Reactive transport and fluid pathways in fracture-controlled flow systems

This thesis uses mapping and analysis of C/O stable isotopes to explore the distribution and evolution of fracture-controlled fluid flow in two vein-rich, limestone-hosted fault systems: The Dar Al Baydha (DAB) Fault system in northern Oman and a network of low-displacement faults in the Helvetic Alps, Switzerland. The DAB Fault is 25km long and has a maximum throw of >750m. There is also a subordinate, low displacement fault network formed adjacent to the DAB Fault. This study has explored a segment of that network in the Hail Ash Shas area (HAS network). In the Helvetic nappes, work has predominantly focused on a late to post-nappe emplacement fault network. Most faults in this network cannot be traced beyond a single outcrop and typically have throws 25.5 per mil) to 13.7 per mil. In the Helvetics, d18O compositions of vein calcite vary from host rock values (>19 per mil) to 10.6 per mil. The extent of 18O-depletion in both systems can be caused only by influx of fluids from one or more external reservoirs with d18O compositions that are in disequilibrium with the host rock. Reactive transport modelling indicates that the DAB Fault has a time-integrated-fluid-flux (TIFF) of 100,000mol/cm2, whereas the HAS network has a modelled TIFF of 1,000,000mol/cm2. In comparison, the Solalex network (in the Helvetic nappes) has an estimated TIFF of 500mol/cm2 . While externally-sourced fluids infiltrated the DAB Fault along much of its strike length, the distribution of strongly 18O depleted vein compositions in the DAB Fault system indicates a very heterogeneous distribution of high fluid flux. Structural features such as some segment boundaries and termination zones locally hosted high fluid fluxes. However, this relationship is not ubiquitous and varies with time. This highlights the 4D complexity of fluid pathways in the DAB Fault. The TIFF estimate for the HAS network is an order of magnitude greater than for the DAB Fault. This demonstrates the effectiveness of low displacement fault networks for fluid transport, even when they are proximal to large co-active faults. The high pore fluid factors and complex hydraulic connectivity in this fault network suggests that it may have predominantly evolved as an invasion percolation network. In contrast to the DAB Fault, the network of faults in the Helvetic nappes has much lower modelled TIFF. However, the limited spatial extent of faults and apparent lack of 2D geometric connectivity, combined with the evidence for transport distances >1km again highlights the complexity of 3D hydraulic connectivity and indicates that relatively immature fault systems can still effectively drain overpressured reservoirs

Using DNA metabarcoding to explore spatial variation in diet across European Hawfinch populations

The investigation of diet in avian species is essential for understanding their ecology and local adaptations, as well as long-term conservation. This can be particularly challenging because of the wide distribution and high ecological plasticity of many bird species. Here, we focused on the Hawfinch (Coccothraustes coccothraustes), which has shown variation in population trends. Across Europe, central and eastern European populations are moderately declining while western European populations are moderately increasing. Ecological drivers behind these differing trends are still unknown; one possibility is differences in diet, yet little research has been conducted into Hawfinch diet in mainland Europe or elsewhere. Dietary richness and variation are under-studied in woodland bird species, due primarily to challenges in accurately identifying plant and invertebrate taxa consumed. This study presents the first molecular dietary analysis of Hawfinch populations across two European countries. Faecal samples were collected between January and July of 2019 from Hawfinch caught at six artificial feed sites: two in Denmark and four in Germany. We successfully extracted DNA from 80 samples by amplifying plant Internal Transcribed Spacer 2 (ITS2) and invertebrate Cytochrome Oxidase Subunit 1 (COI) barcodes. A total of 35 plant and 37 invertebrate taxa were found, with plant and insect orders Fagales and Lepidoptera, respectively, the most frequently detected. Hawfinch dietary composition differed significantly between European countries, suggesting Hawfinch can make use of available food resources that are likely to differ spatially. Our study shows how DNA metabarcoding can be used to provide novel ecological information associated with under-studied bird species, thus providing essential information for future management and conservation of Hawfinch and their habitats

Herbivorous dietary selection shown by hawfinch (Coccothraustes coccothraustes) within mixed woodland habitats

Knowledge of diet and dietary selectivity is vital, especially for the conservation of declining species. Accurately obtaining this information, however, is difficult, especially if the study species feeds on a wide range of food items within heterogeneous and inaccessible environments, such as the tree canopy. Hawfinches (Coccothraustes coccothraustes), like many woodland birds, are declining for reasons that are unclear. We investigated the possible role that dietary selection may have in these declines in the UK. Here, we used a combination of high-throughput sequencing of 261 hawfinch faecal samples assessed against tree occurrence data from quadrats sampled in three hawfinch population strongholds in the UK to test for evidence of selective foraging. This revealed that hawfinches show selective feeding and consume certain tree genera disproportionally to availability. Positive selection was shown for beech (Fagus), cherry (Prunus), hornbeam (Carpinus), maples (Acer) and oak (Quercus), while Hawfinch avoided ash (Fraxinus), birch (Betula), chestnut (Castanea), fir (Abies), hazel (Corylus), rowan (Sorbus) and lime (Tilia). This approach provided detailed information on hawfinch dietary choice and may be used to predict the effects of changing food resources on other declining passerines populations in the future

Processed pseudogenes acquired somatically during cancer development

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)