Biology subjects

de la Fuente, J.

Publications and source records attributed to de la Fuente, J..

16 recordsLinked to original sources

bioRxiv2026

Ultra-Fast Implementation of Multivariate GWAS in Genomic SEM Using Flexible Analytic Estimation

Many medical, physiological, and psychiatric traits and disorders are highly polygenic and exhibit complex patterns of genetic sharing and differentiation. In 2018, we introduced Genomic Structural Equation Modelling (Genomic SEM) as a formal framework and free, open source, R-based software for modelling the multivariate genetic architecture of both continuous and binary Genome-Wide Association Study (GWAS) phenotypes, interrogating their joint and distinct functional genomic pathways, and leveraging empirical models of the genetic relations among phenotypes to guide multivariate GWAS discovery. Here we introduce a closed-form analytic solution for estimating SNP effects within multivariate GWAS in Genomic SEM. This estimator is over 800 times faster than the existing iterative estimator, drastically decreasing reliance on high performance computing (HPC). On a MacBook pro laptop with M4 Max chip, a multivariate GWAS ([~]1M SNPs) of 5 common factors underlying 13 phenotypes takes approximately 2 minutes. Concurrent with the release of this preprint, we are adding an analytic estimation option to the userGWAS function in the GenomicSEM package for alpha testing along with a tutorial on our GitHub wiki.

genetics↗

bioRxiv2026

Genomic Characterization of the RyC collection: 50 Multidrug Resistant Clinical Isolates of Escherichia coli and Klebsiella spp.

Antimicrobial resistance (AMR) is a major global public health threat, and Enterobacterales producing extended-spectrum {beta}-lactamases (ESBLs) represent some of the most common and concerning pathogens in clinical settings. Importantly, the dissemination of these resistance mechanisms is largely driven by mobile genetic elements (MGEs), particularly plasmids. Advancing our understanding of AMR evolution through experimentation requires moving beyond domesticated laboratory strains and towards clinically relevant isolates. However, despite the abundance of genomic data in public repositories, there is a lack of well-characterised clinical collections available for experimental work. Here, we characterise the RyC collection, which includes 50 multidrug-resistant, ESBL-producing Escherichia coli and Klebsiella spp. strains isolated from the gut microbiota of hospitalised patients at Hospital Universitario Ramon y Cajal (Madrid, Spain). We generated high-quality genome assemblies for all strains using a combination of short- and long-read sequencing technologies. From these data, we performed a comprehensive characterisation of the pangenome, mobilome, resistome and defensome of the collection. We present the RyC collection as a robust and experimentally tractable resource to study AMR evolution and MGEs dynamics in clinically relevant bacterial backgrounds. Impact statementAntimicrobial resistance (AMR) is a growing global health threat driven by the rapid dissemination of resistance genes among clinically relevant bacteria. A major challenge in studying AMR evolution is the reliance on domesticated laboratory strains, which poorly represent the complexity of pathogens circulating in hospitals. Here, we introduce the RyC collection, a set of well-characterised, multidrug-resistant Enterobacterales isolates obtained from hospitalised patients. By combining high-quality genome sequencing with detailed analyses of their gene content and mobile genetic elements (MGEs), this collection provides a realistic and experimentally tractable system to study how resistance evolves and spreads. The RyC collection will facilitate research on AMR dynamics, plasmid biology and host-MGEs interactions, ultimately contributing to the development of more effective strategies to combat antibiotic-resistant infections.

microbiology↗

bioRxiv2025

Distinguishing Specific from Broad Genetic Associations between External Correlates and Common Factors

Within the Genomic SEM framework, common factors are often used to index shared genetic etiology across constellations of GWAS phenotypes. A standard common pathway model, in which a genetic association is estimated between an external GWAS phenotype and a common factor, assumes that all genetic associations between the external GWAS phenotype and the individual indicator phenotypes are mediated through the factor. This assumption can be tested using the QTrait statistic, which compares the common pathway model to an independent pathways model that allows for direct genetic associations between the external GWAS phenotype and the individual indicators of the factor. We expand upon the QTrait approach by describing an effect size index that quantifies the degree to which the common pathways model is violated, and we provide a systematic approach for empirically identifying specific direct pathways between an external trait and indicator traits. Our method comprises a series of omnibus tests and outlier detection algorithms indexing the heterogeneity of associations between the genetic component of external traits and the individual indicators of common factors. We provide a set of automated functions which we apply to investigate the patterns of genetic associations across a set of external correlates with respect to indicators of general cognitive ability and case-control and proxy GWAS indices of Alzheimers disease.

genomics↗

bioRxiv2025

Robust inference and widespread genetic correlates from a large-scale genetic association study of human personality

Personality traits describe stable differences in how individuals think, feel, and behave and how they interact with and experience their social and physical environments. We assemble data from 46 cohorts including 611K-1.14M participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), and data from 51K participants for within-family GWAS. We identify 1,257 lead genetic variants associated with personality, including 823 novel variants. Common genetic variants explain 4.8%-9.3% of the variance in each trait, and 10.5%-16.2% accounting for measurement unreliability. Genetic effects on personality are highly consistent across geography, reporter (self vs. close other), age group, and measurement instrument, and we find minimal spousal assortment for personality in recent history. In stark contrast to many other social and behavioral traits, within-family GWAS and polygenic index analyses indicate little to no shared environmental confounding in genetic associations with personality. Polygenic prediction, genetic correlation, and Mendelian randomization analyses indicate that personality genetics have widespread, potentially causal associations with a wide range of consequential behaviors and life outcomes. The genetic architecture of personality is robust and fundamental to being a human.

genomics↗

bioRxiv2024

Understanding the mechanisms underlying microbiota variation in wild tick populations

Ticks are fascinating arthropods that have developed a unique blood-feeding lifestyle, making them intriguing subjects for understanding how they adapt to living with vertebrate hosts, their ability to transmit diseases, and their versatile roles in the ecosystem. Recent research highlights how significantly microbes impact the evolution of ticks, suggesting a genetic link to their hosts. These microbial partnerships are vital in improving tick nutrition, metabolism, reproduction, and overall survival, highlighting their important role as vectors in diverse ecological environments. In this study, we took a close look at the microbial communities present in three wild tick species--Hyalomma lusitanicum, Rhipicephalus sanguineus, and Rhipicephalus bursa--collected from several sites across central Spain. Through high-throughput DNA sequencing of the 16S rRNA gene, we discovered a complex and diverse microbiota largely composed of Proteobacteria, Bacteroidota, and Firmicutes. While all species exhibited a shared core microbiota, notable differences in microbial composition and network microbial interactions suggest that each species may be influenced by ecological and evolutionary factors shaping their microbiota. These insights deepen our understanding of the complex relationships between ticks, their microbiota, and the surrounding environment, which can inform better strategies for managing vectors and controlling pathogens.

genomics↗

bioRxiv2024

Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates

A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV[~]ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h2 = 26%; mean{chi} 2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

genetics↗

bioRxiv2023

GeNNius: An ultrafast drug-target interaction inference method based on graph neural networks

Drug-target interaction (DTI) prediction is a relevant but challenging task in the drug repurposing field. In-silico approaches have drawn particular attention as they can reduce associated costs and time commitment of traditional methodologies. Yet, current state-of-the-art methods present several limitations: existing DTI prediction approaches are computationally expensive, thereby hindering the ability to use large networks and exploit available datasets and, the generalization to unseen datasets of DTI prediction methods remains unexplored, which could potentially improve the development processes of DTI inferring approaches in terms of accuracy and robustness. In this work, we introduce GO_SCPLOWEC_SCPLOWnnO_SCPLOWIUSC_SCPLOW (Graph Embedding Neural Network Interaction Uncovering System), a Graph Neural Network (GNN)-based method that outperforms state-of-the-art models in terms of both accuracy and time efficiency across a variety of datasets. We also demonstrated its prediction power to uncover new interactions by evaluating not previously known DTIs for each dataset. We further assessed the generalization capability of GO_SCPLOWEC_SCPLOWnnO_SCPLOWIUSC_SCPLOW by training and testing it on different datasets, showing that this framework can potentially improve the DTI prediction task by training on large datasets and testing on smaller ones. Finally, we investigated qualitatively the embeddings generated by GO_SCPLOWEC_SCPLOWnnO_SCPLOWIUSC_SCPLOW, revealing that the GNN encoder maintains biological information after the graph convolutions while diffusing this information through nodes, eventually distinguishing protein families in the node embedding space. Code Availabilityhttps://github.com/ubioinformat/GeNNius

bioinformatics↗

bioRxiv2023

High prevalence of Bovine Tuberculosis reported in Cattle and Buffalo of Eastern Nepal

Livestock farming, specifically of cattle and buffalo, is crucial to Nepals economy, with more than 66% of the population involved in agriculture and animal husbandry. Animal tuberculosis (TB) caused by Mycobacterium bovis is a chronic disease that affects these animals and results in economic losses due to reduced milk and meat productivity, fertility and mortality. M. bovis also infects humans, non-human primates, goats and other mammals, and can afflict both cattle and buffalo. Our study is a part of routine surveillance of prevalent diseases, including M. bovis, in cattle and buffalo. We collected blood samples (n=400, 100 samples from each district) from selected eastern districts of Nepal. We used a Rapid Bovine TB Test Kit to test these samples for presence of M. bovis. Of the 400 samples collected, 74 animals (18.75%) tested positive for M. bovis, with the majority of positive samples coming from cattle (n=71, 17.75%) and only three from buffalo (<1%). Among the screened breeds of cattle and buffalo, Holstein Friesian cattle (HF) (n=43, 58%), Jersey-cross cattle (JX) (n=20, 27%), Local buffalo (n=8, 10.8%) and Murra breed buffalo (n=3, 4.1%) were found to carry M. bovis. The majority (50%) of infected animals were between 3-6 years old. Morang (n= 24 positive in cattle; n=1 positive in buffalo) and Jhapa (n= 22 positive in cattle; n=2 positive in buffalo) had the highest prevalence of M. bovis, while all the positive cases in Sunsari (n=19) and Udaypur (n=6) were in cattle. The fact that over 18% of the samples tested positive for M. bovis is of great concern. It is critical to thoroughly test animal products from these livestock prior to human consumption. To prevent and mitigate M. bovis-related infections in Nepal, a more comprehensive screening strategy coupled with more effective animal husbandry practices needs to be adapted.

microbiology↗

bioRxiv2023

Genetic contributions of noncognitive skills to academic development

Noncognitive skills such as motivation and self-regulation, are partly heritable and predict academic achievement beyond cognitive skills. However, how the relationship between noncognitive skills and academic achievement changes over development is unclear. The current study examined how cognitive and noncognitive skills contribute to academic achievement from ages 7 to 16 in a sample of over 10,000 children from England and Wales. Noncognitive skills were increasingly predictive of academic achievement across development. Twin and polygenic scores analyses found that the contribution of noncognitive genetics to academic achievement became stronger over the school years. Results from within-family analyses indicated that associations with noncognitive genetics could not simply be attributed to confounding by environmental differences between nuclear families and are consistent with a possible role for evocative/active gene-environment correlations. By studying genetic effects through a developmental lens, we provide novel insights into the role of noncognitive skills in academic development.

genetics↗

bioRxiv2023

Heat-inactivated mycobacteria activate the Toll-like receptor 2 and 4 pathways in the zebrafish model of tuberculosis

Based on previous evidence demonstrating the efficacy of inactivated mycobacteria for the control of fish mycobacteriosis, we explored the protective efficacy of two inactivated Mycobacterium bovis administered via parenteral and mucosal routes against Mycobacterium marinum infection mimicking natural conditions in the zebrafish model of tuberculosis. Although we did not observe a clear effect of any of the immunostimulants on mycobacterial burden, the results showed a significant increase in TLR2 and TLR4 gene expression levels in fishes parenterally immunized with inactivated Bacillus Calmette-Guerin (BCG). Our findings demonstrated that the TLR2 and the TLR4 signaling pathways are involved in the immune response elicited by inactivated mycobacteria in the zebrafish model of tuberculosis and support the use of inactivated mycobacteria in vaccine formulations for the control of mycobacteriosis.

immunology↗

bioRxiv2022

Identification and Characterization of Probiotics Isolates from Indigenous Chicken (Gallus domesticus) of Nepal

BackgroundExcessive and irrational use of antibiotics as growth promoters in poultry has been one of key factors contributing to increased emergence of antibiotics resistant bacteria. Drug resistant infections are becoming major concerns in poultry production impacting both human and poultry health. Several alternatives for antibiotic growth promoters are being sought, and the search for effective probiotics to be used as feed additives is amongst the promising ones. Our study aimed to isolate and test potential probiotics bacteria from cloacal swabs of various indigenous chicken (Gallus domesticus) breeds from rural outskirts of the Kathmandu valley (Nepal). MethodsSelective isolation of probiotics was conducted by micro-aerophilic enrichment of sample in MRS Broth at 37{degrees}C, followed by culturing on MRS agar supplemented with 5 g/L of CaCO3. Isolated bacterial colonies producing transparent halo were selected as potential lactic acid bacteria (LAB), and tested for their antibacterial activity, phenotypic and biochemical characteristics, acidic yield, and tolerance to acid and bile. ResultsA total of 90 potential LAB were isolated from cloacal samples collected from 41 free-ranging chickens of indigenous breeds. Of these, 52 LAB isolates (57%) showed variable antibacterial activity to at least one bacterial pathogen. Of 52 LAB, 46 isolates fulfilled phenotypic and biochemical criteria of Lactobacillus spp. Of these, 37 isolates produced varying percentage yields of lactic acid, 27 isolates showed survival at pH 3.0, and 17 isolates showed survival tolerances in the presence of 0.3% and 0.5% bile salts for 24 hours. Phylogenetic analysis of 16SrDNA sequencing of LAB isolates fulfilling in vitro probiotics properties showed that 3 isolates had genetic identity of 99.38% with Lactobacillus plantarum, while one isolate was genetically similar (99.85%) with the clade of L. reuteri, L. antri and L. panis. ConclusionsOur study identified four Lactobacillus spp. strains having potential probiotics properties. Further investigations are needed to evaluate these isolates to be used as poultry probiotics feed supplement.

microbiology↗

bioRxiv2021

General dimensions of human brain morphometry inferred from genome-wide association data

BackgroundUnderstanding the neurodegenerative mechanisms underlying cognitive declines in the general population may facilitate early detection of adverse health outcomes in late life. This study investigates biological pathways shared between brain morphometry, ageing, and cognitive ability. MethodsWe develop Genomic Principal Components Analysis (genomic PCA) to model general dimensions of variance in brain morphometry within brain networks at the level of their underlying genetic architecture. With genomic PCA we extract genetic principal components (PCs) that index global dimensions of genetic variance across phenotypes (unlike ancestral PCs that index genetic similarity between participants). Genomic PCA is applied to genome-wide association data for 83 brain regions which we calculated in 36,778 participants of the UK Biobank cohort. Using linkage disequilibrium score regression, we estimate genetic overlap between brain networks and indices of cognitive ability and brain ageing. ResultsA genomic principal component (PC) representing brain-wide dimensions of shared genetic architecture accounted for 40% of the genetic variance across 83 individual brain regions. Genomic PCs corresponding to canonical brain networks accounted for 47-65% of the genetic variance in the corresponding brain regions. These genomic PCs were negatively associated with brain age (rg = -0.34). Loadings of individual brain regions on the whole-brain genomic PC corresponded to sensitivity of a corresponding region to age (r = - 0.27). We identified positive genetic associations between genomic PCs of brain morphometry and general cognitive ability (rg= 0.17-0.21). ConclusionThese results demonstrate substantial shared genetic etiology between connectome-wide dimensions of brain morphometry, ageing, and cognitive ability, which will help guide investigations into risk factors and potential interventions of ageing-related cognitive decline.

genetics↗

bioRxiv2021

Anti-microbiota vaccines modulate the tick microbiome in a taxon-specific manner

Anti-tick microbiota vaccines have been shown to impact tick feeding but its specificity has not been demonstrated. In this study we aimed to investigate the impact of immune targeting of keystone microbiota bacteria on tick performance, and tick microbiota structure and function. Vaccination against Escherichia coli, the selected keystone taxon, increased tick engorgement weight and reduced bacterial diversity in Ixodes ricinus ticks compared to those that fed on mice immunized against Leuconostoc mesenteroides, a non-keystone taxon or mock-immunized group. The abundance of Escherichia-Shigella, but not Leuconostoc was significantly reduced in ticks fed on E. coli-immunized mice and this reduction was correlated with a significant increase in host antibodies (Abs) of the isotype IgM and IgG specific to E. coli proteins. This negative correlation was not observed between the abundance of Leuconostoc in ticks and anti-L. mesenteroides Abs in mice. We also demonstrated by co-occurrence network analysis, that immunization against the keystone bacterium restructure the hierarchy of the microbial community in ticks and that anti-tick microbiota vaccines reduced the resistance of networks to directed removal of taxa. Functional pathways analysis showed that immunization with a live bacterial vaccine can also induce taxon-specific changes in the abundance of pathways. Our results demonstrated that anti-tick microbiota vaccines can modulate the tick microbiome and that the modification is specific to the taxon chosen for host immunization. These results guide interventions for the control of tick infestations and pathogen infection/transmission.

immunology↗

bioRxiv2021

Natural SARS-CoV-2 infection in kept ferrets, Spain

We found SARS-CoV-2 RNA in 6 of 71 ferrets (8.4%) and isolated the virus from one rectal swab. Natural SARS-CoV-2 infection does occur in kept ferrets, at least under circumstances of high viral circulation in the human population. However, small ferret collections are probably unable to maintain prolonged virus circulation.

microbiology↗

bioRxiv2020

The antibody response to the glycan α-Gal correlates with COVID-19 disease symptoms

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide. The characterization of the immunological mechanisms involved in disease symptomatology and protective response is important to advance in disease control and prevention. Humans evolved by losing the capacity to synthesize the glycan Gal1-3Gal{beta}1-(3)4GlcNAc-R (-Gal), which resulted in the development of a protective response against pathogenic viruses and other microorganisms containing this modification on membrane proteins mediated by anti--Gal IgM/IgG antibodies produced in response to bacterial microbiota. In addition to anti--Gal antibody-mediated pathogen opsonization, this glycan induces various immune mechanisms that have shown protection in animal models against infectious diseases without inflammatory responses. In this study, we hypothesized that the immune response to -Gal may contribute to the control of COVID-19. To address this hypothesis, we characterized the antibody response to -Gal in patients at different stages of COVID-19 and in comparison with healthy control individuals. The results showed that while the inflammatory response and the anti-SARS-CoV-2 (Spike) IgG antibody titers increased, reduction in anti--Gal IgE, IgM and IgG antibody titers and alteration of anti--Gal antibody isotype composition correlated with COVID-19 severity. The results suggested that the inhibition of the -Gal-induced immune response may translate into more aggressive viremia and severe disease inflammatory symptoms. These results support the proposal of developing interventions such as probiotics based on commensal bacteria with -Gal epitopes to modify the microbiota and increase the -Gal-induced protective immune response and reduce the severity of COVID-19.

immunology↗

bioRxiv2019

Genetic \"General Intelligence,\" Objectively Determined and Measured

It has been known for 115 years that, in humans, diverse cognitive traits are positively intercorrelated; this forms the basis for the general factor of intelligence (g). We directly test for a genetic basis for g using data from seven different cognitive tests (N = 11,263 to N = 331,679) and genome-wide autosomal single nucleotide polymorphisms. A genetic g factor accounts for 58.4% (SE = 4.8%) of the genetic variance in the cognitive traits, with trait-specific genetic factors accounting for the remaining 41.6%. We distill genetic loci broadly relevant for many cognitive traits (g) from loci associated with only individual cognitive traits. These results elucidate the etiological basis for a long-known yet poorly-understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.

genetics↗