Biology subjects

Hall, T. J.

Publications and source records attributed to Hall, T. J..

13 recordsLinked to original sources

bioRxiv2025

Accurate and robust classification of Mycobacterium bovis-infected cattle using peripheral blood RNA-seq data

Bovine tuberculosis (bTB) remains recalcitrant to eradication in many endemic countries where current diagnostics are suboptimal. Mycobacterium bovis causes bTB and is closely related to Mycobacterium tuberculosis, which causes human tuberculosis (hTB). Although blood-based mRNA biomarkers identified through machine learning can discriminate hTB-positive from hTB-negative individuals, similar approaches have not been explored for bTB. Here, we use RNA-seq and machine learning to investigate the utility of blood mRNA as a host-response biomarker for bTB. We identify a 30-gene signature and a 273-gene elastic net classifier that differentiate bTB-positive from bTB-negative cattle, achieving area under the curve (AUC) values of 0.986/0.900 for the former and 0.968/0.938 for the latter in training and testing, respectively. Additionally, we show that these classifiers distinguish bTB-positive cattle from cattle infected with other microbial pathogens (AUC [≥] 0.819). These mRNA-based classifiers represent a promising tool for augmenting current diagnostics to advance global bTB eradication efforts.

genomics↗

bioRxiv2025

Integrative genomics identifies candidate genes underlying trypanotolerance in hybrid African cattle

Integrative genomics combines data from different omic sources to link genotypes and phenotypes with the aim of unravelling biological networks and pathways that undergird complex traits, particularly with respect to disease. In this respect, integrative genomics using population and functional genomic data can be employed to understand evolutionary processes that have shaped adaptation to infectious diseases in domestic cattle. This approach can be particularly informative for African cattle, which exhibit a complex mosaic of Bos taurus (taurine) and Bos indicus (indicine) genomic ancestry. Some African taurine populations have an important evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites (Trypanosoma spp.) that cause African animal trypanosomiasis (AAT) disease. AAT is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. In this study we identified putative candidate genes underlying trypanotolerance through the integration of local ancestry inference (LAI) from genome-wide SNP data for multiple trypanotolerant and trypanosusceptible hybrid cattle populations with RNA-seq and expression microarray transcriptomics data from multiple tissues collected across time course trypanosome infection experiments. These candidate genes included AGO2, CBL, CNOT1, EDN1, IL1B, NFKB1, RIPK1, and TRAF2. Functional analysis of the gene set outputs from this work highlighted GO terms associated with the immune system (including the major histocompatibility complex - MHC) and cell signalling processes. These results signpost future work to elucidate the cellular networks and pathways that drive trypanotolerance. Author SummaryIntegrative genomics combines different types of data to identify links between genes and traits, particularly with respect to disease. In this respect, integrative genomics can be used to understand the admixture and adaptation to infectious diseases that have shaped the genomes of domestic cattle. This is particularly noticeable in the case of African cattle, which form a complex mosaic of Bos taurus (taurine) and Bos indicus (indicine) ancestry. Some African taurine populations exhibit an evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites (Trypanosoma spp.) that cause African animal trypanosomiasis (AAT) disease. AAT is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. In this study we identify potential candidate genes underlying trypanotolerance through integration of subchromosomal genomic ancestry data from multiple trypanotolerant and trypanosusceptible hybrid cattle populations with gene expression data from multiple tissues collected across time course trypanosome infection experiments.

genomics↗

bioRxiv2025

An Anisotropic Reactive Viscoelastic Model of the Rhesus Macaque Cervix for Studying Cervical Remodeling

The uterine cervix is a soft biological tissue with critical biomechanical functions in pregnancy. It is a mechanical barrier that supports the growing fetus. As pregnancy progresses, the cervix becomes more compliant and eventually opens in late pregnancy to facilitate childbirth. This dual function is facilitated by extensive remodeling of the cervical extracellular matrix (ECM), giving rise to its complex time-dependent material properties. Premature cervical remodeling is known to result in preterm birth, defined as birth before 37 weeks of gestation. While previous work has studied cervical remodeling using various biomechanical methods, it remains unclear how the intrinsic or flow-independent viscoelastic behavior of the cervix is influenced by cervical remodeling. In this study, an anisotropic reactive viscoelastic material model was formulated and investigated under tensile deformation to understand material behavior in cervical remodeling. To calibrate the model, experimental force relaxation data was used from uniaxial tension tests on Rhesus macaque cervical specimens from four gestational time points. The results showed that cervical tissue equilibrium and instantaneous stiffness significantly decreased from the non-pregnant to the late pregnancy status. In addition, cervical tissue in the late third trimester relaxed faster to equilibrium than the other gestational groups, particularly at prescribed tensile strains greater than 30%. This fast relaxation to equilibrium helps the cervix dissipate tensile hoop stresses induced by the fetus during labor, preventing its rupture. This work provides insights into time-dependent cervical remodeling features, which are crucial for developing diagnostic methods and treatments for preterm birth.

bioengineering↗

bioRxiv2025

Functional genomics of trypanotolerant and trypanosusceptible cattle infected with Trypanosoma congolense across multiple time points and tissues

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease caused by infection with trypanosome parasites (Trypanosoma spp.). These are transmitted by infected tsetse flies (Glossina spp.) and cause a similar disease in animals, known as African animal trypanosomiasis (AAT). AAT is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. Some African Bos taurus cattle populations have an important evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites (Trypanosoma spp.). Trypanotolerant African B. taurus NDama and trypanosusceptible Bos indicus Boran cattle responded in largely similar ways during trypanosome infection when gene expression was examined using blood, liver, lymph node, and spleen samples with peaks and troughs of gene expression differences following the cyclic pattern of parasitaemia exhibited during trypanosome infection. However, differences in response to infection between the two breeds were reflected in differential expression of genes related to the immune system such as those encoding antimicrobial peptides and cytokines, including, for example, the antimicrobial peptide encoding genes LEAP2, CATHL3, DEFB4A, and S100A7 and the cytokine genes CCL20, CXCL11, CXCL13, CXCL16, CXCL17, IL33, and TNFSF13B. In addition, transcriptional profiling of peripheral blood identified expression differences in genes relating to coagulation and iron homeostasis, which supports the hypothesis that the dual control of parasitaemia and the anaemia resulting from the innate immune response to trypanosome parasites is key to trypanotolerance and provide new insights into the molecular mechanisms underlying this phenomenon. Author SummaryTrypanosome parasites are transmitted by infected tsetse flies and cause the neglected tropical disease human African trypanosomiasis (HAT) and the similar African animal trypanosomiasis (AAT), which is one of the largest impediments to livestock production in sub-Saharan Africa. Taurine (Bos taurus) and indicine (Bos indicus) cattle shared a common ancestor more than 150,000 years ago, and in the intervening period significant genomic differences have evolved between the two groups. Importantly, several African B. taurus populations have evolved an adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites. Trypanotolerant African taurine and trypanosusceptible indicine cattle responded in largely similar ways during trypanosome infection when gene expression was examined using blood, liver, lymph node, and spleen samples with peaks and troughs of gene expression differences following the cyclic pattern of the number of trypanosome parasites in the blood. Transcriptional profiling of these tissues highlighted genes related to the multiple facets of the immune system; notably, for peripheral blood, differences observed for genes relating to coagulation and iron homeostasis support the existing hypothesis that control of both parasite number and anaemia is an important feature of the trypanotolerance trait and provide new insights into the molecular mechanisms underlying this phenomenon.

genomics↗

bioRxiv2024

Genome-wide local ancestry and the functional consequences of admixture in African and European cattle populations

Bos taurus (taurine) and Bos indicus (indicine) cattle diverged at least 150,000 years ago and, since that time, substantial genomic differences have evolved between the two lineages. During the last two millennia, genetic exchange in Africa has resulted in a complex tapestry of taurine-indicine ancestry, with most cattle populations exhibiting varying levels of admixture. Similarly, there are several Southern European cattle populations that also show evidence for historical gene flow from indicine cattle, the highest levels of which are found in the Central Italian White breeds. Here we use two different software tools (MOSAIC and ELAI) for local ancestry inference (LAI) with genome-wide high-and low-density SNP array data sets in hybrid African and Italian cattle populations and obtained broadly similar results despite critical differences in the two LAI methodologies used. Our analyses identified genomic regions with elevated levels of retained or introgressed ancestry from the African taurine, European taurine, Asian indicine lineages. Functional enrichment of genes underlying these ancestry peaks highlighted biological processes relating to immunobiology and olfaction, some of which may relate to differing susceptibilities to infectious diseases, including bovine tuberculosis, East Coast fever, and tropical theileriosis. Notably, for retained African taurine ancestry in admixed trypanotolerant cattle we observed enrichment of genes associated with haemoglobin and oxygen transport. This may reflect positive selection of genomic variants that enhance control of severe anaemia, a debilitating feature of trypanosomiasis disease, which severely constrains cattle agriculture across much of sub-Saharan Africa.

genomics↗

bioRxiv2024

Integrative genomics sheds light on the immunobiology of tuberculosis in cattle

Mycobacterium bovis causes bovine tuberculosis (bTB), an infectious disease of cattle that poses a zoonotic threat to humans. Research has shown that bTB susceptibility is a heritable trait, and that the peripheral blood (PB) transcriptome is perturbed during bTB disease. Hitherto, no study has integrated PB transcriptomic, genomic and GWAS data to study bTB disease, and little is known about the genomic architecture underpinning the PB transcriptional response to M. bovis infection. Here, we perform transcriptome profiling of PB from 63 control and 60 confirmed M. bovis infected animals and detect 2,592 differently expressed genes that perturb multiple immune response pathways. Leveraging imputed genome-wide SNP data, we characterise thousands of cis- and trans-expression quantitative trait loci (eQTLs) and show that the PB transcriptome is substantially impacted by intrapopulation genomic variation. We integrate our gene expression data with summary statistics from multiple GWAS data sets for bTB susceptibility and perform the first transcriptome-wide association study (TWAS) in the context of tuberculosis disease. From this TWAS, we identify 136 functionally relevant genes (including RGS10, GBP4, TREML2, and RELT) and provide important new omics data for understanding the host response to mycobacterial infections that cause tuberculosis in mammals.

genomics↗

bioRxiv2023

Preferential differential gene expression within the WC1.1+ γδ T cell compartment in cattle naturally infected with Mycobacterium bovis.

Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, continues to cause significant issues for the global agriculture industry as well as for human health. An incomplete understanding of the host immune response contributes to the challenges of control and eradication of this zoonotic disease. In this study, high-throughput bulk RNA sequencing (RNA-seq) was used to characterize differential gene expression in {gamma}{delta} T cells - a subgroup of T cells that bridge innate and adaptive immunity and have known anti-mycobacterial response mechanisms. {gamma}{delta} T cell subsets are classified based on expression of a pathogen-recognition receptor known as Workshop Cluster 1 (WC1) and we hypothesised that bTB disease may alter the phenotype and function of specific {gamma}{delta} T cell subsets. Peripheral blood was collected from naturally M. bovis-infected (positive for single intradermal comparative tuberculin test (SICTT) and IFN-{gamma} ELISA) and age- and sex-matched, non-infected control Holstein-Friesian cattle. {gamma}{delta} T subsets were isolated using fluorescence activated cell sorting (n = 10-12 per group) and high-quality RNA extracted from each purified lymphocyte subset (WC1.1+, WC1.2+, WC1- and {gamma}{delta}-) was used to generate transcriptomes using bulk RNA-seq (n = 6 per group, representing a total of 48 RNA-seq libraries). Relatively low numbers of differentially expressed genes (DEGs) were observed between most cell subsets; however, 189 genes were significantly differentially expressed in the M. bovis-infected compared to the control groups for the WC1.1+ {gamma}{delta} T cell compartment (absolute log2 FC [≥] 1.5 and FDR Padj. [≤] 0.1). The majority of these DEGs (168) were significantly increased in expression in cells from the bTB+ cattle and included genes encoding transcription factors (TBX21 and EOMES), chemokine receptors (CCR5 and CCR7), granzymes (GZMA, GZMM, and GZMH) and multiple killer cell immunoglobulin-like receptor (KIR) proteins indicating cytotoxic functions. Biological pathway overrepresentation analysis revealed enrichment of genes with multiple immune functions including cell activation, proliferation, chemotaxis, and cytotoxicity of lymphocytes. In conclusion, WC1.1+ {gamma}{delta} T cells have been proposed as major regulatory cell subset in cattle, and we provide evidence for preferential differential activation of this specific subset in cattle naturally infected with M. bovis.

immunology↗

bioRxiv2023

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

Mycobacterium tuberculosis, the causative agent of human tuberculosis (hTB), is currently classed as the thirteenth leading cause of death worldwide. Mycobacterium bovis, a close evolutionary relative of M. tuberculosis, causes bovine tuberculosis (bTB) and is one of the most damaging infectious diseases to livestock agriculture. Previous studies have shown that the pathogenesis of bTB disease is comparable to hTB disease, and that the bovine and human alveolar macrophage (bAM and hAM, respectively) transcriptomes are extensively reprogrammed in response to infection with these intracellular mycobacterial pathogens. However, although M. bovis and M. tuberculosis share over 99% identity at the genome level, the innate immune responses to these pathogens have been shown to be different in human or cattle hosts. In this study, a multi-omics integrative approach was applied to encompass functional genomics and GWAS data sets across the two primary hosts (Bos taurus and Homo sapiens) and both pathogens (M. bovis and M. tuberculosis). Four different experimental infection groups were used, each with parallel non-infected control cells: 1) bAM infected with M. bovis, 2) bAM infected with M. tuberculosis, 3) hAM infected with M. tuberculosis, and 4) human monocyte-derived macrophages (hMDM) infected with M. tuberculosis. RNA-seq data from these experiments 24 hours post-infection (24 hpi) was analysed using three separate computational pipelines: 1) differentially expressed genes, 2) differential gene expression interaction networks, and 3) combined pathway analysis. The results of these analyses were then integrated with high-resolution bovine and human GWAS data sets to detect novel quantitative trait loci (QTLs) for resistance to mycobacterial infection and resilience to disease. Results from this study revealed common and unique response macrophage pathways for both pathogens and identified 32 genes (12 bovine and 20 human) significantly enriched for SNPs associated with disease resistance, the majority of which encode key components of the NF-{kappa}B signalling pathway and that also drive formation of the granuloma.

genomics↗

bioRxiv2023

Optical coherence tomography of human fetal membrane sub-layers during dynamic loading

Fetal membranes have important mechanical and antimicrobial roles in maintaining pregnancy. However, the small thickness (<800 m) of fetal membranes places them outside the resolution limits of most ultrasound and magnetic resonance systems. Optical imaging methods like optical coherence tomography (OCT) have the potential to fill this resolution gap. Here, OCT and machine learning methods were developed to characterize the ex vivo properties of human fetal membranes under dynamic loading. A saline inflation test was incorporated into an OCT system, and tests were performed on n=33 and n=32 human samples obtained from labored and C-section donors, respectively. Fetal membranes were collected in near-cervical and near-placental locations. Histology, endogenous two photon fluorescence microscopy, and second harmonic generation microscopy were used to identify sources of contrast in OCT images of fetal membranes. A convolutional neural network was trained to automatically segment fetal membrane sub-layers with high accuracy (Dice coefficients >0.8). Intact amniochorion bilayer and separated amnion and chorion were individually loaded, and the amnion layer was identified as the load-bearing layer within intact fetal membranes for both labored and C-section samples, consistent with prior work. Additionally, the rupture pressure and thickness of the amniochorion bilayer from the near-placental region were greater than those of the near-cervical region for labored samples. This location-dependent change in fetal membrane thickness was not attributable to the load-bearing amnion layer. Finally, the initial phase of the loading curve indicates that amniochorion bilayer from the near-cervical region is strain-hardened compared to the near-placental region in labored samples. Overall, these studies fill a gap in our understanding of the structural and mechanical properties of human fetal membranes at high resolution under dynamic loading events.

biophysics↗

bioRxiv2021

Genome-wide local ancestry and direct evidence for mitonuclear co-adaptation in African hybrid cattle populations (Bos taurus/indicus)

The phenotypic diversity of African cattle reflects adaptation to a wide range of agroecological conditions, human-mediated selection preferences, and complex patterns of admixture between the humpless Bos taurus (taurine) and humped Bos indicus (zebu) subspecies, which diverged 150-500 thousand years ago. Despite extensive admixture, all African cattle possess taurine mitochondrial haplotypes, even populations with significant zebu biparental and male uniparental nuclear ancestry. This has been interpreted as the result of a human-mediated dispersal ultimately stemming from zebu bulls imported from South Asia during the last three millennia. Here we assess whether ancestry at mitochondrially-targeted nuclear genes in African admixed cattle is impacted by mitonuclear functional interactions. Using high-density SNP data, we find evidence for mitonuclear coevolution across hybrid African cattle populations with a significant increase of taurine ancestry at mitochondrially-targeted nuclear genes. Our results, therefore, support the hypothesis of incompatibility between the taurine mitochondrial genome and the zebu nuclear genome. GRAPHICAL SUMMARY O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/457829v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1031fb0org.highwire.dtl.DTLVardef@1575faorg.highwire.dtl.DTLVardef@f4795corg.highwire.dtl.DTLVardef@4ba74e_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights* Using high-density genome-wide SNP data, we present evidence for mitonuclear coevolution in hybrid African cattle. * We observe a significant increase of taurine ancestry across multiple hybrid populations at mitochondrially-targeted nuclear genes. * Our results provide support for the hypothesis of mitonuclear incompatibility between the zebu nuclear genome and the taurine mitochondrial genome.

evolutionary biology↗

bioRxiv2020

Integrative genomics of the mammalian alveolar macrophage response to intracellular mycobacteria

Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, is a major disease affecting cattle globally as well as being a zoonotic risk to human health. The key innate immune cell that first encounters M. bovis is the alveolar macrophage, previously shown to be substantially reprogrammed during intracellular infection by the pathogen. Here we use multi-omics and network biology approaches to analyse the macrophage transcriptional response to M. bovis infection and identify core infection response pathways and gene modules. These outputs were integrated with results from genome-wide associations of M. bovis infection to enhance the detection of putative genomic variants for disease resistance. Our results show that network-based integration of relevant transcriptomics data can extract additional information from large genome-wide associations and that this approach could also be used to integrate relevant functional genomics outputs with results from genomic association studies for human tuberculosis caused by the related Mycobacterium tuberculosis.

genomics↗

bioRxiv2019

Alveolar macrophage chromatin is uniquely modified to orchestrate host response to Mycobacterium bovis infection

Mycobacterium bovis, the causative pathogen of bovine tuberculosis (bTB), induces extensive reprogramming of the macrophage transcriptome during infection. To identify key transcriptional changes in infected bovine alveolar macrophages (bAM), we have performed both gene expression (RNA-seq) and epigenomic (ChIP-seq) analyses using two key histone modification marks associated with activation (H3K4me3) and repression (H3K27me3). Together with RNA polymerase II (PolII) occupancy data, we show that reprogramming of the bAM transcriptome after M. bovis infection affects key immune response genes. Identification of these genes also facilitated integration of GWAS data, which identified genomic regions and SNPs significantly associated with resilience to infection with M. bovis in cattle.\n\nHighlightsO_LIComprehensive analysis of bovine alveolar macrophage (bAM) transcriptome and chromatin architecture revealed Mycobacterium bovis (M. bovis) induces genome-wide chromatin remodelling in bAM\nC_LIO_LIM. bovis induces transcriptional changes of immune response genes, associated with changes of histone modifications and RNA Polymerase II (PolII) occupancy\nC_LIO_LIGWAS integration of our ChIP study enabled the identification of important SNPs for bovine tuberculosis (bTB) susceptibility\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC=\"FIGDIR/small/520098_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (19K):\norg.highwire.dtl.DTLVardef@1946689org.highwire.dtl.DTLVardef@1d7c0aborg.highwire.dtl.DTLVardef@1aa5c1forg.highwire.dtl.DTLVardef@1860ea5_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2017

The bovine alveolar macrophage DNA methylome is resilient to infection with Mycobacterium bovis

DNA methylation is pivotal in orchestrating gene expression patterns in various mammalian biological processes. Perturbation of the bovine alveolar macrophage (bAM) transcriptome, due to Mycobacterium bovis (M. bovis) infection, has been well documented; however, the impact of this intracellular pathogen on the bAM epigenome has not been determined. Here, whole genome bisulfite sequencing (WGBS) was used to assess the effect of M. bovis infection on the bAM DNA methylome. The methylomes of bAM infected with M. bovis were compared to those of non-infected bAM 24 hours post-infection (hpi). No differences in DNA methylation (CpG or non-CpG) were observed. Analysis of DNA methylation at proximal promoter regions uncovered >250 genes harbouring intermediately methylated (IM) promoters (average methylation of 33-66%). Gene ontology analysis, focusing on genes with low, intermediate or highly methylated promoters, revealed that genes with IM promoters were enriched for immune-related GO categories; this enrichment was not observed for genes in the high or low methylation groups. Targeted analysis of genes in the IM category confirmed the WGBS observation. This study is the first in cattle examining genome-wide DNA methylation at single nucleotide resolution in an important bovine cellular host-pathogen interaction model, providing evidence for IM promoter methylation in bAM.

genomics↗