The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake

Nachtigall, Pedro G., Hamilton, Brett R., Kazandjian, Taline ORCID: https://orcid.org/0000-0002-5383-0505, Stincone, Paolo, Petras, Daniel, Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 and Undheim, Eivind A. B. (2025) 'The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake'. Genome Biology, Vol 26, Issue 1, p. 130.

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Abstract

Background
Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in patterns that are not necessarily adaptive but instead likely result from constraints associated with protein secretion.

Results
We generate a high-quality draft genome of the Cape coral snake (Aspidelaps lubricus) and combine analyses of venom gland single-cell RNA-seq data with spatial venom gland in situ toxin distributions. Our results reveal that while different toxin families are produced by distinct populations of cells, toxin expression is fine-tuned by regulatory modules that result in further specialization of toxin production within each cell population. We also find that the evolution of regulatory elements closely mirrors the evolution of their associated toxin genes, resulting in spatial association of closely related and functionally similar toxins in the venom gland. While this compartmentalization is non-adaptive, the modularity of the underlying regulatory network likely facilitated the repeated evolution of defensive venom in spitting cobras.

Conclusions
Our results provide new insight into the variability of toxin regulation across snakes, reveal the molecular mechanisms underlying the heterogeneous toxin production in snake venom glands, and provide an example of how constraints can result in non-adaptive character states that appear to be adaptive, which may nevertheless facilitate evolutionary innovation and novelty.

Item Type:	Article
Subjects:	QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 630 Toxins. Antitoxins WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1186/s13059-025-03602-w
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	02 Jun 2025 14:51
Last Modified:	02 Jun 2025 14:51
URI:	https://archive.lstmed.ac.uk/id/eprint/26702

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