Persistent low-level variants in a subset of viral genes are highly predictive of poor outcome in immunocompromised patients with cytomegalovirus infection

ABSTRACT Background Human cytomegalovirus is the most common and serious opportunistic infection after solid organ and haematopoietic stem cell transplantation. In this study, we used whole-genome cytomegalovirus data to investigate viral factors associated with the clinical outcome. Methods We sequenced cytomegalovirus samples from 16 immunocompromised paediatric patients with persistent viraemia. 8/16 patients died of complications due to cytomegalovirus infection. We also sequenced samples from 35 infected solid organ adult recipients of whom one died with cytomegalovirus infection. Results We showed that samples from both groups have fixed variants at resistance sites and mixed infections. NGS sequencing also revealed non-fixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with non-fixed variants in these patients. These genes formed a viral signature which discriminated patients with cytomegalovirus infection who died from those that survived with high accuracy (AUC=0.96). Lymphocyte numbers for a subset of patients showed no recovery post-transplant in the patients who died. Conclusions We hypothesise that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T cell function, potentially identifying early, those patients requiring non-pharmacological interventions

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Habitat associations of freshwater sawfish (Pristis microdon) and Northern River sharks (Glyphis sp. C): including genetic analysis of P. microdon across northern Australia

This study investigated the ecology, morphology, habitat utilisation and population genetics of the vulnerable (Environment Protection and Biodiversity Conservation Act (EPBC) 1999) or critically endangered (IUCN) Freshwater Sawfish (Pristis microdon). It also examined the distribution and utility of satellite tags in tracking the movements of the endangered (EPBC Act 1999) or critically endangered (IUCN) Northern River Shark (Glyphis sp. C) in the Kimberley

North-western Australia as a hotspot for endangered Elasmobranchs with particular reference to sawfishes and the Northern river Shark

Recent targeted surveys, together with the collection of sawfish (Pristidae) rostra from the general public, have demonstrated that the Kimberley and northern Pilbara are important refuges for sawfish, with four of the world's seven species found here. These comprise all of Australia's known sawfish species, including the three species protected under the Environment Protection and Biodiversity Conservation (EPBC) Act 1999, i.e. Freshwater Sawfish (Pristis microdon), Dwarf Sawfish (Pristis clavata) and Green Sawfish (Pristis zijsron). The Northern River Shark (Glyphis garricki), which was only described in 2008, has only recently been discovered in the Kimberley and is listed as Endangered under the EPBC Act. These species are listed as Critically Endangered on the IUCN Red List and collectively represent ~45% of Australia's elasmobranchs that are listed as Vulnerable or higher under the EPBC Act. There is, however, limited information on the spatial extent of these species throughout Western Australia, particularly as most sawfish surveys have targeted only a few specific areas over a vast coastline. We therefore encouraged public participation in providing Pristis rostra, taken from the fish as curios, in order to extend the known locations of the species and relate these to life history stages based on their size. Here we report on the published records and our unpublished catches (n = 376) across three Pristis spp., and collate this with data from donated rostra, 73% (n = 283) of which were considered usable, in that catch locations were reliable and they were from Western Australian waters. We provide information on sawfish distributions in Western Australia and identify areas that are important as pupping grounds, nursery areas or harbour mature individuals. We also collate known records of G. garricki and provide information on the ecology of this and the EPBC listed sawfish species

Freshwater Sawfish (Pristis microdon) movements and population demographics in the Fitzroy River, Western Australia and genetic analysis of P. microdon and Pristis zijsron

This report is a continuation of the study that was presented to the DEWHA in 2008 entitled: Whitty, J.M., Phillips, N.M., Morgan, D.L., Chaplin, J.A., Thorburn, D.C. & Peverell, S.C. (2008). Habitat associations of Freshwater Sawfish (Pristis microdon) and Northern River Shark (Glyphis sp. C): including genetic analysis of P. microdon across northern Australia. Centre for Fish & Fisheries Research, Murdoch University report to Australian Government, Department of the Environment, Water, Heritage and the Arts

J.M. Thorburn & Co.\u27s annual descriptive catalogue of flower seeds : with practical directions for their culture and treatment; also, a choice list of beautiful French hybrid gladiolus, and other spring bulbous roots /

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