Genomic insights into the evolution and ecology of botulinum neurotoxins

Pathog Dis. 2018 Jun 1;76(4). doi: 10.1093/femspd/fty040.


Clostridial neurotoxins, which include botulinum neurotoxins (BoNTs) and tetanus neurotoxins, have evolved a remarkably sophisticated structure and molecular mechanism fine-tuned for the targeting and cleavage of vertebrate neuron substrates leading to muscular paralysis. How and why did this toxin evolve? From which ancestral proteins are BoNTs derived? And what is, or was, the primary ecological role of BoNTs in the environment? In this article, we examine these questions in light of recent studies identifying homologs of BoNTs in the genomes of non-clostridial bacteria, including Weissella, Enterococcus and Chryseobacterium. Genomic and phylogenetic analysis of these more distantly related toxins suggests that they are derived from ancient toxin lineages that predate the evolution of BoNTs and are not limited to the Clostridium genus. We propose that BoNTs have therefore evolved from a precursor family of BoNT-like toxins, and ultimately from non-neurospecific toxins that cleaved different substrates (possibly non-neuronal SNAREs). Comparison of BoNTs with these related toxins reveals several unique molecular features that underlie the evolution of BoNT's unique function, including functional shifts involving all four domains, and gain of the BoNT gene cluster associated proteins. BoNTs then diversified to produce the existing serotypes, including TeNT, and underwent repeated substrate shifts from ancestral VAMP2 specificity to SNAP25 specificity at least three times in their history. Finally, similar to previous proposals, we suggest that one ecological role of BoNTs could be to create a paralytic phase in vertebrate decomposition, which provides a competitive advantage for necrophagous scavengers that in turn facilitate the spread of Clostridium botulinum and its toxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chryseobacterium / classification
  • Chryseobacterium / genetics
  • Chryseobacterium / pathogenicity
  • Clostridium botulinum / classification
  • Clostridium botulinum / genetics*
  • Clostridium botulinum / pathogenicity
  • Clostridium tetani / classification
  • Clostridium tetani / genetics*
  • Clostridium tetani / pathogenicity
  • Enterococcus / classification
  • Enterococcus / genetics
  • Enterococcus / pathogenicity
  • Evolution, Molecular
  • Gene Expression Regulation, Bacterial*
  • Genetic Loci
  • Genome, Bacterial*
  • Host-Pathogen Interactions
  • Humans
  • Metalloendopeptidases / biosynthesis
  • Metalloendopeptidases / genetics*
  • Multigene Family
  • Phylogeny
  • Tetanus Toxin / biosynthesis
  • Tetanus Toxin / genetics*
  • Weissella / classification
  • Weissella / genetics
  • Weissella / pathogenicity


  • Tetanus Toxin
  • tetanospasmin
  • Metalloendopeptidases