Biology subjects

Todd, M.

Publications and source records attributed to Todd, M..

4 recordsLinked to original sources

bioRxiv2025

Pronounced genetic structure associated with differences in a reproductive trait and climatic barriers in Canadian populations of the western toad (Anaxyrus boreas)

Identifying genetic groups within species is critical for inventorying biodiversity, understanding species distributions, and delineating conservation units. The western toad (Anaxyrus boreas) is one of the most widespread amphibians in western Canada and one of just two amphibian species to maintain an extensive range on both sides of the Canadian Rocky Mountains. Curiously, toads on the eastern side of the mountains have a vocal sac and produce a distinct advertisement call whereas toads on the western side of the mountains lack these traits. However, the extent to which these "Calling" and "Non-Calling" populations are genetically and ecologically distinct remains unclear. We used reduced representation sequencing (ddRAD-seq) to genotype individuals from across the Canadian portion of the species range. Combining population genomic analysis with the original phenotypic data used to delineate the Calling and Non-Calling populations and with predictions from ecological niche models, we show that Calling and Non-Calling populations of western toads represent distinct genetic groups separated by both differences in a major reproductive trait and by climate barriers. We additionally find evidence for a third, undescribed group in southwestern Alberta and southeastern British Columbia. Our results suggest Calling and Non-Calling populations should be managed as distinct groups and highlight the potential for there to be cryptic and strong genetic structure among northern populations of widespread species.

evolutionary biology↗

bioRxiv2023

High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus

Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (IKZF1), thereby modulating expression of IKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-{kappa}B regulator IKK{varepsilon}. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a new regulatory pathway involving rs2297550, Ikaros, and IKK{varepsilon} implicated by human genetics in risk for SLE.

genetics↗

bioRxiv2019

Randomly primed, strand-switching MinION-based sequencing for the detection and characterization of cultured RNA viruses

RNA viruses rapidly mutate, which can result in increased virulence, increased escape from vaccine protection, and false negative detection results. Targeted detection methods have a limited ability to detect unknown viruses and often provide insufficient data to detect coinfections or identify antigenic variants. Random, deep sequencing is a method that can more fully detect and characterize RNA viruses and is often coupled with molecular techniques or culture methods for viral enrichment. Viral culture coupled with third-generation sequencing were tested for the ability to detect and characterize RNA viruses. Cultures of bovine viral diarrhea virus, canine distemper virus, epizootic hemorrhagic disease virus, infectious bronchitis virus, two influenza A viruses, and porcine respiratory and reproductive syndrome virus were sequenced on the MinION platform using a random, reverse primer in a strand-switching reaction, coupled with PCR-based barcoding. Reads were taxonomically classified and used for reference-based sequence building using a stock personal computer. This method accurately detected and identified complete coding sequence genomes with a minimum of 20x coverage depth for all seven viruses, including a sample containing two viruses. Each lineage-typing region had at least 26x coverage depth for all viruses. Furthermore, analyzing the canine distemper virus sample through a pipeline devoid of canine distemper virus reference sequences modeled the ability of this protocol to detect unknown viruses. These results show the ability of this technique to detect and characterize dsRNA, negative- and positive-sense ssRNA, nonsegmented, and segmented RNA viruses.

pathology↗

bioRxiv2018

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.\n\nAuthor summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungus Madurella mycetomatis. Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

pharmacology and toxicology↗