Biology subjects

O'Grady, J. F.

Publications and source records attributed to O'Grady, J. F..

6 recordsLinked to original sources

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

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↗

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↗