Biology subjects

MacHugh, D. E.

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

26 records · Page 2Linked to original sources

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

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

The Thoroughbred horse is a highly valued domestic animal population under strong selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of inbreeding in the population that may form the basis for evidence-based discussion amid concerns in the breeding industry over the increasing use of small numbers of popular sire lines, which may accelerate a loss of genetic diversity. In the most comprehensive globally representative sample of Thoroughbreds to-date (n = 10,118), including prominent stallions (n = 305) from the major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has been a highly significant decline in global genetic diversity during the last five decades (FIS R2 = 0.942, P = 2.19 x 10-13; FROH R2 = 0.88, P = 1.81 x 10-10) that has likely been influenced by the use of popular sire lines. Estimates of effective population size in the global and regional populations indicate that there is some level of regional variation that may be exploited to improve global genetic diversity. Inbreeding is often a consequence of selection, which in managed animal populations tends to be driven by preferences for cultural, aesthetic or economically advantageous phenotypes. Using a composite selection signals approach, we show that centuries of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal growth and development, cellular stress and injury, metabolic pathways and neurotransmitters and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our results demonstrate that genomics-based approaches to identify genetic outcrosses will add valuable objectivity to augment traditional methods of stallion selection and that genomics-based methods will be beneficial to actively monitor the population to address the marked inbreeding trend.\n\nAuthor SummaryIn the highly valuable global Thoroughbred horse industry, there is no systematic industry-mediated genetic population management. Purposeful inbreeding is common practice and there is an increasing use of popular sires. Inbreeding can lead to population health and fertility decline, but there is little objective genomics-based data for the Thoroughbred to catalyse action and support changes in breeding practices. Here, we describe the most comprehensive genetic analysis in the population among 10,000 Thoroughbreds from the major bloodstock regions of the world and reveal a highly significant increase in inbreeding during the last five decades. The main drivers of genetic diversity are the most influential breed-shaping sire lines, Sadlers Wells, Danehill and A.P. Indy. We identified genomic regions subject to positive selection containing genes for athletic traits. Our results highlight the need for population-wide efforts to proactively avert the potential increase of deleterious alleles that may impact on animal health in order to safeguard the future of a breed that is admired for its athleticism and enjoyed for sport worldwide.

genetics↗

bioRxiv2019

Identification of expression quantitative trait loci in the skeletal muscle of Thoroughbreds reveals heritable variation in expression of genes relevant to cofactor metabolism

SummaryWhile over ten thousand genetic loci have been associated with phenotypic traits and inherited diseases in genome-wide association studies, in most cases only a relatively small proportion of the trait heritability is explained and biological mechanisms underpinning these traits have not been clearly identified. Expression quantitative trait loci (eQTL) are subsets of genomic loci shown experimentally to influence gene expression. Since gene expression is one of the primary determinants of phenotype, the identification of eQTL may reveal biologically relevant loci and provide functional links between genomic variants, gene expression and ultimately phenotype. Skeletal muscle (gluteus medius) gene expression was quantified by RNA-seq for 111 Thoroughbreds (47 male, 64 female) in race training at a single training establishment sampled at two time-points: at rest (n = 92) and four hours after high-intensity exercise (n = 77); n = 60 were sampled at both time points. Genotypes were generated from the Illumina Equine SNP70 BeadChip. Applying a Benjamini-Hochberg corrected P-value threshold (PFDR < 0.05), association tests identified 3,583 cis-eQTL associated with expression of 1,456 genes at rest; 4,992 cis-eQTL associated with the expression of 1,922 genes post-exercise; 1,703 trans-eQTL associated with 563 genes at rest; and 1,219 trans-eQTL associated with 425 genes post-exercise. The gene with the highest cis-eQTL association at both time-points was the endosome-associated-trafficking regulator 1 gene (ENTR1; Rest: PFDR = 3.81 x 10-27, Post-exercise: PFDR = 1.66 x 10-24), which has a potential role in the transcriptional regulation of the solute carrier family 2 member 1 glucose transporter protein (SLC2A1). Functional analysis of genes with significant eQTL revealed significant enrichment for cofactor metabolic processes. These results suggest heritable variation in genomic elements such as regulatory sequences (e.g. gene promoters, enhancers, silencers), microRNA and transcription factor genes, which are associated with metabolic function and may have roles in determining end-point muscle and athletic performance phenotypes in Thoroughbred horses.

genomics↗

bioRxiv2019

A Population Genomics Analysis of the Native Irish Galway Sheep Breed

The Galway sheep population is the only native Irish sheep breed and represents an important livestock genetic resource, which is currently categorised as \"at-risk\". In the present study, comparative population genomics analyses of Galway sheep and other sheep populations of European origin were used to investigate the microevolution and recent genetic history of the breed. These analyses support the hypothesis that British Leicester sheep were used in the formation of the Galway breed and suggest more recent gene flow from the Suffolk sheep breed. When compared to conventional and endangered breeds, the Galway breed was intermediate in effective population size, genomic inbreeding and runs of homozygosity. This indicates that, although the Galway breed is declining, it is still relatively genetically diverse and that conservation and management plans informed by genomic information may aid its recovery. The Galway breed also exhibited distinct genomic signatures of artificial or natural selection when compared to other breeds, which highlighted candidate genes that may be involved in meat and wool production.

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↗

bioRxiv2018

RNA sequencing (RNA-seq) reveals extremely low levels of reticulocyte-derived globin gene transcripts in peripheral blood from horses (Equus caballus) and cattle (Bos taurus)

RNA-seq has emerged as an important technology for measuring gene expression in peripheral blood samples collected from humans and other vertebrate species. In particular, transcriptomics analyses of whole blood can be used to study immunobiology and develop novel biomarkers of infectious disease. However, an obstacle to these methods in many mammalian species is the presence of reticulocyte-derived globin mRNAs in large quantities, which can complicate RNA-seq library sequencing and impede detection of other mRNA transcripts. A range of supplementary procedures for targeted depletion of globin transcripts have, therefore, been developed to alleviate this problem. Here, we use comparative analyses of RNA-seq data sets generated from human, porcine, equine and bovine peripheral blood to systematically assess the impact of globin mRNA on routine transcriptome profiling of whole blood in cattle and horses. The results of these analyses demonstrate that total RNA isolated from equine and bovine peripheral blood contains very low levels of globin mRNA transcripts, thereby negating the need for globin depletion and greatly simplifying blood-based transcriptomic studies in these two domestic species.

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↗

bioRxiv2017

Genomic characterisation and conservation genetics of the indigenous Irish Kerry cattle breed

Kerry cattle are an endangered landrace heritage breed of cultural importance to Ireland. In the present study we have used genome-wide SNP data (Illumina(R) BovineSNP50 array) to evaluate genomic diversity within the Kerry cattle population and between Kerry cattle and other European cattle breeds. Visualisation of patterns of genetic differentiation and gene flow among cattle breeds using phylogenetic trees with ancestry graphs highlighted, in particular, historical gene flow from the British Shorthorn breed into the ancestral population of modern Kerry cattle. Principal component analysis (PCA) and genetic clustering emphasised the genetic distinctiveness of Kerry cattle relative to comparator British and European cattle breeds. Modelling of genetic effective population size (Ne) revealed a demographic trend of diminishing Ne over time and that recent estimated Ne values for the Kerry breed may be less than the threshold for sustainable genetic conservation. In addition, analysis of genome-wide autozygosity (FROH) showed that genomic inbreeding has increased significantly during the 20 years between 1992 and 2012. Finally, signatures of selection revealed genomic regions subject to natural and artificial selection as Kerry cattle adapted to the climate, physical geography and agro-ecology of southwest Ireland.\n\nNote 1: This is an Associate Editor (D.E.M) Inaugural Article submission to Frontiers in Genetics: Livestock Genomics\n\nNote 2: British English language style preferred for publication of this article.

genomics↗