Nachtigall Pedro G, Hamilton Brett R, Kazandjian Taline D, Stincone Paolo, Petras Daniel, Casewell Nicholas R, Undheim Eivind A B
Centre for Ecological and Evolutionary Synthesis, Department of Biosciences, University of Oslo, PO Box 1066 Blindern, Oslo, 0316, Norway.
Centre for Microscopy and Microanalysis, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
Genome Biol. 2025 May 19;26(1):130. doi: 10.1186/s13059-025-03602-w.
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.
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.
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.
毒液及其相关腺体和输送结构在动物界已经多次进化。在这些毒液系统中，分子、细胞和形态学成分相互作用并共同进化，以产生独特的毒液表型，这些表型越来越被视为研究适应性进化的模型。然而，毒素在产毒组织中的分布往往不均匀，其模式不一定具有适应性，而可能是由与蛋白质分泌相关的限制因素导致的。
我们生成了开普珊瑚蛇（Aspidelaps lubricus）的高质量基因组草图，并将毒液腺单细胞RNA测序数据的分析与毒液腺毒素原位空间分布相结合。我们的结果表明，虽然不同的毒素家族由不同的细胞群体产生，但毒素表达通过调控模块进行微调，从而在每个细胞群体中进一步实现毒素产生的专业化。我们还发现，调控元件的进化与其相关毒素基因的进化密切相关，导致毒液腺中密切相关且功能相似的毒素在空间上相互关联。虽然这种分区并非适应性的，但潜在调控网络的模块化可能促进了喷毒眼镜蛇防御性毒液的多次进化。
我们的结果为蛇类毒素调控的变异性提供了新的见解，揭示了蛇毒腺中异质毒素产生的分子机制，并提供了一个例子，说明限制因素如何导致看似适应性的非适应性特征状态，而这可能仍然促进进化创新和新奇性。
