Biology subjects

Coffey, M.

Publications and source records attributed to Coffey, M..

5 recordsLinked to original sources

bioRxiv2026

Integrating temporal genomic and transcriptomic analyses to decipher genetic basis of feed intake in dairy cattle

BackgroundFood intake is a complex trait in living organisms, where the genetics of food intake have been widely studied in humans, mice, Drosophila, cattle, pigs, chicken, and fish. In dairy cattle, intake of feed is highly linked to individuals energy balance, health, production, efficiency, and the environmental footprint of the individual to the society. Recent studies have provided solid evidence of the genetic variation of feed intake (FI) in dairy cattle population, but the genetic basis and molecular mechanism of dairy feed intake is still far from clear especially considering the lactation cycles of dairy cattle. This study aims to integrate stage-dependent genome-wide association (GWA) analyses, regional heritability mapping (RHM), and RNA-seq gene expression analyses to identify temporal functional variants associated with cattle dry matter intake (DMI) across multiple stages in lactation cycles. A total of 750,000 daily DMI records from 7,500 lactations of 2,300 cows were available with animals genotype and pedigree information. Total RNA-seq from blood were generated for 121 individuals in this population from 2 lactation stages. Data were split into multiple lactations stages for GWA, RHM, and transcriptomic analyses. ResultsStage-dependent GWAS and RHM identified 21 significant loci associated with DMI across multiple lactation stages. A total of 45 candidate genes were identified from GWA and RHM. Among all the 45 genes, six genes were later found significantly differently expressed between high and low feed intake animal groups using gene expression information from RNA-seq data. These genes show links to sugar and adipose metabolism, milk production, body weight, dopamine-reward pathways and immune functions. ConclusionsOur multi-omics analyses provide molecular evidence that the genetic basis of cattle DMI across lactation is not static. Temporal genomic variants associated with FI were identified with their transcriptomic patterns investigated, decoding the molecular mechanisms underlying DMI. Overall, the associated variants and candidate genes uncovered herein decoded genetic architecture of dairy feed intake on a temporal and multi-omics basis, enhancing the understanding of basic biology of dairy feed intake and informing breeding strategies aimed at improving dairy feed efficiency.

genomics↗

bioRxiv2020

Oncolytic virus treatment differentially affects the CD56dim and CD56bright NK cell subsets in vivo and regulates a spectrum of human NK cell activity

Natural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where anti-viral responses enhance anti-tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN-I) dependent manner, resulting in STAT1 and STAT4 signalling in both CD56dim and CD56bright NK cell subsets. Gene expression profiling revealed the dominance of IFN-I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56dim and CD56bright subsets. However, reovirus treatment, acting via IFN-I, inhibited NK cell proliferative responses to IL-15 and was associated with reduced AKT signalling. In vivo, human CD56dim and CD56bright NK cells responded with similar kinetics to reovirus treatment, but CD56bright NK cells were transiently lost from the peripheral circulation at the peak of the IFN-I response, suggestive of their redistribution to secondary lymphoid tissue. These results show that reovirus modulates a spectrum of NK cell activity in vivo, encompassing direct action on tumour cells and the regulation of adaptive immunity. Such activity is likely to mirror NK cell responses to natural viral infection.

immunology↗

bioRxiv2020

Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.

cancer biology↗

bioRxiv2020

Life-long telomere attrition predicts health and lifespan in a large mammal

Telomere length measured in blood cells is predictive of subsequent adult health and survival across a range of vertebrate species. However, we currently do not know whether such associations result from among-individual differences in telomere length determined genetically or by environmental factors early in life, or from differences in the rate of telomere attrition over the course of life. Here, we measured relative leukocyte telomere length (RLTL) multiple times across the entire lifespan of dairy cattle in a research population that is closely monitored for health and milk production and where individuals are only culled in response to health issues and less due to poor milk production than on purely commercial farms. Our results clearly show that the average amount of telomere attrition over an individuals life, not their average or early life telomere length predicted when an individual was culled. Within-individual telomere length attrition could reflect environmental or physiological insults which may accumulate to predict individual health-span. We also show that animals with more telomere attrition in their first year of life were culled at a younger age, indicating that early life stressors may have a prolonged effect on adult life.

evolutionary biology↗

bioRxiv2019

Toxoplasma gondii bradyzoites induce transcriptional changes to host cells and prevent IFNγ-mediated cell death

Toxoplasma gondii, the causative agent of toxoplasmosis, lies dormant for life and is a reservoir for disease reactivation, causing blindness, encephalitis and congenital birth defects. Acute-stage tachyzoites extensively manipulate their host cell by exporting a repertoire of proteins across the parasitophorous vacuolar membrane (PVM). This interferes with the hosts transcriptional program, allowing for persistence during immune attack. It is unknown how bradyzoites persist and what role host manipulation plays in latency. Here we show that bradyzoite-containing host cells have a unique transcriptional landscape when compared to tachyzoite infection. We demonstrate that many of these changes are dependent parasite protein export. Furthermore, we show that bradyzoite effector proteins protect host cells from IFN{gamma}-mediated cell death, thus highlighting the functional importance of host manipulation. Together, our work provides the first understanding of how Toxoplasma sets up latency to persist in its host.

microbiology↗