Biology subjects

Houston, R.

Publications and source records attributed to Houston, R..

8 recordsLinked to original sources

bioRxiv2026

A dual-clam species 63K SNP array for sustainable production and conservation of wild resources

Bivalves play an essential role in coastal ecosystems and their aquaculture represents an important economic sector in Europe playing a pivotal role within the EU Blue Growth Strategy. Among clam species, the Manila clam, Ruditapes philippinarum, and the grooved carpet shell, R. decussatus, are within the top five species in terms of production volume and economic value. In this study we designed and validated the first medium-density 63K single nucleotide polymorphism (SNP) array for these two commercially important species. By leveraging a new chromosome-level genome assembly for R. philippinarum and that of R. decussatus, we identified over 300 million SNPs through whole-genome resequencing and genotyping-by-sequencing strategies. After stringent filtering, we selected 49,392 high-quality SNPs for R. philippinarum and 14,193 for R. decussatus to construct a dual-species array. Array validation was carried out by genotyping 384 individuals across multiple wild populations and hatchery samples, demonstrating excellent performance, with 67.7% and 67.5% of SNPs classified as high-quality polymorphic markers for R. philippinarum and R. decussatus, respectively. Minor allele frequency, missing data rate, and inter-marker distance met stringent quality thresholds, confirming the array robustness for clam population genetics. Parentage analysis in R. philippinarum families highlighted significant power for pedigree reconstruction in breeding programs. This publicly available genomic resource provides a reliable, cost-effective genotyping platform to enable population genomics and advanced selective breeding, genome-wide association studies, and genetic monitoring, ultimately strengthening management of genetic diversity and sustainable farming for two key clam species.

genomics↗

bioRxiv2022

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation.1 Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele.2 While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients.3, 4 This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles;5 however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617Fabrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet26, 7 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.

cancer biology↗

bioRxiv2022

A mitochondrial iron-sensing pathway regulated by DELE1

The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron deficiency-induced HRI activation involves a heme-independent mechanism that requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Moreover, depletion of the mitochondrial ABC transporter ABCB7 that is involved in iron-sulfur cluster (ISC) metabolism markedly abrogates iron deficiency-induced ISR activation, suggesting the possible involvement of ISC-related molecules in this activation. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized iron monitoring system that connects the mitochondria to the cytosol.

cell biology↗

bioRxiv2021

Discovery of bactericides as an acute mitochondrial membrane damage inducer

Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The defined lipid composition and structure of mitochondrial membranes are critical for the proper functioning of mitochondria. However, mitochondrial stress responses that help maintain the integrity of mitochondrial membranes against internal or external insults are not well understood. One reason for this lack of insight is the absence of efficient tools to specifically damage mitochondrial membranes. Here, through a compound screen originally aimed at identifying inhibitors of the inner mitochondrial membrane (IMM)-resident protease OMA1, we found that two bis-biguanide compounds, Chlorhexidine and Alexidine, modified OMA1 activity by altering the integrity of the IMM. Interestingly, these compounds are well-known bactericides whose mechanism of action has centered on their damage-inducing activity on bacterial membranes. We found Alexidine binds to the IMM likely through the electrostatic interaction driven by the membrane potential as well as an affinity for anionic phospholipids. Electron microscopic analysis revealed that Alexidine severely perturbated the IMM, especially the cristae structure. Along with this, we observed the altered localization of IMM-resident membrane-shaping proteins, including Mic60. Notably, Alexidine evoked a specific transcriptional/proteostasis signature that was not induced by other typical mitochondrial stressors, highlighting the unique property of Alexidine as a novel mitochondrial membrane stressor. Our findings provide a chemical-biological tool that can induce acute and selective perturbation of the IMM integrity, which should enable the delineation of mitochondrial stress-signaling pathways required to maintain the mitochondrial membrane homeostasis.

cell biology↗

bioRxiv2020

Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses

The metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

cell biology↗

bioRxiv2019

Potential of genomic selection for improvement of resistance to Ostreid Herpes virus in Pacific oyster (Crassostrea gigas)

In genomic selection (GS), genome-wide SNP markers are used to generate genomic estimated breeding values (gEBVs) for selection candidates. The application of GS in shellfish looks promising and has the potential to help in dealing with one of the main issues currently affecting Pacific oyster production worldwide, which is the \"summer mortality syndrome\". This causes periodic mass mortality in farms worldwide and has mainly been attributed to a specific variant of the Ostreid herpesvirus (OsHV-1-var). In the current study, we evaluated the potential of genomic selection for host resistance OsHV in Pacific oysters, and compared it to pedigree-based approaches. An OsHV-1 disease challenge was performed using an immersion-based virus exposure treatment for oysters for seven days. 768 samples were genotyped using the medium density SNP array for oysters. GWAS was performed for the survival trait using a GBLUP approach in BLUPF90 software. Heritability ranged from 0.25{+/-}0.05 to 0.37{+/-}0.05 (mean{+/-}s.e) based on pedigree and genomic information, respectively. Genomic prediction was more accurate than pedigree prediction, and SNP density reduction had little impact on prediction accuracy until marker densities dropped below [~]500 SNPs. This demonstrates the potential for GS in Pacific oyster breeding programs and importantly, demonstrates that a low number of SNPs might suffice to obtain accurate gEBVs, thus potentially making the implementation of GS more cost effective.

genomics↗

bioRxiv2019

Characterising the mechanisms underlying genetic resistance to amoebic gill disease in Atlantic salmon using RNA sequencing

BackgroundGill health is one of the main concerns for Atlantic salmon aquaculture, and Amoebic Gill Disease (AGD), attributable to infection by the amoeba Neoparamoeba perurans, is a frequent cause of morbidity. In the absence of preventive measures, increasing genetic resistance of salmon to AGD via selective breeding can reduce the incidence of the disease and mitigate gill damage. Understanding the mechanisms leading to AGD resistance and the underlying causative genomic features can aid in this effort, while also providing critical information for the development of other control strategies. AGD resistance is considered to be moderately heritable, and several putative QTL have been identified. The aim of the current study was to improve understanding of the mechanisms underlying AGD resistance, and to identify putative causative genomic factors underlying the QTL. To achieve this, RNA was extracted from the gill and head kidney of AGD resistant and susceptible animals following a challenge with N. perurans, and sequenced.\n\nResultsComparison between resistant and susceptible animals pointed to differences mainly in the local immune response in the gill, involving red blood cell genes and genes related to immune function and cell adhesion. Differentially expressed immune genes highlighted differences in the Th2 and Th17 responses, which are consistent with the increased heritability observed after successive challenges with the amoeba. Five QTL-region candidate genes showed differential expression, including a gene connected to interferon responses (GVINP1), a gene involved in systemic inflammation (MAP4K4), and a positive regulator of apoptosis (TRIM39). Analyses of allele-specific expression highlighted a gene in the QTL region on chromosome 17, cellular repressor of E1A-stimulated genes 1 (CREG1), showing allelic differential expression suggestive of a cis-acting regulatory variant.\n\nConclusionsIn summary, this study provides new insights into the mechanisms of resistance to AGD in Atlantic salmon, and highlights candidate genes for further functional studies that can further elucidate the genomic mechanisms leading to resistance and contribute to enhancing salmon health via improved genomic selection.

genomics↗

bioRxiv2018

Genetic differences in host infectivity affect disease spread and survival in epidemics

Survival during an epidemic is partly determined by host genetics. While quantitative genetic studies typically consider survival as an indicator for disease resistance, mortality rates of populations undergoing an epidemic are also affected by tolerance and infectivity (i.e. the propensity of an infected individual to transmit disease). Few studies have demonstrated genetic variation in disease tolerance, and no study has demonstrated genetic variation in host infectivity, despite strong evidence for considerable phenotypic variation in this trait. Here we propose an experimental design and statistical models for estimating genetic diversity in all three host traits. Using an infection model in fish we provide, for the first time, direct evidence for genetic variation in host infectivity, in addition to variation in resistance and tolerance. We also demonstrate how genetic differences in these three traits contribute to survival. Our results imply that animals can evolve different disease response types affecting epidemic survival rates, with important implications for understanding and controlling epidemics.

genetics↗