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Edited by David B. Wake, University of California, Berkeley, CA, and approved October 22, 2013 (received for review August 2, 2013)
Significance
Snake venoms are toxic protein cocktails used for prey capture. To investigate the evolution of these complex biological weapon systems, we sequenced the genome of a venomous snake, the king cobra, and assessed the composition of venom gland expressed genes, small RNAs, and secreted venom proteins. We show that regulatory components of the venom secretory system may have evolved from a pancreatic origin and that venom toxin genes were co-opted by distinct genomic mechanisms. After co-option, toxin genes important for prey capture have massively expanded by gene duplication and evolved under positive selection, resulting in protein neofunctionalization. This diverse and dramatic venom-related genomic response seemingly occurs in response to a coevolutionary arms race between venomous snakes and their prey.
Abstract
Snakes are limbless predators, and many species use venom to help overpower relatively large, agile prey. Snake venoms are complex protein mixtures encoded by several multilocus gene families that function synergistically to cause incapacitation. To examine venom evolution, we sequenced and interrogated the genome of a venomous snake, the king cobra (Ophiophagus hannah), and compared it, together with our unique transcriptome, microRNA, and proteome datasets from this species, with data from other vertebrates. In contrast to the platypus, the only other venomous vertebrate with a sequenced genome, we find that snake toxin genes evolve through several distinct co-option mechanisms and exhibit surprisingly variable levels of gene duplication and directional selection that correlate with their functional importance in prey capture. The enigmatic accessory venom gland shows a very different pattern of toxin gene expression from the main venom gland and seems to have recruited toxin-like lectin genes repeatedly for new nontoxic functions. In addition, tissue-specific microRNA analyses suggested the co-option of core genetic regulatory components of the venom secretory system from a pancreatic origin. Although the king cobra is limbless, we recovered coding sequences for all Hox genes involved in amniote limb development, with the exception of Hoxd12. Our results provide a unique view of the origin and evolution of snake venom and reveal multiple genome-level adaptive responses to natural selection in this complex biological weapon system. More generally, they provide insight into mechanisms of protein evolution under strong selection.
Footnotes
↵1F.J.V. and N.R.C. contributed equally to this work.
- ↵2To whom correspondence should be addressed. E-mail: M.K.Richardson{at}biology.leidenuniv.nl.
Author contributions: F.J.V., N.R.C., and M.K.R. designed research; F.J.V. acquired samples for sequencing and estimated genome size; H.J.J., and R.P.D. prepared sequencing libraries; M.B., and W.P. developed assembly software; C.V.H. assembled the genome; H.J.J., M.Y., D.C., and H.P.S. annotated the genome; J.M.C.R. assembled and annotated RNA-seq libraries; F.J.V., N.R.C., H.M.E.K., and A.S.H. analyzed RNA-seq libraries; A.M.H., D.S., and E.M. annotated and analyzed small RNA libraries; H.M.E.K., I.G., H.P.S., and D.D. annotated and analyzed Hox genes; F.J.V., N.R.C., C.V.H., R.J.R.M., H.M.E.K., A.S.H., R.P.D., R.M.K., and M.K.R. annotated venom toxin genes and performed synteny analyses; N.R.C., R.A.V., and W.W. analyzed gene family evolution; A.M.H. performed miRNA in situ hybridization; A.E.W., and J.M.L. performed lectin in situ hybridization; N.R.C., R.J.R.M., J.J.C., R.A.H., C.R., R.B.C., D.P., L.S., and R.M.K. analyzed the venom proteome; T.A.C., A.P.J.d.K., and D.D.P. contributed Burmese python genome data and assisted with comparative analyses; H.J.J., J.W.A., G.E.E.J.M.v.d.T., R.P.D., H.P.S., and M.K.R. organized sequencing platforms and facilities; F.J.V., N.R.C., W.W., and M.K.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The king cobra genome assembly and reads reported in this paper have been deposited in the GenBank database (bioproject no. PRJNA201683). The transcriptome sequences reported in this paper have been deposited in the GenBank Short Read Archive database (bioproject no. PRJNA222479). The microRNA sequences reported in this paper have been deposited in miRBase, www.mirbase.org.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1314702110/-/DCSupplemental.
Freely available online through the PNAS open access option.
King cobra genome and snake venom evolution
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