Biology subjects

Swofford, R.

Publications and source records attributed to Swofford, R..

10 recordsLinked to original sources

bioRxiv2025

Population genetics, trait mapping and fungal pathogen surveillance using untargeted sequencing in timber rattlesnakes (Crotalus horridus)

Timber rattlesnakes (Crotalus horridus) face escalating threats in the Northeastern Appalachians, including habitat fragmentation, human encroachment, and the fungal pathogen Ophidiomyces ophiodiicola. Using untargeted sequencing of DNA extracted from scale clips, we generated both host whole-genome and metagenomic data for 97 snakes from eight populations. Analysis of the snake genomes shows the populations surveyed exhibit relatively low levels of inbreeding and are genetically distinct, but that the degree of separation correlates only weakly with geographic distance. A genome-wide association analysis identified a locus associated with black-to-yellow color variation that contains an aldehyde dehydrogenase gene (ALDH4A1) related to genes involved in hair color differences in humans. Metagenomic analysis showed that O. ophiodiicola read counts were generally higher in snakes exhibiting clinical signs of Snake Fungal Disease, but some visually asymptomatic snakes had high pathogen loads. Together, these findings highlight the dual utility of untargeted sequencing for population genetics and pathogen surveillance, providing a foundation for future studies of adaptation, disease dynamics, and conservation in this declining species.

genomics↗

bioRxiv2025

The shared selection landscape of dog and human cancers

Cancers in pet dogs are prevalent, progress rapidly, and closely resemble human cancers, positioning them as powerful models for precision oncology. While genetic drivers of human cancer often transcend histologic boundaries, most comparative studies have focused on matched cancer types, leaving the broader scope of genomic similarity unresolved. We performed the first exome-wide, histology-agnostic comparison of canine and human cancers, analyzing 429 dog and 14,966 human tumors across 39 types. Mutational signatures and genes under selection are widely shared between species, and cancer types are as genomically similar between species as within species, with no greater similarity within dog breeds than between breeds. Machine-learning models identify genetic features shared by dog and human tumors of different histologies, mirroring cross-histology patterns in human cancer. These findings establish dog cancer as a powerful system for genomics-informed precision oncology and support pan-cancer approaches to discover translationally relevant models beyond histologic classification.

cancer biology↗

bioRxiv2024

An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional Regulation

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. Previously, The ENCODE consortium mapped biochemical signals across many cell types and tissues and integrated these data to develop a Registry of 0.9 million human and 300 thousand mouse candidate cis-Regulatory Elements (cCREs) annotated with potential functions1. We have expanded the Registry to include 2.35 million human and 927 thousand mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded Registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays like STARR-seq, MPRA, CRISPR perturbation, and transgenic mouse assays now cover over 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer/silencer roles in different cellular contexts. Integrating the Registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by discovering KLF1 as a novel causal gene for red blood cell traits. This expanded Registry is a valuable resource for studying the regulatory genome and its impact on health and disease.

genomics↗

bioRxiv2024

Impact of preanalytical factors on liquid biopsy in the canine cancer model

While liquid biopsy has potential to transform cancer diagnostics through minimally-invasive detection and monitoring of tumors, the impact of preanalytical factors such as the timing and anatomical location of blood draw is not well understood. To address this gap, we leveraged pet dogs with spontaneous cancer as a model system, as their compressed disease timeline facilitates rapid diagnostic benchmarking. Key liquid biopsy metrics from dogs were consistent with existing reports from human patients. The tumor content of samples was higher from venipuncture sites closer to the tumor and from a central vein. Metrics also differed between lymphoma and non-hematopoietic cancers, urging cancer-type-specific interpretation. Liquid biopsy was highly sensitive to disease status, with changes identified soon after post chemotherapy administration, and trends of increased tumor fraction and other metrics observed prior to clinical relapse in dogs with lymphoma or osteosarcoma. These data support the utility of pet dogs with cancer as a relevant system for advancing liquid biopsy platforms.

genomics↗

bioRxiv2023

Evolutionary constraint and innovation across hundreds of placental mammals

Evolutionary constraint and acceleration are powerful, cell-type agnostic measures of functional importance. Previous studies in mammals were limited by species number and reliance on human-referenced alignments. We explore the evolution of placental mammals, including humans, through reference-free whole-genome alignment of 240 species and protein-coding alignments for 428 species. We estimate 10.7% of the human genome is evolutionarily constrained. We resolve constraint to single nucleotides, pinpointing functional positions, and refine and expand by over seven-fold the catalog of ultraconserved elements. Overall, 48.5% of constrained bases are as yet unannotated, suggesting yet-to-be-discovered functional importance. Using species-level phenotypes and an updated phylogeny, we associate coding and regulatory variation with olfaction and hibernation. Focusing on biodiversity conservation, we identify genomic metrics that predict species at risk of extinction.

genomics↗

bioRxiv2020

Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs

Sporadic angiosarcomas (ASs) are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic ASs. In this study, we leveraged RNA sequencing data from thirteen human ASs and 76 spontaneous canine hemangiosarcomas (HSAs) to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the thirteen human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in ASs without fusions or TP53 mutations. We found fifteen novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in eleven of the 76 canine HSAs; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 co-occurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human ASs and canine HSAs identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data show that, while driver events of malignant vasoformative tumors of humans and dogs include diverse mutations and stochastic rearrangements that create novel fusion genes, convergent transcriptional programs govern the highly conserved morphological organization and biological behavior of these tumors in both species.

cancer biology↗

bioRxiv2020

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

genomics↗

bioRxiv2019

Genomic analysis reveals shared genes and pathways in human and canine angiosarcoma

Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with high fatality and few effective treatment options. It is both rare and heterogenous, making large, well powered genomic studies nearly impossible. In dogs, angiosarcoma is common, with breeds like the golden retriever carrying heritable genetic factors that put them at very high risk. If the clinical similarity of canine and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine angiosarcoma via whole exome sequencing (47 golden retriever angiosarcomas) and RNA sequencing (74 angiosarcomas from multiple breeds). The predominant mutational signature was the age-associated deamination of cytosine to thymine, and somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). We compared the canine data to human data recently released by The Angiosarcoma Project, and found the same genes and many of the same pathways significantly enriched for somatic mutations, most notably protein kinases, glycoproteins, fibronectin Type III domains, EGF-like domains, and cell adhesion proteins such as cadherins. As in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. Canine angiosarcoma closely models human angiosarcoma on a genomic level, and is a powerful tool for investigating the pathogenesis of this devastating disease.

genomics↗

bioRxiv2017

A quantitative model for characterizing the evolutionary history of mammalian gene expression

Characterizing the evolutionary history of a genes expression profile is a critical component for understanding the relationship between genotype, expression, and phenotype. However, it is not well-established how best to distinguish the different evolutionary forces acting on gene expression. Here, we use RNA-seq across 7 tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein-Uhlenbeck (OU) process. This stochastic process models expression trajectories across time as Gaussian distributions whose variance is parameterized by the rate of genetic drift and strength of stabilizing selection. We use these mathematical properties to identify expression pathways under neutral, stabilizing, and directional selection, and quantify the extent of selective pressure on a genes expression. We further detect deleterious expression levels outside expected evolutionary distributions in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.\n\nOne Sentence SummaryWe demonstrate the power of a stochastic model for quantifying selective pressure on expression and estimating evolutionary distributions of optimal gene expression.

genomics↗

bioRxiv2017

Evolutionary and functional data power search for obsessive-compulsive disorder genes

Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37x10-11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.

genomics↗