Herd-level bovine tuberculosis risk factors:assessing the role of low-level badger population disturbance

Bovine TB (bTB) is endemic in Irish cattle and has eluded eradication despite considerable expenditure, amid debate over the relative roles of badgers and cattle in disease transmission. Using a comprehensive dataset from Northern Ireland (>10,000 km2; 29,513 cattle herds), we investigated interactions between host populations in one of the first large-scale risk factor analyses for new herd breakdowns to combine data on both species. Cattle risk factors (movements, international imports, bTB history, neighbours with bTB) were more strongly associated with herd risk than area-level measures of badger social group density, habitat suitability or persecution (sett disturbance). Highest risks were in areas of high badger social group density and high rates of persecution, potentially representing both responsive persecution of badgers in high cattle risk areas and effects of persecution on cattle bTB risk through badger social group disruption. Average badger persecution was associated with reduced cattle bTB risk (compared with high persecution areas), so persecution may contribute towards sustaining bTB hotspots; findings with important implications for existing and planned disease control programmes

A new phylodynamic model of Mycobacterium bovis transmission in a multi-host system uncovers the role of the unobserved reservoir

Multi-host pathogens are particularly difficult to control, especially when at least one of the hosts acts as a hidden reservoir. Deep sequencing of densely sampled pathogens has the potential to transform this understanding, but requires analytical approaches that jointly consider epidemiological and genetic data to best address this problem. While there has been considerable success in analyses of single species systems, the hidden reservoir problem is relatively under-studied. A well-known exemplar of this problem is bovine Tuberculosis, a disease found in British and Irish cattle caused by Mycobacterium bovis, where the Eurasian badger has long been believed to act as a reservoir but remains of poorly quantified importance except in very specific locations. As a result, the effort that should be directed at controlling disease in badgers is unclear. Here, we analyse densely collected epidemiological and genetic data from a cattle population but do not explicitly consider any data from badgers. We use a simulation modelling approach to show that, in our system, a model that exploits available cattle demographic and herd-to-herd movement data, but only considers the ability of a hidden reservoir to generate pathogen diversity, can be used to choose between different epidemiological scenarios. In our analysis, a model where the reservoir does not generate any diversity but contributes to new infections at a local farm scale are significantly preferred over models which generate diversity and/or spread disease at broader spatial scales. While we cannot directly attribute the role of the reservoir to badgers based on this analysis alone, the result supports the hypothesis that under current cattle control regimes, infected cattle alone cannot sustain M. bovis circulation. Given the observed close phylogenetic relationship for the bacteria taken from cattle and badgers sampled near to each other, the most parsimonious hypothesis is that the reservoir is the infected badger population. More broadly, our approach demonstrates that carefully constructed bespoke models can exploit the combination of genetic and epidemiological data to overcome issues of extreme data bias, and uncover important general characteristics of transmission in multi-host pathogen systems

Engaging Sources: Information Literacy and theFreshman Research Paper (Part II)

The colonization of Ireland by mammals, has been the subject of extensive study using genetic methods, and forms a central problem in understanding the phylo-geography of European mammals after the Last Glacial Maximum. Ireland exhibits a de-pauperate mammal fauna relative to Great Britain and continental Europe, and a range of natural and anthropogenic processes have given rise to its modern fauna. Previous Europe-wide surveys of the European badger (Meles meles) have found conflicting microsatellite and mitochondrial DNA evidence in Irish populations, suggesting Irish badgers have arisen from admixture between human imported British and Scandinavian animals. . The extent and history of contact between British and Irish badger populations remains unclear. We use comprehensive genetic data from Great Britain and Ireland to demonstrate that badgers in Ireland’s northeastern and southeastern counties are genetically similar to contemporary British populations. Simulation analyses suggest this admixed population arose in Ireland 600-700 (CI 100-2600) years before present most likely through introduction of British badgers by people. These findings add to our knowledge of the complex colonization history of Ireland by mammals, and the central role of humans in facilitating it

Development of polymorphic markers in the immune gene complex loci of cattle

Publication history: Accepted - 18 January 2021; Published online - 6 March 2021The addition of cattle health and immunity traits to genomic selection indices holds promise to increase individual animal longevity and productivity, and decrease economic losses from disease. However, highly variable genomic loci that contain multiple immune-related genes were poorly assembled in the first iterations of the cattle reference genome assembly and underrepresented during the development of most commercial genotyping platforms. As a consequence, there is a paucity of genetic markers within these loci that may track haplotypes related to disease susceptibility. By using hierarchical assembly of bacterial artificial chromosome inserts spanning 3 of these immune-related gene regions, we were able to assemble multiple full-length haplotypes of the major histocompatibility complex, the leukocyte receptor complex, and the natural killer cell complex. Using these new assemblies and the recently released ARS-UCD1.2 reference, we aligned whole-genome shotgun reads from 125 sequenced Holstein bulls to discover candidate variants for genetic marker development. We selected 124 SNPs, using heuristic and statistical models to develop a custom genotyping panel. In a proof-of-principle study, we used this custom panel to genotype 1,797 Holstein cows exposed to bovine tuberculosis (bTB) that were the subject of a previous GWAS study using the Illumina BovineHD array. Although we did not identify any significant association of bTB phenotypes with these new genetic markers, 2 markers exhibited substantial effects on bTB phenotypic prediction. The models and parameters trained in this study serve as a guide for future marker discovery surveys particularly in previously unassembled regions of the cattle genome.Hammond, Heimeier, and Schwartz were supported by United Kingdom Research and Innovation, Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) funding awards BB/M027155/1, BBS/E/I/00007031, BBS/E/I/00007038, BBS/E/I/00007039, BBS/OS/GC/000015B, and BBS/OS/GC/200016. Glass was supported by UKRI-BBSRC funding awards BB/J004227/1, BB/J004235/1, and BB/P013740; Glass, Skuce, and Allen were also supported by UKRI-BBSRC BB/E018386/1, BB/E018335/1 and 2, and BB/L004054/1; Glass was also supported by UKRI-BBSRC award BB/M027155/1 and BB/P013740/1. Wilkinson was supported by UKRI-BBSRC BB/L004054/1. We gratefully acknowledge the Agri-Food and Biosciences Institute (AFBI, Northern Ireland) who collected and provided samples in the form of phenotyped bTB case/control samples for use within this project. Bickhart, Bakshy, McClure, and Null were supported by appropriated projects 5090-31000-026-00-D, Investigating Microbial, Digestive, and Animal Factors to Increase Dairy Cow Performance and Nutrient Use Efficiency, and 8042-31000-001-00-D, Enhancing Genetic Merit of Ruminants Through Improved Genome Assembly, Annotation, and Selection, of the Agricultural Research Service (ARS) of the USDA. Cole and Null were supported by appropriated project 8042-31000-002-00-D, “Improving Dairy Animals by Increasing Accuracy of Genomic Prediction, Evaluating New Traits, and Redefining Selection Goals of ARS-USDA. Cole was also partially supported by the grant “Reducing Mastitis in the Dairy Cow by Increasing the Prevalence of Beneficial Polymorphisms in Genes Associated with Mastitis Resistance” from the Minnesota Agricultural Experiment Station Rapid Agricultural Response Fund. Smith was supported by appropriated project 3040-31000-100-00-D, “Developing a Systems Biology Approach to Enhance Efficiency and Sustainability of Beef and Lamb Production,” of ARS-USDA. Bickhart, Bakshy, Young, and Smith were supported by USDA NIFA grant number 2015-67015-22970, “US-UK Collaborative project: “Reassembly of cattle immune gene clusters for quantitative analysis.

Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations

Whole genome sequencing (WGS) technology holds great promise as a tool for the forensic epidemiology of bacterial pathogens. It is likely to be particularly useful for studying the transmission dynamics of an observed epidemic involving a largely unsampled ‘reservoir' host, as for bovine tuberculosis (bTB) in British and Irish cattle and badgers. BTB is caused by Mycobacterium bovis, a member of the M. tuberculosis complex that also includes the aetiological agent for human TB. In this study, we identified a spatio-temporally linked group of 26 cattle and 4 badgers infected with the same Variable Number Tandem Repeat (VNTR) type of M. bovis. Single-nucleotide polymorphisms (SNPs) between sequences identified differences that were consistent with bacterial lineages being persistent on or near farms for several years, despite multiple clear whole herd tests in the interim. Comparing WGS data to mathematical models showed good correlations between genetic divergence and spatial distance, but poor correspondence to the network of cattle movements or within-herd contacts. Badger isolates showed between zero and four SNP differences from the nearest cattle isolate, providing evidence for recent transmissions between the two hosts. This is the first direct genetic evidence of M. bovis persistence on farms over multiple outbreaks with a continued, ongoing interaction with local badgers. However, despite unprecedented resolution, directionality of transmission cannot be inferred at this stage. Despite the often notoriously long timescales between time of infection and time of sampling for TB, our results suggest that WGS data alone can provide insights into TB epidemiology even where detailed contact data are not available, and that more extensive sampling and analysis will allow for quantification of the extent and direction of transmission between cattle and badgers

Use of bacterial whole-genome sequencing to investigate local persistence and spread in bovine tuberculosis

Mycobacterium bovis is the causal agent of bovine tuberculosis, one of the most important diseases currently facing the UK cattle industry. Here, we use high-density whole genome sequencing (WGS) in a defined sub-population of M. bovis in 145 cattle across 66 herd breakdowns to gain insights into local spread and persistence. We show that despite low divergence among isolates, WGS can in principle expose contributions of under-sampled host populations to M. bovis transmission. However, we demonstrate that in our data such a signal is due to molecular type switching, which had been previously undocumented for M. bovis. Isolates from farms with a known history of direct cattle movement between them did not show a statistical signal of higher genetic similarity. Despite an overall signal of genetic isolation by distance, genetic distances also showed no apparent relationship with spatial distance among affected farms over distances <5 km. Using simulations, we find that even over the brief evolutionary timescale covered by our data, Bayesian phylogeographic approaches are feasible. Applying such approaches showed that M. bovis dispersal in this system is heterogeneous but slow overall, averaging 2 km/year. These results confirm that widespread application of WGS to M. bovis will bring novel and important insights into the dynamics of M. bovis spread and persistence, but that the current questions most pertinent to control will be best addressed using approaches that more directly integrate WGS with additional epidemiological data

A genome-wide association study of bovine tuberculosis resistance in the Northern Ireland Holstein-Friesian dairy cattle population

The aim of this study was to determine whether herbage allowance (3000±200kg DM ha-1-high or 1800±200kg DM ha-1-low) had an influence on dairy cow preference to be indoors or at pasture. The preference of mid-late lactation Holstein dairy cows (n=16) for high/low pasture or being indoors (free-stall housing with mattresses; 1.5/cow) was tested during July-September 2011. Cows were randomly allocated into two groups of 8; each group of 8 was further divided into two groups of four, and tested during two study periods for 6 weeks each. In order to test cow motivation for access to pasture, each treatment was offered at two distances (38m-near or 254m-far). A Latin square was used to allocate each group to the order of low/high herbage and near/far distances. Cows were given 8 day training periods with access to both herbage allowances (high vs. low) followed by 5 days of measurement for each treatment. During measurements cows had free access to either being indoors or at pasture with

Ground deformation analysis at Campi Flegrei (Southern Italy) by CGPS and tide-gauge network

Campi Flegrei caldera is located 15 km west of the city of Naples, within the central-southern sector of a large graben called Campanian Plain. It is an active volcanic area marked by a quasi-circular caldera depression, formed by a huge ignimbritic eruption occurred about 37000 years ago. This caldera was generated by several collapses produced by strong explosive eruptions (the last eruption, occurred in 1538, built an about 130 m spatter cone called Mt. Nuovo). Campi Flegrei area periodically experiences significant deformation episodes, with uplift phenomena up to more than 3.5 m in 15 years (from 1970 to 1984), which caused during 1983-84 the temporary evacuation of about 40000 people from the ancient part of Pozzuoli town. The deformation field obtainable by CGPS and tidegauge stations plays an important role for the modelling and interpretation of volcanic phenomena, as well as for forecasting purposes. The structural complexity of the Campi Flegrei area, together with the evidence of a strong interaction between magmatic chamber and shallow geothermal system, calls for a detailed characterization of the substructure and of magma-water interaction processes. The incoming experiment of deep drilling, down to about 4 km, will give detailed structural and physical constraints able to resolve the intrinsic ambiguities of geophysical data and in particular geodetic ones. In this poster we describe the recent ground deformations at Campi Flegrei area by means of GPS technique and tide gauge stations, discussing the possible interpretations also in light of further constraints likely coming from the next CFDDP (Campi Flegrei Deep Drilling) deep drilling experiment

Relative abundance of Mycobacterium bovis molecular types in cattle:a simulation study of potential epidemiological drivers

Background: The patterns of relative species abundance are commonly studied in ecology and epidemiology to provide insights into underlying dynamical processes. Molecular types (MVLA-types) of Mycobacterium bovis, the causal agent of bovine tuberculosis, are now routinely recorded in culture-confirmed bovine tuberculosis cases in Northern Ireland. In this study, we use ecological approaches and simulation modelling to investigate the distribution of relative abundances of MVLA-types and its potential drivers. We explore four biologically plausible hypotheses regarding the processes driving molecular type relative abundances: sampling and speciation; structuring of the pathogen population; historical changes in population size; and transmission heterogeneity (superspreading). Results: Northern Irish herd-level MVLA-type surveillance shows a right-skewed distribution of MVLA-types, with a small number of types present at very high frequencies and the majority of types very rare. We demonstrate that this skew is too extreme to be accounted for by simple neutral ecological processes. Simulation results indicate that the process of MVLA-type speciation and the manner in which the MVLA-typing loci were chosen in Northern Ireland cannot account for the observed skew. Similarly, we find that pathogen population structure, assuming for example a reservoir of infection in a separate host, would drive the relative abundance distribution in the opposite direction to that observed, generating more even abundances of molecular types. However, we find that historical increases in bovine tuberculosis prevalence and/or transmission heterogeneity (superspreading) are both capable of generating the skewed MVLA-type distribution, consistent with findings of previous work examining the distribution of molecular types in human tuberculosis. Conclusion: Although the distribution of MVLA-type abundances does not fit classical neutral predictions, our simulations show that increases in pathogen population size and/or superspreading are consistent with the pattern observed, even in the absence of selective pressures acting on the system