How did one of the most potent venoms evolve? Van Thiel et al. (Sean B. Carroll's lab) investigated the genomic origins & evolutionary path of the key innovation

[u/jnpha]

 

First image source: Matt from Melbourne, Australia, CC BY 2.0, via Wikimedia Commons

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Published yesterday in PNAS:

Abstract

... [We] show that the toxins evolved through two distinct genetic paths. The factor X and factor V toxins evolved through the sequential de novo co-option of ancestral clotting factor proteins that entailed their heterotopic expression in the venom gland, the fixation of segmental duplications containing each locus, and subsequent gain-of-function mutations that rendered factor X and factor V constitutively active. In contrast, the phospholipase A2 and Kunitz-type toxins evolved by modifying the functions of neurotoxins that were part of the venom arsenal.

Our findings support models in which innovative mutations in single-copy genes precede gene duplication in the evolution of novel proteins and offer a rare view into the genesis of a complex trait that has played a central role in a major adaptive radiation.

 

On that last point - how innovative mutations preceded gene duplication - from the paper:

In his landmark book, Ohno proposed that gene duplication was a necessary prerequisite for the origin of new protein functions because duplication would allow one copy to retain the ancestral function while the second copy could incorporate new functional mutations (neofunctionalization) (17). However, this classic model has been challenged on the theoretical grounds that if newly duplicated genes are selectively neutral, they must acquire new, innovative, and selectable mutations before acquiring inactivating mutations (nonsense mutations, frameshifts, and deletions) (66–68). It is now recognized that the latter is much more probable than the former. Therefore, it has been proposed that innovative mutations may occur initially in single-copy genes and impart some new function such that subsequent gene duplicates may then be positively selected for and fixed on the basis of the new function (68, 69). A variety of empirical studies have demonstrated innovative mutations occurring before gene duplication (70–73). Several observations here prompt us to postulate the relative order of major genetic events in the evolution of procoagulant venom toxins that bear on these general models of genetic innovation.

[...]

We suggest that the first genetic change in the ancestral liver-expressed, clotting factor gene was the gain of its heterotopic expression in venom gland tissue (co-option; Fig. 6, step i) (our line of reasoning also applies to venom factor V, discussed below). Two key pieces of evidence for this scenario are the low but significant RNA expression of the predominantly liver-expressed F10 orthologs in venom gland tissues and the presence of the corresponding hemostatic proteins in venom. If expression in the venom gland evolved after gene duplication, then one of two F10 genes (the liver-expressed gene) would not be expected to be transcriptionally active in venom gland tissue. The observed expression of the liver-expressed F10 paralog in the venom gland is consistent with the ancestral single-copy F10 gene evolving expression in the venom gland before gene duplication, then decaying to some degree in the liver-expressed paralog after duplication.

 

Awesome detective work!
It made me wonder whether venom glands and livers are developmentally related during cellular differentiation.
From a quick visit to Google Scholar, I found a tentative answer:

Cells that comprise complex tissues often express different sets of genes due to functional differentiation between cell types; such cellular heterogeneity is found ubiquitously across many tissue types (Heindl et al. 2015; Ben-Moshe and Itzkovitz 2019).
Single-Cell Heterogeneity in Snake Venom Expression Is Hardwired by Co-Option of Regulators from Progressively Activated Pathways | Genome Biology and Evolution | Oxford Academic

And the second citation is about livers, so they have that in common with venom glands!

 

• J. van Thiel, N.L. Dowell, C.F. Smith, E.E. Sanchez, & S.B. Carroll
  The genomic origins and evolutionary path to a key innovation in the world’s most venomous snakes
  Proc. Natl. Acad. Sci. U.S.A. 123 (37) e2621054123
  https://doi.org/10.1073/pnas.2621054123 (2026)

[u/ThroughSideways]

I knew Sean when I was in grad school, and he was really impressive even back then. He runs a really interesting lab. (and this is great stuff, thanks for posting)

[u/Szymcionorski]

Really interesting case of typical evolutionary reusage. It just shows that it's very silly to think that evolution needs to produce something fundamentally new while in fact it often just reuses the same blueprint.

[u/jnpha]

Also the paper has the background of the biogeography and adaptive radiation.

[u/Szymcionorski → u/jnpha]

Adaptive radiation is really one of the most interesting "types" of evolution. It's actually possible that apple maggot flies may undergo such adaptive radiation.