Biology subjects

Nelson, E. A.

Publications and source records attributed to Nelson, E. A..

8 recordsLinked to original sources

bioRxiv2026

A novel wild-derived MHC-linked locus regulates host immunity to gammaherpesvirus infection

Inefficient host control of infection by gammaherpesviruses is a risk factor for lymphoproliferative disease, autoimmunity, and cancer, yet naturally occurring genetic determinants of viral control remain poorly defined. Previously, we discovered that wild-derived PWD/PhJ (PWD) mice exhibit markedly improved control of murine gammaherpesvirus 68 (MHV-68) replication compared with C57BL/6J (B6) mice. This elite control of viral replication was linked to muted T cell responses, but partially dependent on NK cells. Here, we used genetic approaches to identify host determinants controlling MHV-68 resistance in PWD mice. Analysis of B6PWDF1 and B6PWDF2 populations suggested the existence of a major locus in the PWD genome contributing to MHV-68 resistance. Using B6.ChrPWD chromosome substitution (consomic) mice, we mapped a major resistance locus to Chr 17 and refined the required interval to 27.6-49.4 Mb, including the MHC locus. While B6.Chr17PWD mice recapitulated muted T cell responses observed in PWD mice, they controlled viral burden independent of NK cells and without reduced frequencies of infected germinal center B cells, indicating that resistance of PWD mice comprises multiple genetically and mechanistically distinct pathways. While the NK cell receptor complex on PWD chromosome 6 did not provide protection, genotype-phenotype analysis of the B6PWDF2 cohort revealed additional non-Chr 17-linked loci contributing to viral control. Together, our results identify a novel MHC-linked locus regulating gammaherpesvirus burden with minimal cytotoxic T cell expansion, demonstrating that effective host control of gammaherpesviruses can be achieved by diverse immune mechanisms. ImportancePoor host control of human gammaherpesvirus infection is linked to cancer and autoimmunity, but how natural genetic variation impacts immune mechanism of control is poorly defined. In this study, we examined genetic mechanisms linked to superior control of gammaherpesvirus infection. We identified a novel MHC-linked locus that regulates gammaherpesvirus burden without a large expansion of cytotoxic T cells and independent of NK cells. These findings show that host control of gammaherpesviruses can be achieved through diverse immune mechanisms that are driven by variation in host genetic background.

immunology↗

bioRxiv2026

The Genomic Legacy of the Norman Conquest in Rural England

The Norman Conquest of 1066 CE reshaped the political and cultural landscape of England, yet its demographic consequences remain poorly understood, particularly outside elite and urban contexts where historical evidence is concentrated. Here, we investigate the population history of a rural English community spanning the Conquest using genome-wide ancient DNA from the Priory Orchard site, a cemetery in Godalming (Surrey) in use between the 9th and early 13th centuries CE. We generated genomic data from 78 individuals and established radiocarbon dates for 98 individuals from the site. Population genetic analyses place Priory Orchard individuals within the genetic continuum of early medieval populations from the North Sea region. Ancestry modelling indicates that this rural community carried substantial Scandinavian/Viking-related ancestry alongside a persistent Saxon-related component and a smaller French-related contribution. However, stratifying individuals by date, before and after 1066 CE, reveals no clear genome-wide discontinuity across the Conquest horizon, suggesting demographic continuity through this crucial political and social transition. This pattern is consistent with historical and archaeological evidence indicating that many of the most visible transformations following the Conquest occurred primarily among the elite. Our results provide the first genomic perspective on communities living through the Norman Conquest and indicate that rural southern England saw persistent migration links with other areas facing the North Sea rather than abrupt population replacement.

genetics↗

bioRxiv2026

Integrated multi-omics analysis identifies microbial and metabolic signatures and drivers of CNS autoimmunity

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) driven by genetic and environmental determinants. The gut microbiome of people with MS (pwMS) is distinct and influences disease through immunomodulatory metabolite production. Circulating metabolites are altered in pwMS, but identifying microbial-metabolic drivers remains challenging. We previously showed that colonization by the gut commensal Limosilactobacillus reuteri (L. reuteri) exacerbates disease in the experimental autoimmune encephalomyelitis (EAE) model of MS, in a tryptophan-dependent manner. Here, we integrated microbiomic and metabolomic datasets from a longitudinal EAE study utilizing high and low tryptophan diets in mice colonized or not with L. reuteri. Gut microbiome dynamics under short- and long-term alterations in tryptophan bioavailability, were affected by diet, microbiome context, or disease. During short-term dietary intervention, L. reuteri colonization exerted a greater impact on microbiome composition than tryptophan bioavailability. With longer dietary exposure and EAE progression, high dietary tryptophan and L. reuteri colonization synergized to elicit profound microbiota changes, including alterations in Lachnospiraceae, Blautia, and Akkermansia. Integration of metabolomic and microbiomic datasets using joint Robust Aitchison PCA revealed clusters of associated metabolites and microbiota enriched for functional pathways, including bile acid and tryptophan metabolism. Metabolites outperformed microbiota in predicting EAE severity, identifying p-cresols and indoles as top disease-associated metabolites. Treatment with p-cresol or 3-indoleglyoxylic acid exacerbated EAE, enhanced proinflammatory T cell responses, and increased cerebellar pathology. These data demonstrate that dietary responses are shaped by gut microbiome composition and that integrated microbiomic-metabolomic analyses can identify drivers of disease worsening in MS. IMPORTANCEMS is a multifactorial disease influenced not only by genetics but also by environmental factors, potentially including diet and the composition of the gut microbiome. We show that interactions between diet and commensal gut microbiota profoundly impact levels of immunomodulatory systemic metabolites, including several that are associated with disease in pwMS. Importantly, we demonstrate that individual gut microbiota produced metabolites are sufficient to worsen disease in a mouse model of MS. Integration of gut microbiome and blood metabolite datasets combined with subsequent predictive modeling, may bolster biomarker identification and the capacity to predict disease severity in pwMS, as compared to performance of individual datasets alone. These findings highlight metabolites as key mediators linking diet and the gut microbiota to neuroinflammation. Importantly, this work suggests that targeting microbial metabolites or modifying diet-microbiome interactions may represent new strategies to reduce disease activity in MS and related autoimmune disorders.

bioinformatics↗

bioRxiv2025

Probing the zooarchaeological record across time and space for ancient pathogens

Zoonoses are among the greatest threats to human health, with many zoonotic pathogens believed to have emerged during prehistory. Palaeomicrobiological investigations of the zooarchaeological record hold potential to uncover the reservoirs, host ranges, and host adaptations of zoonotic pathogens but face challenges in identifying promising specimens and pathogen DNA preservation. We performed palaeopathological and genetic examinations of 346 skeletal elements from domesticated and wild animals collected from 34 Eurasian sites dating across the last six millennia. We identified 68 signatures of ancient (opportunistic) pathogens, including the important zoonotic pathogen Salmonella enterica, and found support that palaeopathological lesions provide guidance for specimen selection. For two pathogen species, Erysipelothrix rhusiopathiae and Streptococcus lutetiensis, we confirmed their ancient authenticity using phylogenetics, showcasing an approach to explore the relationship between ancient low-coverage genomes and their modern-day relatives. Our work presents a pathway to understanding prehistoric zoonotic diseases by integrating zooarchaeological, palaeopathological, and genetic data.

microbiology↗

bioRxiv2022

Transformation of alignment files improves performance of variant callers for long-read RNA sequencing data

Long-read RNA sequencing (lrRNA-seq) produces detailed information about full-length transcripts, including novel and sample-specific isoforms. Furthermore, there is opportunity to call variants directly from lrRNA-seq data. However, most state-of-the-art variant callers have been developed for genomic DNA. Here, there are two objectives: first, we perform a mini-benchmark on GATK, DeepVariant, Clair3, and NanoCaller primarily on PacBio Iso-Seq, data, but also on Nanopore and Illumina RNA-seq data; second, we propose a pipeline to process spliced-alignment files, making them suitable for variant calling with DNA-based callers. With such manipulations, high calling performance can be achieved using DeepVariant on Iso-seq data.

bioinformatics↗

bioRxiv2021

The United States Swine Pathogen Database: integrating veterinary diagnostic laboratory sequence data to monitor emerging pathogens of swine

Veterinary diagnostic laboratories annually derive thousands of nucleotide sequences from clinical samples of swine pathogens such as porcine reproductive and respiratory syndrome virus (PRRSV), Senecavirus A, and swine enteric coronaviruses. In addition, next generation sequencing has resulted in the rapid production of full-length genomes. Presently, sequence data are released to diagnostic clients for the purposes of informing control measures, but are not publicly available as data may be associated with sensitive information. However, public sequence data can be used to objectively design field-relevant vaccines; determine when and how pathogens are spreading across the landscape; identify virus transmission hotspots; and are a critical component in genomic surveillance for pandemic preparedness. We have developed a centralized sequence database that integrates a selected set of previously private clinical data, using PRRSV data as an exemplar, alongside publicly available genomic information. We implemented the Tripal toolkit, using the open source Drupal content management system and the Chado database schema. Tripal consists of a collection of Drupal modules that are used to manage, visualize, and disseminate biological data stored within Chado. Hosting is provided by Amazon Web Services (AWS) EC2 cloud instance with resource scaling. New sequences sourced from diagnostic labs contain at a minimum four data items: genomic information; date of collection; collection location (state or province level); and a unique identifier. Users can download annotated genomic sequences from the database using a customized search interface that incorporates data mined from published literature; search for similar sequences using BLAST-based tools; and explore annotated reference genomes. Additionally, because the bulk of data presently are PRRSV sequences, custom curation and annotation pipelines have determined PRRSV genotype (Type 1 or 2), the location of open reading frames and nonstructural proteins, generated amino acid sequences, the occurrence of putative frame shifts, and restriction fragment length polymorphism (RFLP) classification of GP5 genes. Genomic data from seven major swine pathogens have been curated and annotated. The resource provides researchers timely access to sequences discovered by veterinary diagnosticians, allowing for epidemiological and comparative virology studies. The result will be a better understanding on the emergence of novel swine viruses in the United States (US), and how these novel strains are disseminated in the US and abroad. Database URLhttps://swinepathogendb.org

bioinformatics↗

bioRxiv2020

Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues1-3. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression4,5, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations6. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying retinal vascular development in Fucci2aR reporter mice7, we found that venous and arterial endothelial cells are in distinct cell cycle states during development and in adulthood. That is, venous endothelial cells reside in early G1 state, while arterial endothelial cells reside in late G1 state. Endothelial cells in early vs. late G1 exhibited significant differences in gene expression and activity, especially among BMP/TGF-{beta} signaling components. The early G1 state was found to be essential for BMP4-induced venous specification, whereas late G1 state is essential for TGF-{beta}1-induced arterial specification. In a mouse model of endothelial cell hyperproliferation and disrupted vascular remodeling, pharmacological inhibition of endothelial cell cycle rescues the arterial-venous specification defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

developmental biology↗

bioRxiv2018

A phylogeography of the second plague pandemic revealed through the analysis of historical Y. pestis genomes

The second plague pandemic (14th - 18th century AD), caused by the bacterium Yersinia pestis, is infamous for its initial wave, the Black Death (1346-1353 AD), and its repeated scourges in Europe and the vicinity until the Early Modern Era. Here, we report 32 ancient Y. pestis genomes spanning the 14th to 17th century AD through the analysis of human remains from nine European archaeological sites. Our data support an initial entry of the bacterium from Eastern Europe and the absence of genetic diversity during the Black Death as well as low diversity during local outbreaks thereafter. Moreover, analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. Finally, we show the loss of a genomic region that includes virulence-associated genes in strains associated with late stages of the second plague pandemic (17th - 18th century AD). This deletion could not be detected in extant strains within our modern dataset, though it was identified in a today-extinct lineage associated with the first plague pandemic (6th - 8th century AD), suggesting convergent evolution during both pandemic events.

evolutionary biology↗