrogen species (RNS) as intermediates form a complex network, the kinetic properties of which have been shown to be critical to understanding the distribution of NO within the bacterial cell as well as identifying the primary cellular pathways responsible for NO detoxification and repair of NO-damaged cellular components. In this thesis, we begin the expansion of an existing kinetic model for NO metabolism in Escherichia coli to incorporate the reactions of central metabolism. The respective roles of glycolysis and the pentose phosphate pathway in supplying the reducing equivalents necessary for NO detoxification and damage repair during NO stress appear to be distinct from one another, with glycolysis showing the greater capacity for NAD(P)H production. While our extended model is still unsuitable for making quantitative predictions, it shows good qualitative agreement with experimental data and represents a significant conceptual improvement over previous models in that concentrations of NAD(P)H and NAD(P)$^{+}$ are fully simulated by the model equations instead of being fixed or defined empirically by analytic functions

Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries

More than 25 inherited human disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why some STRs are susceptible to pathologic expansion, whereas thousands of repeat tracts across the human genome are relatively stable. Here, we discover that nearly all disease-associated STRs (daSTRs) are located at boundaries demarcating 3D chromatin domains. We identify a subset of boundaries with markedly higher CpG island density compared to the rest of the genome. daSTRs specifically localize to ultra-high-density CpG island boundaries, suggesting they might be hotspots for epigenetic misregulation or topological disruption linked to STR expansion. Fragile X syndrome patients exhibit severe boundary disruption in a manner that correlates with local loss of CTCF occupancy and the degree of FMR1 silencing. Our data uncover higher-order chromatin architecture as a new dimension in understanding repeat expansion disorders

Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming

Pluripotent genomes are folded in a topological hierarchy that reorganizes during differentiation. The extent to which chromatin architecture is reconfigured during somatic cell reprogramming is poorly understood. Here we integrate fine-resolution architecture maps with epigenetic marks and gene expression in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and NPC-derived induced pluripotent stem cells (iPSCs). We find that most pluripotency genes reconnect to target enhancers during reprogramming. Unexpectedly, some NPC interactions around pluripotency genes persist in our iPSC clone. Pluripotency genes engaged in both fully-reprogrammed and persistent-NPC interactions exhibit over/undershooting of target expression levels in iPSCs. Additionally, we identify a subset of poorly reprogrammed interactions that do not reconnect in iPSCs and display only partially recovered, ESC-specific CTCF occupancy. 2i/LIF can abrogate persistent-NPC interactions, recover poorly reprogrammed interactions, reinstate CTCF occupancy, and restore expression levels. Our results demonstrate that iPSC genomes can exhibit imperfectly rewired 3D-folding linked to inaccurately reprogrammed gene expression