Biology subjects

Calvete, J. J.

Publications and source records attributed to Calvete, J. J..

5 recordsLinked to original sources

bioRxiv2024

Unveiling the evolutionary history of European vipers and their venoms from a multi-omic approach

Snake genomes attract significant attention from multiple disciplines, including medicine, drug bioprospection, and evolutionary biology, due to the unique features found in snakes, especially, the evolution of venom. However, genomic research within the family Viperidae has mostly focused to date on the subfamily Crotalinae, while overlooking Viperinae, the Old World vipers. Among Viperinae, European vipers (Vipera) have been the subject of extensive research because of their venoms, phylogeographic, and ecological diversification. Nevertheless, venom research in this group has been conducted using mostly proteomes alone, while phylogeography and systematics in the genus have relied on biased information from mitochondrial phylogenies. Here, we generated chromosome-level genome assemblies for three Vipera species and whole-genome sequencing data for 94 samples representing 15 Vipera taxa. This comprehensive dataset has enabled us to disentangle the phylogenomic relationships of this genus, affected by mito-nuclear discordance and pervaded by ancestral introgression. Population-level analyses in the Iberian Peninsula, where the three oldest lineages within Vipera meet, revealed signals of recent adaptive introgression between ecologically dissimilar species, whereas chromosomal rearrangements isolate species occupying similar niches. Finally, using transcriptomic and proteomic data, we characterized the Vipera toxin-encoding genes, in which opposing selective forces were unveiled as common drivers of the evolution of venom as an integrated phenotype.

genomics↗

bioRxiv2024

Chromosome-level reference genome for the medically important Arabian horned viper (Cerastes gasperettii)

Venoms have traditionally been studied from a proteomic and/or transcriptomic perspective, often overlooking the true genetic complexity underlying venom production. The recent surge in genome-based venom research (sometimes called "venomics") has proven to be instrumental in deepening our molecular understanding of venom evolution, particularly through the identification and mapping of toxin-coding loci across the broader chromosomal architecture. Although venomous snakes are a model system in venom research, the number of high-quality reference genomes in the group remains limited. In this study, we present a chromosome-resolution reference genome for the Arabian horned viper (Cerastes gasperettii), a venomous snake native to the Arabian Peninsula. Our highly-contiguous genome allowed us to explore macrochromosomal rearrangements within the Viperidae family, as well as across squamates. We identified the main highly-expressed toxin genes compousing the venoms core, in line with our proteomic results. We also compared microsyntenic changes in the main toxin gene clusters with those of other venomous snake species, highlighting the pivotal role of gene duplication and loss in the emergence and diversification of Snake Venom Metalloproteinases (SVMPs) and Snake Venom Serine Proteases (SVSPs) for Cerastes gasperettii. Using Illumina short-read sequencing data, we reconstructed the demographic history and genome-wide diversity of the species, revealing how historical aridity likely drove population expansions. Finally, this study highlights the importance of using long-read sequencing as well as chromosome-level reference genomes to disentangle the origin and diversification of toxin gene families in venomous species.

genomics↗

bioRxiv2023

ASSESSING TARGET SPECIFICITY OF THE SMALL MOLECULE INHIBITOR MARIMASTAT TO SNAKE VENOM TOXINS: A NOVEL APPLICATION OF THERMAL PROTEOME PROFILING

New treatments that circumvent the pitfalls of traditional antivenom therapies are critical to address the problem of snakebite globally. Numerous snake venom toxin inhibitors have shown promising cross-species neutralization of medically significant venom toxins in vivo and in vitro. The development of high-throughput approaches for the screening of such inhibitors could accelerate their identification, testing, and implementation, and thus holds exciting potential for improving the treatments and outcomes of snakebite envenomation worldwide. Energetics-based proteomic approaches, including Thermal Proteome Profiling (TPP) and Proteome Integral Solubility Alteration (PISA), assays represent "deep proteomics" methods for high throughput, proteome-wide identification of drug targets and ligands. In the following study, we apply TPP and PISA methods to characterize the interactions between venom toxin proteoforms in Crotalus atrox (Western Diamondback Rattlesnake) and the snake venom metalloprotease (SVMP) inhibitor marimastat. We investigate its venom proteome-wide effects and characterize its interactions with specific SVMP proteoforms, as well as its potential targeting of non-SVMP venom toxin families. We also compare the performance of PISA thermal window and soluble supernatant with insoluble precipitate using two inhibitor concentrations, providing the first demonstration of the utility of a sensitive high-throughput PISA-based approach to assess the direct targets of small molecule inhibitors for snake venom.

biochemistry↗

bioRxiv2019

Preclinical validation of a repurposed metal chelator as a community-based therapeutic for hemotoxic snakebite

Snakebite envenoming causes 138,000 deaths annually and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: Echis) leads to systemic hemorrhage and coagulopathy, and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity, low affordability, and must be administered in clinical settings due to its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and impacts substantially on patient outcomes following envenoming. Here we investigated the value of metal chelators as novel community-based therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS), were found to potently antagonize the activity of Zn2+-dependent snake venom metalloproteinase toxins in vitro. Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also significantly extended survival in a challenge and treat model, where drug administration was delayed post-venom injection, and the oral administration of this chelator provided partial protection against envenoming. Finally, the potential clinical scenario of early oral DMPS therapy combined with a later, delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that safe and affordable repurposed metal chelators effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the great promise of DMPS as a novel, community-based, early therapeutic intervention for hemotoxic snakebite envenoming.

pharmacology and toxicology↗

bioRxiv2018

When one phenotype is not enough - divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species

Understanding the relationship between genome, phenotypic variation, and the ecological pressures that act to maintain that variation, represents a fundamental challenge in evolutionary biology. Functional polymorphisms typically segregate in spatially isolated populations [1, 2] and/or discrete ecological conditions [3-5], whereas dissecting the evolutionary processes involved in adaptive geographic variation across a continuous spatial distribution is much more challenging [6]. Additionally, pleiotropic interactions between genes and phenotype often complicate the identification of specific genotype-phenotype links [7-8], and thus of the selective pressures acting on them. Animal venoms are ideal systems to overcome these constraints: they are complex and variable, yet easily quantifiable molecular phenotypes with a clear function and a direct link to both genome and fitness [9]. Here, we use dense and widespread population-level sampling of the Mohave rattlesnake, Crotalus scutulatus, and show that genomic structural variation at multiple loci underlies extreme geographic variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, selection for diet does not explain venom variation, contrary to the dominant paradigm of venom evolution, and neither does neutral population structure caused by past vicariance. Instead, different toxin genes correlate with distinct environmental factors, suggesting that divergent selective pressures can act on individual loci independently of their genomic proximity or co-expression patterns. Local-scale spatial heterogeneity thus appears to maintain a remarkably ancient complex of molecular phenotypes, which have been retained in populations that diverged more than 1.5-2 MYA, representing an exceptional case of long-term structural polymorphism. These results emphasize how the interplay between genomic architecture and spatial heterogeneity in selective pressures may facilitate the retention of functional polymorphisms of an adaptive phenotype.

evolutionary biology↗