Species and strain differences in the lethal factor of the mouse submandibular gland

Background Evolution can occur with surprising predictability when organisms face similar ecological challenges. For most traits, it is difficult to ascertain whether this occurs due to constraints imposed by the number of possible phenotypic solutions or because of parallel responses by shared genetic and regulatory architecture. Exceptionally, oral venoms are a tractable model of trait evolution, being largely composed of proteinaceous toxins that have evolved in many tetrapods, ranging from reptiles to mammals. Given the diversity of venomous lineages, they are believed to have evolved convergently, even though biochemically similar toxins occur in all taxa. Results Here, we investigate whether ancestral genes harbouring similar biochemical activity may have primed venom evolution, focusing on the origins of kallikrein-like serine proteases that form the core of most vertebrate oral venoms. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Additionally, phylogenetic analysis of vertebrate serine proteases revealed that kallikrein-like toxins in mammals and reptiles are genetically distinct from non-toxin ones. Conclusions Given the shared regulatory and genetic machinery, these findings suggest that tetrapod venoms evolved by co-option of proteins that were likely already present in saliva. We term such genes ‘toxipotent’—in the case of salivary kallikreins they already had potent vasodilatory activity that was weaponized by venomous lineages. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.

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Section: Discussionmentioning

confidence: 99%

Co-option of the same ancestral gene family gave rise to mammalian and reptilian toxins

2021

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“…In fact, Hiramatsu et al (63) effectively blurred the lines between venomous and nonvenomous mammals by proposing that male mice secrete "toxic proteins (kallikrein-like enzymes) into saliva, as an effective weapon." Lethality of saliva differs between mouse strains, suggesting that heritable variability in this trait exists within species, a necessary prerequisite for adaptation (65). Thus, under ecological conditions where venom lethality promotes reproductive success, natural selection should favor the evolution of an envenomation system from this starting point.…”

Section: The Upr and Erad System Promoted The Evolution Of An Oral Venommentioning

confidence: 99%

An ancient, conserved gene regulatory network led to the rise of oral venom systems

Barua

Mikheyev

2021

Proc. Natl. Acad. Sci. U.S.A.

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Oral venom systems evolved multiple times in numerous vertebrates enabling the exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focused strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterized the “metavenom network,” a network of ∼3,000 nonsecreted housekeeping genes that are strongly coexpressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was coopted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation, Heloderma lizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated cooption of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.

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“…KLK1 genes in mammals and their reptilian homologs share kininogenase activity, which results in the release of bradykinin, a potent hypotensive agent, when injected into the bloodstream (Komori and Nikai 1998;Kita et al 2004) . This is true even of salivary kallikreins of non-venomous mammals, such as mice, which can induce hypotension and even death (Huang et al 1977;Hiramatsu, Hatakeyama, and Minami 1980;Dean and Hiramoto 1985) . Hypotension is also one of two major strategies which venomous snakes use to immobilize their prey (Aird 2002) , and the biochemical link between bradykinin-producing enzymes in mammals and snakes was evident to researchers who first characterized kallikrein-like properties of a snake venom enzymes, calling them "the salivary kallikrein of the snake" (Iwanaga et al 1965) .…”

Section: Discussionmentioning

confidence: 99%

The parallel origins of vertebrate venoms

Barua

Koludarov

2021

Preprint

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Evolution can occur with surprising predictability when faced with similar ecological challenges. How and why this repeatability occurs remains a central question in evolutionary biology, but the complexity of most traits makes it challenging to answer. Reptiles and mammals independently evolved oral venoms that consist of proteinaceous cocktails which allow straightforward mapping between genotype and phenotype. Although biochemically similar toxins can occur as major venom components across many taxa, whether these toxins evolved via convergent or parallel means remains unknown. Most notable among them are kallikrein-like serine proteins, which form the core of most vertebrate venoms, and are employed by all venomous snake families. Here we used a combination of comparative genomics and phylogenetics to investigate whether serine protease recruitment into the venom occurred independently or in parallel across the different tetrapod lineages. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Independently, phylogenetic analysis of vertebrate serine proteases revealed that the same gene cluster gave rise to toxins in mammals and reptiles. Given the shared regulatory and genetic machinery underlying venom evolution, these findings suggest a unified model underlying vertebrate venom evolution by exaptation of homologous ancestral kallikreins. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.

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Species and strain differences in the lethal factor of the mouse submandibular gland

Cited by 6 publications

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Co-option of the same ancestral gene family gave rise to mammalian and reptilian toxins

Co-option of the same ancestral gene family gave rise to mammalian and reptilian toxins

An ancient, conserved gene regulatory network led to the rise of oral venom systems

The parallel origins of vertebrate venoms

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