Biology subjects

Siegel, S. V.

Publications and source records attributed to Siegel, S. V..

3 recordsLinked to original sources

bioRxiv2026

The GA4GH Workflow Execution Service: A Standard API for Workflow Execution and Management in Genomics

Rapid growth in life science data generation has led to large and increasingly distributed collections of sensitive genomic data. To analyse this data, researchers increasingly rely on computational workflows to enable scalable, portable and reproducible analysis. However, these workflows are executed by specialized workflow engines across heterogeneous compute environments, each with its own requirements. As a result, users often need engine- and compute-environment-specific knowledge to submit, monitor and manage workflow execution, increasing the barriers to interoperability. These challenges are compounded in large-scale projects, where workflow runs must be dispatched to local clusters, cloud platforms or data hosting infrastructures with different underlying technologies. We describe the Global Alliance for Genomics and Health (GA4GH) Workflow Execution Service (WES) API, an approved GA4GH standard first released in 2018, together with its data model and the endpoints that define a unified interface for workflow execution. By standardizing workflow invocation, the WES API allows a single client to submit, monitor and cancel workflow runs across diverse workflow engines and compute backends, such as scheduling clusters or cloud platforms. We surveyed thirteen adoptions of the standard, covering standalone services and platforms in four programming languages. In a two-site demonstration, a WES implementation from Germany and one from Japan executed the same federated allele-frequency analysis with site-specific adjustments and only aggregated results leaving either site, demonstrating that it is possible to run the same analysis across independently built and operated WES services in different countries. From the gaps identified, we propose extensions for community discussion.

bioinformatics↗

bioRxiv2020

Analysis of Plasmodium vivax schizont transcriptomes from field isolates reveals heterogeneity of expression of genes involved in host-parasite interactions

Plasmodium vivax gene regulation remains difficult to study due to the lack of a robust in vitro culture method, low parasite densities in peripheral circulation and asynchronous parasite development. We adapted an RNA-seq protocol "DAFT-seq" to sequence the transcriptome of four P. vivax field isolates that were cultured for a short period ex vivo before using a density gradient for schizont enrichment. Transcription was detected from 78% of the PvP01 reference genome, despite being schizont-enriched samples. This extensive data was used to define thousands of 5 and 3 untranslated regions (UTRs), some of which overlapped with neighbouring transcripts, and to improve the gene models of 352 genes, including identifying 20 novel gene transcripts. This dataset has also significantly increased the known amount of heterogeneity between P. vivax schizont transcriptomes from individual patients. The majority of genes found to be differentially expressed between the isolates lack Plasmodium falciparum homologs and are predicted to be involved in host-parasite interactions, with an enrichment in reticulocyte binding proteins, merozoite surface proteins and exported proteins with unknown function. An improved understanding of the diversity within P. vivax transcriptomes will be essential for the prioritisation of novel vaccine targets.

genomics↗

bioRxiv2017

Mitochondrial heteroplasmy is responsible for Atovaquone drug resistance in Plasmodium falciparum

Malaria is the most significant parasitic disease affecting humans, with 212 million cases and 429,000 deaths in 2 0151, and resistance to existing drugs endangers the global malaria elimination campaign. Atovaquone (ATO) is a safe and potent antimalarial drug that acts on cytochrome b (cyt. b) of the mitochondrial electron transport chain (mtETC) in Plasmodium falciparum, yet treatment failures result in resistance-conferring SNPs in cyt. b. Herein we report that rather than the expected de novo selection of resistance, previously unknown mitochondrial diversity is the genetic mechanism responsible for resistance to ATO, and potentially other cyt. b targeted drugs. We found that P. falciparum harbors cryptic cyt. b. Y268S alleles in the multicopy ([~]22 copies) mitochondrial genome prior to drug treatment, a phenomenon known as mitochondrial heteroplasmy. Parasites with cryptic Y268S alleles readily evolve into highly resistant parasites with >95% Y268S copies under in vitro ATO selection. Further we uncovered high mitochondrial diversity in a global collection of 1279 genomes in which heteroplasmic polymorphisms were >3-fold more prevalent than homoplasmic SNPs. Moreover, significantly higher mitochondrial genome copy number was found in Asia (e.g., Cambodia) versus Africa (e.g., Ghana). Similarly, ATO drug selections in vitro induced >3-fold mitochondrial copy number increases in ATO resistant lines. Hidden mitochondrial diversity is a previously unknown mechanism of antimalarial drug resistance and characterization of mitochondrial heteroplasmy will be of paramount importance in combatting resistance to antimalarials targeting the electron transport chain.

cell biology↗