The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

Globetrotting strangles: the unbridled national and international transmission of Streptococcus equi between horses.

The equine disease strangles, which is characterized by the formation of abscesses in the lymph nodes of the head and neck, is one of the most frequently diagnosed infectious diseases of horses around the world. The causal agent, Streptococcus equi subspecies equi, establishes a persistent infection in approximately 10 % of animals that recover from the acute disease. Such 'carrier' animals appear healthy and are rarely identified during routine veterinary examinations pre-purchase or transit, but can transmit S. equi to naïve animals initiating new episodes of disease. Here, we report the analysis and visualization of phylogenomic and epidemiological data for 670 isolates of S. equi recovered from 19 different countries using a new core-genome multilocus sequence typing (cgMLST) web bioresource. Genetic relationships among all 670 S. equi isolates were determined at high resolution, revealing national and international transmission events that drive this endemic disease in horse populations throughout the world. Our data argue for the recognition of the international importance of strangles by the Office International des Épizooties to highlight the health, welfare and economic cost of this disease. The Pathogenwatch cgMLST web bioresource described herein is available for tailored genomic analysis of populations of S. equi and its close relative S. equi subspecies zooepidemicus that are recovered from horses and other animals, including humans, throughout the world. This article contains data hosted by Microreact

Loss of the extracellular matrix protein Perlecan disrupts axonal and synaptic stability during Drosophila development

Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here, we identify a role for Drosophila Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecan’s role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia, or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development

Globetrotting strangles: the unbridled national and international transmission of Streptococcus equi between horses

International audienceBackground: Streptococcus equi subspecies equi (S.equi) is the cause of the highly contagious equine respiratory disease ‘strangles’. Approximately 10% of recovered animals can persistently carry the bacteria and transmit it to naïve animals. The global movement of horses is an ideal mechanism for widespread transmission to geographically distant locations.Objectives: Utilise whole-genome sequence data to disentangle the transmission of S. equi and subsequent outbreaks of strangles.Study design: In vitro analysis of micro-organisms.Methods: Isolates (n = 670) of S. equi were recovered from clinical samples submitted to multiple collaborating clinics and institutions globally. Following species confirmation, isolates underwent whole-genome sequencing using Illumina technology. Sequence reads passing quality control measures were assembled and uploaded to Pathogenwatch, which assigned a phylogeny based upon sequences of core genome alleles. Population structure was inferred using the population mixture analysis in BAPS.Results: BAPS clustered the isolates into six different clusters (BAPS 1-6) and showed dominant lineages in different geographical areas but also global transmission within the clusters. Sub-groups within the clusters highlighted multiple outbreaks at local, national and international scales and highlighted population structures and transmission dynamics within single locations. For example, four different strains collected over just seven months were identified in a single location. Sequence data also identified a statistically significant decline in BAPS-5 since 2010.Main limitations: Pathogenwatch has shown its utility in investigating S. equi transmission and population structure. However, it is based upon a curated set of 1286 core genome loci. Further investigations will need to be conducted using the full spectrum of data available from whole-genome sequencing.Conclusions: Pathogenwatch was used as a tool to rapidly identify and visualise the whole-genome sequence data of a large S. equi dataset. The data demonstrate widespread transmission of multiple S. equi lineages and provide strong evidence that asymptomatic carrier horses are perpetuating this dissemination