Biology subjects

Hume, D.

Publications and source records attributed to Hume, D..

6 recordsLinked to original sources

bioRxiv2023

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic metabolism to fuel growth.

Background and AimMacrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Methods and ResultsAcute administration of a CSF1-Fc fusion protein led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilisation of body fat. The impacts of CSF1 on macrophage abundance, liver size and body composition were rapidly reversed to restore homeostasis. CSF1s effects on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. ConclusionThese results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, metabolic regulation and homeostatic control of liver:body weight ratio.

immunology↗

bioRxiv2020

Genetic control of Campylobacter colonisation in broiler chickens: genomic and transcriptomic characterisation

Campylobacter is the leading cause of bacterial foodborne gastroenteritis in many countries. Source attribution studies unequivocally identify the handling or consumption of contaminated poultry meat as the primary risk factor. One potential strategy to control Campylobacter is to select poultry with increased resistance to colonisation. We conducted genomic and transcriptomic analyses of commercial pedigree broilers exposed to Campylobacter to examine persistent colonisation of the caecum as a quantitative trait. 3,000 broilers were genotyped using a 50K single nucleotide polymorphism (SNP) array and imputed to 600K SNPs. Genotypes were analysed for associations with the number of viable Campylobacter in the caeca. Heritability of the trait was modest but significantly greater than zero (h2=0.11 {+/-} 0.03). Genome-wide association analyses confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified using the progeny of crosses of inbred lines differing in resistance, and detected two additional genome-wide significant QTLs on chromosomes 19 and 26. RNA-Seq analysis of the transcriptome of caecal tonsils from birds at the low and high extremes of C. jejuni colonisation phenotype identified differentially transcribed genes, mainly located within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We also identified strong cis-QTLs located within the MHC suggesting the presence of cis-acting variation in both MHC class I, class II and BG genes. Multiple other cis-acting variants were identified in association with key immune genes (COPS3, CCL4, CR1L, C4BP, PLGR) in the other QTLs. Pathway and network analysis implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin-angiotensin signalling. While co-selection for enhanced resistance and other breeding goal traits is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influence Campylobacter colonisation in poultry. Author summaryCampylobacter infection is estimated to cause 95 million illnesses in people worldwide each year. Human infections mostly involve gastroenteritis, but can have severe complications. The handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. The bacteria reach high numbers in the intestines of chickens reared for meat (broilers) and are frequently found on carcasses after slaughter. Effective vaccines against Campylobacter are not yet available, and treatments to reduce carcass contamination (e.g. chlorination) are not acceptable in some markets. One alternative is to breed for chickens with improved resistance to Campylobacter colonisation. To test the feasibility of this option in commercial birds, we analysed the genetic make-up of 3,000 pedigree broilers and determined the number of Campylobacter in their gut. There were associations between specific regions of the chicken genome and resistance to Campylobacter. Within some of these regions, expression of certain genes differed between birds at the low and high extremes of Campylobacter colonisation, providing a potential explanation for genetic variation in resistance. Selection of poultry with increased resistance to Campylobacter colonisation may be a complementary strategy to improved biosecurity, management, handling and processing procedures to reduce the burden of Campylobacter on human health.

genomics↗

bioRxiv2019

Comprehensive characterisation of molecular host-pathogen interactions in influenza A virus-infected human macrophages

Macrophages in the lung detect and respond to influenza A virus (IAV), determining the nature of the immune response. Using terminal depth 5-RNA sequencing (CAGE) we quantify transcriptional activity of both host and pathogen over a 24-hour timecourse of IAV infection in primary human monocyte-derived macrophages (MDM). We use a systems approach to describe the transcriptional landscape of the host response to IAV contrasted with bacterial lipopolysaccharide treated MDMs, observing a failure of IAV-treated MDMs to induce feedback inhibitors of inflammation. Systematic comparison of host RNA sequences incorporated into viral mRNA (\"snatched\") against a complete survey of background RNA in the host cell enables an unbiased quantification of over-represented features of snatched host RNAs. We detect preferential snatching of RNAs associated with snRNA transcription and demonstrate that cap-snatching avoids transcripts encoding host ribosomal proteins, which are required by IAV for replication.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC=\"FIGDIR/small/670919v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (34K):\norg.highwire.dtl.DTLVardef@b05478org.highwire.dtl.DTLVardef@79a519org.highwire.dtl.DTLVardef@462739org.highwire.dtl.DTLVardef@1b91eb6_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical Abstract(A) Overview of bioinformatics pipeline. (B) Host gene expression reveals that human macrophages exposed to IAV exhibit sustained production of key inflammatory mediators and failure to induce expression of feedback inhibitors of inflammation. (C) Unbiased comparison with total background RNA expression demonstrates that IAV cap-snatching has a strong preference for, and aversion to, different groups of host transcripts.

immunology↗

bioRxiv2019

Elimination of reference mapping bias reveals robust immune related allele-specific expression in cross-bred sheep

Pervasive allelic variation at both gene and single nucleotide level (SNV) between individuals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript we describe an unbiased standardised computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open licence. The analysis pipeline we present is designed to minimise reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel x Scottish Blackface sheep, using the sheep gene expression atlas dataset. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited and instead they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for example, to improve the accuracy of genomic selection in breeding programmes for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq datasets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterisation of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling, to provide both a novel analysis of the multi-dimensional sheep gene expression atlas dataset, and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock.

genomics↗

bioRxiv2019

Genomic analyses underpin the feasibility of concomitant genetic improvement of milk yield and mastitis resistance in dairy sheep

Milk yield is the most important dairy sheep trait and constitutes the key genetic improvement goal via selective breeding. Mastitis is one of the most prevalent diseases, significantly impacting on animal welfare, milk yield and quality, while incurring substantial costs. Our objectives were to determine the feasibility of a concomitant genetic improvement programme for enhanced milk production and resistance to mastitis. Individual records for milk yield and four mastitis-related traits were collected monthly throughout lactation for 609 ewes of the Chios breed. All ewes were genotyped with a mastitis specific custom-made 960 single nucleotide polymorphism array. We performed genomic association studies, (co)variance component estimation and pathway enrichment analysis, and characterised gene expression levels and the extent of allelic expression imbalance. Presence of heritable variation for milk yield was confirmed. There was no significant genetic correlation between milk yield and mastitis. Environmental factors appeared to favour both milk production and udder health. Four Quantitative Trait Loci (QTLs) affecting milk yield were detected on chromosomes 2, 12, 16 and 19, in locations distinct from those previously identified to affect mastitis resistance. Pathways, networks and functional gene clusters for milk yield were identified. Seven genes (DNAJA1, DNAJC10, FGF10, GHR, HMGCS1, LYPLA1, OXCT1) located within the QTL regions were highly expressed in both the mammary gland and milk transcriptome, suggesting involvement in milk synthesis and production. Furthermore, the expression of four genes (DNAJC10, FGF10, OXCT1, EMB) was enriched in immune tissues implying a favourable pleiotropic effect or likely role in milk production during udder infection. In conclusion, the absence of genetic antagonism between milk yield and mastitis resistance suggests that simultaneous genetic improvement of both traits be achievable. The detection of milk yield QTLs with the mastitis array underpins the latters utility as a breeding tool for the genetic enhancement of both traits.

genetics↗

bioRxiv2018

Linked mutations at adjacent nucleotides have shaped human population differentiation and protein evolution

Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution there are still large gaps in our understanding of the forces that shape their distribution across the genome. SNPs have been shown to not be distributed evenly, with directly adjacent SNPs found unusually frequently. Why this is the case is unclear. We illustrate how neighbouring SNPs that cant be explained by a single mutation event (that we term here sequential dinucleotide mutations, SDMs) are driven by distinct mutational processes and selective pressures to SNPs and multinucleotide polymorphisms (MNPs). By studying variation across multiple populations, including a novel cohort of 1,358 Scottish genomes, we show that, SDMs are over twice as common as MNPs and like SNPs, display distinct mutational spectra across populations. These biases are though not only different to those observed among SNPs and MNPs, but also more divergent between human population groups. We show that the changes that make up SDMs are not independent, and identify a distinct mutational profile, CA [->] CG [->] TG, that is observed an order of magnitude more often than other SDMs, including others that involve the gain and subsequent deamination of CpG sites. This suggests these specific changes are driven by a distinct process. In coding regions particular SDMs are favoured, and especially those that lead to the creation of single codon amino acids. Intriguingly selection has favoured particular pathways through the amino acid code, with epistatic selection appearing to have disfavoured sequential non-synonymous changes.

genomics↗