Biology subjects

Pardo Manuel de Villena, F.

Publications and source records attributed to Pardo Manuel de Villena, F..

8 recordsLinked to original sources

bioRxiv2022

A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to SARS-CoV disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse Chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6 that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2 and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species.

microbiology↗

bioRxiv2022

Population structure and inbreeding in wild house mice (Mus musculus) at different geographic scales

House mice (Mus musculus) have spread globally as a result of their commensal relationship with humans. In the form of laboratory strains, both inbred and outbred, they are also among the most widely-used model organisms in biomedical research. Although the general outlines of house mouse dispersal and population structure are well known, details have been obscured by either limited sample size or small numbers of markers. Here we examine ancestry, population structure and inbreeding using SNP microarray genotypes in a cohort of 814 wild mice spanning five continents and all major subspecies of Mus, with a focus on M. m. domesticus. We find that the major axis of genetic variation in M. m. domesticus is a south-to-north gradient within Europe and the Mediterranean. The dominant ancestry component in North America, Australia, New Zealand and various small offshore islands is of northern European origin. Next we show that inbreeding is surprisingly pervasive and highly variable, even between nearby populations. By inspecting the length distribution of homozygous segments in individual genomes, we find that inbreeding in commensal populations is mostly due to consanguinity. Our results offer new insight into the natural history of an important model organism for medicine and evolutionary biology.

genetics↗

bioRxiv2021

Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Sarbecovirus (CoV) infections, including Severe Acute Respiratory CoV (SARS-CoV) and SARS-CoV-2, are considerable human threats. Human GWAS studies have recently identified loci associated with variation in SARS-CoV-2 susceptibility. However, genetically tractable models that reproduce human CoV disease outcomes are needed to mechanistically evaluate genetic determinants of CoV susceptibility. We used the Collaborative Cross (CC) and human GWAS datasets to elucidate host susceptibility loci that regulate CoV infections and to identify host quantitative trait loci that modulate severe CoV and pan-CoV disease outcomes including a major disease regulating loci including CCR9. CCR9 ablation resulted in enhanced titer, weight loss, respiratory dysfunction, mortality, and inflammation, providing mechanistic support in mitigating protection from severe SARS-CoV-2 pathogenesis across species. This study represents a comprehensive analysis of susceptibility loci for an entire genus of human pathogens conducted, identifies a large collection of susceptibility loci and candidate genes that regulate multiple aspects type-specific and cross-CoV pathogenesis, and also validates the paradigm of using the CC platform to identify common cross-species susceptibility loci and genes for newly emerging and pre-epidemic viruses.

microbiology↗

bioRxiv2019

Collaborative Cross Mouse Populations as a Resource for the Study of Epilepsy

Epilepsy is a neurological disorder with complex etiologies and genetic architecture. Animal models have a critical role in understanding the pathophysiology of epilepsy. Here we studied epilepsy utilizing a genetic reference population of Collaborative Cross (CC) mice with publicly available whole genome sequences. We measured multiple epilepsy traits in 35 CC strains, and we identified novel animal models that exhibit extreme outcomes in seizure susceptibility, seizure propagation, epileptogenesis, and sudden unexpected death in epilepsy. We performed QTL mapping in an F2 population and identified seven novel and one previously identified loci associated with seizure sensitivity. We combined whole genome sequence and hippocampal gene expression to pinpoint biologically plausible candidate genes and candidate variants associated with seizure sensitivity. These resources provide a powerful toolbox for studying complex features of seizures and for identifying genes associated with particular seizure outcomes, and hence will facilitate the development of new therapeutic targets for epilepsy.

neuroscience↗

bioRxiv2019

Instability of the pseudoautosomal boundary in house mice

Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here we estimate the genetic map in a previously-documented expansion of the PAR in the Mus musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the Mus musculus musculus subspecies and show that it involves a complex rearrangement but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance in the population of unusual levels of polymorphism of unknown functional significance.

genetics↗

bioRxiv2018

Genetic characterization of invasive house mouse populations on small islands

House mice (Mus musculus) have dispersed to nearly every major landmass around the globe as a result of human activity. They are a highly successful invasive species, but their presence can be devastating for native ecosystems. This is particularly true on small offshore islands where mouse populations may grow unchecked by predators. Here we use genome-wide SNP genotypes to examine ancestry and population structure on two islands of ecological interest - Southeast Farallon Island, near San Francisco, CA; and Floreana Island in the Galapagos - in the context of a total cohort of 520 mice with diverse geographic origins, as a first step towards genetically-based eradication campaigns. We show that Farallon and Floreana mice, like those from previously-studied islands in both the Atlantic and Pacific Oceans, are of admixed European ancestry. We find that these populations are on average more inbred than mainland ones and passed through a strong colonization bottleneck with little subsequent genetic exchange. Finally we show that rodenticide resistance alleles present in parts of Europe are absent from all island populations studied. Our results add nuance to previous studies of island populations based on mitochondrial sequences or small numbers of microsatellites and will be useful for future eradication and monitoring efforts.

genetics↗

bioRxiv2017

Hierarchical Analysis of Multi-mapping RNA-Seq Reads Improves the Accuracy of Allele-specific Expression

Allele-specific expression (ASE) refers to the differential abundance of the allelic copies of a transcript. Direct RNA sequencing (RNA-Seq) can provide quantitative estimates of ASE for genes with transcribed polymorphisms. However, estimating ASE is challenging due to ambiguities in read alignment. Current approaches do not account for the hierarchy of multiple read alignments to genes, isoforms, and alleles. We have developed EMASE (Expectation-Maximization for Allele Specific Expression), an integrated approach to estimate total gene expression, ASE, and isoform usage based on hierarchical allocation of multi-mapping reads. In simulations, EMASE outperforms standard ASE estimation methods. We apply EMASE to RNA-Seq data from F1 hybrid mice where we observe widespread ASE associated with cis-acting polymorphisms and a small number of parent-of-origin effects at known imprinted genes. The EMASE software is freely available under GNU license at https://github.com/churchill-lab/emase and it can be adapted to other sequencing applications.

bioinformatics↗

bioRxiv2016

Sequence and structural diversity of mouse Y chromosomes

Over the 180 million years since their origin, the sex chromosomes of mammals have evolved a gene repertoire highly specialized for function in the male germline. The mouse Y chromosome is unique among mammalian Y chromosomes characterized to date in that it is large, gene-rich and euchromatic. Yet little is known about its diversity in natural populations. Here we take advantage of published whole-genome sequencing data to survey the diversity of sequence and copy number of sex-linked genes in three subspecies of house mice. Copy number of genes on the repetitive long arm of both sex chromosomes is highly variable, but sequence diversity in non-repetitive regions is decreased relative to expectations based on autosomes. We use simulations and theory to show that this reduction in sex-linked diversity is incompatible with neutral demographic processes alone, but is consistent with recent positive selection on genes active during spermatogenesis. Our results support the hypothesis that the mouse sex chromosomes are engaged in ongoing intragenomic conflict.

genetics↗