Biology subjects

MacHugh, D. E.

Publications and source records attributed to MacHugh, D. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomic status of the Eurasian curlew Numenius arquata : estimating Essential Biodiversity Variables and selection signals for a declining migratory bird

Understanding how contemporary population declines affect the genomic diversity and structure of threatened species is important for effective conservation. The Eurasian curlew (Numenius arquata) is experiencing severe population declines across Europe, with Ireland among the most extreme, showing declines exceeding 90% over 40 years. Genomic data are increasingly incorporated into policy and used to assess conservation status by estimating genetic diversity, differentiation, inbreeding, effective population size, and adaptive divergence. Such data for curlew is scarce, and the population structure among northern and north-western European breeding populations remains unclear. To address this, we generated whole-genome resequencing data for 56 curlews across Ireland, Britain and Sweden. Irish and British populations showed minimal interpopulation differentiation, but both were substantially differentiated from Sweden. This was apparent from principal component analysis, and admixture and FST analyses. Measures of genetic diversity (nucleotide diversity, heterozygosity, Watterson's{theta} ) were similar across populations. A slightly elevated Tajima's D in Ireland, along with elevated FROH in Ireland and Britain relative to Sweden, may be the early genomic signs of recent population declines. We identified locally selected candidate genes. These had putative roles in metabolic processes, the immune response, and were potentially associated with distinct migratory behaviours and environmental conditions. We find a potential lag in genomic effects of decline being detectable following population contraction. We also show highly migratory species can exhibit differentiation in ecologically relevant traits, potentially driven by high site fidelity. These findings warrant consideration in translocation planning and broader conservation strategies.

genomics↗

bioRxiv2026

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.

genetics↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

Comparative multi-omics of the macrophage response to infection with Mycobacterium tuberculosis complex bacteria reveals pathogen-driven epigenomic reprogramming

BackgroundBovine tuberculosis (bTB) is a chronic infectious disease primarily caused by Mycobacterium bovis, which inflicts significant economic losses on the global livestock industry worldwide and can also cause tuberculosis (TB) disease in other mammalian species, including humans. Alveolar macrophages are the host cells targeted by the pathogen during the early stages of infection. While they play a crucial role in controlling infection, the exact nature of the host-pathogen interaction and the genetic and epigenetic factors that modulate infection outcome remain poorly understood. ResultsHere, we used transcriptomics (RNA-seq), chromatin accessibility (ATAC-seq), and chromatin configuration (ChIP-seq) analyses to examine the effects of intracellular mycobacterial infection on the bovine alveolar macrophage (bAM) transcriptome and epigenome. The primary focus was M. bovis infection, but we also conducted parallel comparative analyses using M. tuberculosis (the primary cause of human TB--hTB), M. bovis BCG (the vaccine strain), and gamma-irradiated (killed) M. bovis. Integration of RNA-seq, ChIP-seq, and ATAC-seq data revealed coordinated remodelling of chromatin accessibility and histone modification landscapes underpinning transcriptional activation of key immune and metabolic pathways in response to infection. The identification of candidate genes, including ERBB4, LRCH1, MRTFA, and RNPC3, through integrative analysis with a genome-wide association study (GWAS) for M. bovis infection susceptibility underscores the functional relevance of these regulatory networks. ConclusionsOur results demonstrate that M. bovis drives extensive reprogramming of the bAM epigenome, distinct from the responses elicited by other members of the M. tuberculosis complex (MTBC). The results of this multi-omics comparison provide new insights into the function of pivotal response genes and support the hypothesis that pathogen-driven epigenetic reprogramming of the bovine host macrophage is key to M. bovis survival. It also identifies molecular targets that may inform genome-enabled breeding strategies to enhance resilience to bTB in cattle.

genomics↗

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 atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2025

Genetic control of the transcriptional response to active tuberculosis disease and treatment

Understanding the functional impact of genomic sequence variants is critical for evaluating the role of genetic variation in the host response during tuberculosis (TB) disease and anti-TB treatment (ATT). Hitherto, there have been no genome-wide in vivo response expression quantitative trait loci (reQTL) studies conducted for active TB and ATT. Here, using longitudinal peripheral blood RNA-seq data from n = 48 patients with active TB who underwent ATT, we call sequence variants directly from these transcriptomes and impute them with a multi-ancestry reference panel. Associating our variants with the expression of nearby genes, we characterise thousands of cis-eQTL and hundreds of reQTL. We further show significant changes in cell type proportions during ATT through deconvolution of the bulk RNA-seq data and identify the putative cell type specific nature of cis-eQTL. Our work sheds light on the immunogenetics of TB disease and treatment, while providing a framework for studies using only RNA-seq data.

genetics↗

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

Genomic Insights into the Population History and Adaptive Traits of Latin American Criollo Cattle

Criollo cattle, descendants of animals brought by Iberian colonists to the Americas, have been subject to centuries of natural and human-mediated selection in novel tropical agroecological zones. Consequently, these breeds have evolved distinct characteristics such as resistance to disease and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity, and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux, and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

genomics↗

bioRxiv2023

Unveiling the Role of Endoplasmic Reticulum Stress Pathways in Canine Demodicosis

Canine demodicosis is a prevalent skin disease caused by overpopulation of a commensal species of Demodex mite, yet its precise cause remains unknown. Research suggests that T cell exhaustion, increased immunosuppressive cytokines, induction of regulatory T cells, and increased expression of immune checkpoint inhibitors may contribute to its pathogenesis. This study aimed to gain a deeper understanding of the molecular changes occurring in canine demodicosis using mass spectrometry and pathway enrichment analysis. The results indicate that endoplasmic reticulum stress is promoting canine demodicosis through regulation of three linked signalling pathways: eIF2, mTOR, and eIF4 and p70S6K. These pathways are involved in the modulation of Toll-like receptors, most notably TLR2, and have been shown to play a role in the pathogenesis of skin diseases in both dogs and humans. Moreover, these pathways are also implicated in the promotion of immunosuppressive M2 phenotype macrophages. Immunohistochemical analysis, utilizing common markers of dendritic cells and macrophages, verified the presence of M2 macrophages in canine demodicosis. The proteomic analysis also identified immunological disease, organismal injury and abnormalities, and inflammatory response as the most significant underlying diseases and disorders associated with canine demodicosis. This study demonstrates that Demodex mites, through ER stress, unfolded protein response and M2 macrophages contribute to an immunosuppressive microenvironment thereby assisting in their proliferation.

immunology↗

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↗

bioRxiv2022

High-resolution transcriptomics of bovine purified protein derivative-stimulated peripheral blood from cattle infected with Mycobacterium bovis across an experimental time course

ObjectivesImproved bovine tuberculosis (bTB) diagnostics with higher sensitivity and specificity are urgently required. A better understanding of the peripheral blood transcriptional response of Mycobacterium bovis-infected animals after bovine purified protein derivative (PPD-b) stimulation of whole blood--an important component of current bTB diagnostics--will provide new information for development of better diagnostics. MethodsRNA sequencing (RNA-seq) was used to study the peripheral blood transcriptome after stimulation with PPD-b across four time points (-1 wk pre-infection, and +1 wk, +2 wk, and +10 wk post-infection) from a 14-week M. bovis infection time course experiment with ten age-matched Holstein-Friesian cattle. ResultsIn vitro PPD-b stimulation of peripheral blood from M. bovis-infected and non-infected cattle elicited a strong transcriptional response. Comparison of PPD-b stimulated, and unstimulated samples revealed higher expression of genes encoding cytokine receptors, transcription factors, and interferon-inducible proteins. Lower expression was seen for genes encoding proteins involved in antimicrobial activity, C-type lectin receptors, inhibition of signal transduction, and genes encoding metal ion transporters. ConclusionsA transcriptional signature associated with the peripheral blood response to PPD-b stimulation consisting of 170 genes was identified exclusively in the post-infection time points. Therefore, this represents a panel of potential biomarkers of M. bovis infection.

genomics↗

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↗

bioRxiv2021

Timing of transcriptomic peripheral blood mononuclear cell responses of sheep to Fasciola hepatica infection differs from those of cattle, reflecting different disease phenotypes

Infection with the zoonotic trematode Fasciola hepatica, common in many regions with a temperate climate, leads to delayed growth and loss of productivity in cattle, while infection in sheep can have more severe effects, potentially leading to death. Previous transcriptomic analyses revealed upregulation of TGFB1, cell death and Toll-like receptor signalling, T-cell activation, and inhibition of nitric oxide production in macrophages in response to infection. However, the differences between ovine and bovine responses have not yet been explored. The objective of this study was to further investigate the transcriptomic response of ovine peripheral blood mononuclear cells (PBMC) to F. hepatica infection, and to elucidate the differences between ovine and bovine PBMC responses. Sixteen male Merino sheep were randomly assigned to infected or control groups (n = 8 per group) and orally infected with 120 F. hepatica metacercariae. Transcriptomic data was generated from PBMC at 0, 2 and 16 weeks post-infection (wpi), and analysed for differentially expressed (DE) genes between infected and control animals at each time point (analysis 1), and for each group relative to time 0 (analysis 2). Analysis 2 was then compared to a similar study performed previously on bovine PBMC. A total of 453 DE genes were found at 2 wpi, and 2 DE genes at 16 wpi (FDR < 0.1, analysis 1). Significantly overrepresented biological pathways at 2 wpi included role of PKR in interferon induction and anti-viral response, death receptor signalling and RIG-I-like receptor signalling, which suggested that an activation of innate response to intracellular nucleic acids and inhibition of cellular apoptosis were taking place. Comparison of analysis 2 with the previous bovine transcriptomic study revealed that anti-inflammatory response pathways which were significantly overrepresented in the acute phase in cattle, including IL-10 signalling, Th2 pathway, and Th1 and Th2 activation were upregulated only in the chronic phase in sheep. We propose that the earlier activation of anti-inflammatory responses in cattle, as compared with sheep, may be related to the general absence of acute clinical signs in cattle. These findings offer scope for "smart vaccination" strategies for this important livestock parasite.

immunology↗