Biology subjects

Hill, E. W.

Publications and source records attributed to Hill, E. W..

6 recordsLinked to original sources

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

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↗

bioRxiv2019

Inspiratory muscle training in young, race-fit Thoroughbred racehorses during a period of detraining

Although inspiratory muscle training (IMT) is reported to improve inspiratory muscle strength in humans little has been reported for horses. We tested the hypothesis that IMT would maintain and/or improve inspiratory muscle strength variables measured in Thoroughbreds during detraining. Thoroughbreds from one training yard were placed into a control (Con, n=3 males n=7 females; median age 2.2{+/-}0.4 years) or treatment group (Tr, n=5 males, n=5 females; median age 2.1{+/-}0.3 years) as they entered a detraining period at the end of the racing/training season. The Tr group underwent eight weeks of IMT twice a day, five days per week using custom-made training masks with resistance valves and an incremental threshold of breath-loading protocol. An inspiratory muscle strength test to fatigue using an incremental threshold of breath-loading was performed in duplicate before (T0) and after four (T1) and eight weeks (T2) of IMT/no IMT using a custom-made testing mask and a commercial testing device. Inspiratory measurements included the total number of breaths achieved during the test, average load, peak power, peak volume, peak flow, energy and the mean peak inspiratory muscle strength index (IMSi). Data was analysed using a linear mixed effects model, P[≤]0.05 significant. There were no differences for inspiratory measurements between groups at T0. Compared to T0, the total number of breaths achieved (P=0.02), load (P=0.003) and IMSi (P=0.01) at T2 had decreased for the Con group while the total number of breaths achieved (P<0.001), load (P=0.03), volume (P=0.004), flow (P=0.006), energy (P=0.01) and IMSi (P=0.002) had increased for the Tr group. At T2 the total number of breaths achieved (P<0.0001), load (P<0.0001), volume (P=0.02), energy (P=0.03) and IMSi (P<0.0001) were greater for the Tr than Con group. In conclusion, our results support that IMT can maintain and/or increase aspects of inspiratory muscle strength for horses in a detraining programme.

physiology↗

bioRxiv2019

Prolonged oral coenzyme Q10-β-cyclodextrin supplementation increases plasma CoQ10 concentration and skeletal muscle complex I+III activity in young, untrained healthy Thoroughbreds

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain (ETC). Decreased skeletal muscle CoQ10 content may result in decreased ETC activity and energy production. This study aimed to test the hypothesis that prolonged supplementation with oral CoQ10 will increase plasma CoQ10 concentrations and skeletal muscle CoQ10 content in young, healthy untrained Thoroughbreds. Nineteen Thoroughbreds (27.5{+/-}9.7 months old; 11 males, 8 females) from one farm and maintained on a grass pasture with one grain meal per day were supplemented orally once per day for 9 weeks with 1.5 mg/kg body weight of a CoQ10-{beta}-cyclodextrin inclusion complex. Whole-blood and skeletal muscle biopsies were collected before (T0) and after (T1) 9 weeks of supplementation. Plasma CoQ10 concentrations were determined via high-performance liquid chromatography. Skeletal muscle mitochondrial ETC combined complex I+III enzyme activity (an indirect measurement of CoQ10 content) was assessed spectrophotometrically and normalised to mitochondrial abundance. Results were analysed using a paired two-tailed Students t-test with P[≤]0.05 significant. Horses accepted supplementation with no adverse effects. The mean change in plasma CoQ10 concentration from T0 to T1 was significantly greater than zero (0.13{+/-}0.02 vs. 0.25{+/-}0.03 {micro}g/ml, mean difference 0.12{+/-}0.03; P=0.004), although variability in absorbance resulted in only a 58% response rate. The mean change in skeletal muscle complex I+III activity from T0 to T1 was significantly greater than zero (0.36{+/-}0.04 vs. 0.59{+/-}0.05 pmol/min/mg of muscle, mean difference 0.23{+/-}0.05; P=0.0004), although T1 values for 3/19 horses decreased on average by 23% below T0 values. In conclusion, prolonged oral supplementation of the diet of young, healthy untrained Thoroughbreds with CoQ10 increased mean plasma CoQ10 concentration by 99% and mean skeletal muscle complex I+III activity by 65% with variability in absorbance among horses. Additional research is warranted investigating training and exercise effects on skeletal muscle CoQ10 content in CoQ10 supplemented and un-supplemented Thoroughbreds.

biochemistry↗

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↗