How the Toxin got its Toxicity

Abstract

Venom systems are functional and ecological traits, typically used by one organism to subdue or deter another. A predominant subset of their constituent molecules-"toxins"-share this ecological function and are therefore molecules that mediate interactions between organisms. Such molecules have been referred to as "exochemicals." There has been debate within the field of toxinology concerning the evolutionary pathways leading to the "recruitment" of a gene product for a toxic role within venom. We review these discussions and the evidence interpreted in support of alternate pathways, along with many of the most popular models describing the origin of novel molecular functions in general. We note that such functions may arise with or without gene duplication occurring and are often the consequence of a gene product encountering a novel "environment," i.e., a range of novel partners for molecular interaction. After stressing the distinction between "activity" and "function," we describe in detail the results of a recent study which reconstructed the evolutionary history of a multigene family that has been recruited as a toxin and argue that these results indicate that a pluralistic approach to understanding the origin of novel functions is advantageous. This leads us to recommend that an expansive approach be taken to the definition of "neofunctionalization"-simply the origins of a novel molecular function by any process-and "recruitment"-the "weaponization" of a molecule via the acquisition of a toxic function in venom, by any process. Recruitment does not occur at the molecular level or even at the level of gene expression, but only when a confluence of factors results in the ecological deployment of a physiologically active molecule as a toxin. Subsequent to recruitment, the evolutionary regime of a gene family may shift into a more dynamic form of "birth-and-death." Thus, recruitment leads to a form of "downwards causation," in which a change at the ecological level at which whole organisms interact leads to a change in patterns of evolution at the genomic level.

Keywords: duplication; evolution; function; gene expression; genomics; molecule; toxin; venom.

FIGURE 1

Models of gene evolution. Schematic representation of the most prominent models of gene evolution, with genes and their functions being represented as human tools. Note that moonlighting occurs in the absence of any duplication, with the product of a single gene fulfilling multiple functional roles—pleiotropy of this kind is likely extremely widespread (Paaby and Rockman, 2013), and though genes are depicted as having single functions at the base of the moonlighting and neofunctionalization models in this figure, this should be understood as purely illustrative.

FIGURE 2

Schematic representation of “concerted evolution” and “innovation-amplification-diversification” using human tools. Note that gene conversion/unequal crossover in concerted evolution result in each gene within a homogenized tandem array having multiple ancestors in the previous generation.

FIGURE 3

Schematic representation of “birth-and-death” molecular evolution. Genes are continuously duplicated; some go on to develop novel functions whereas others are pseudogenized (“death”).

FIGURE 4

Schematic representation of tissue kallikrein gene cluster in selected species of mammals after (Casewell et al., 2019). Solenodon venom genes are colored green, “physiological” genes are colored violet. Note that all expansion occurs within the same region of the cluster, and that much “exonic debris” remains after the partial deletion of genes, a characteristic sign of “birth-and-death”

FIGURE 5

Schematic representation of Pla2g2 gene cluster in vertebrate lineages after (Koludarov et al., 2019). Note that all expansion within the cluster takes place at the same location, and all novel clades (g2B in birds; g2G in squamates; and g2A and g2V in mammals) are descended from the same subclade (g2D).

FIGURE 6

Lineage-specific expansion and diversification of the Pla2g2 subfamily in viperid snakes after (Koludarov et al., 2019). Note the presence of multiple fragments of “exonic debris” (mainly from g2E and g2D) that make possible the reconstruction of the evolutionary history, including all duplication events, of this genomic region in viperid snakes. Arrows indicate birth and death events. A number of the duplication events (bold arrows) do not involve single genes (unlike g2A of mammals) but rather small groups which are duplicated as units (“cassettes”), typically composed of a g2G gene flanked by parts of g2E and g2D.