The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

Abstract

ossil remains from ~100 million years ago (Ma) show that snakes were widely distributed across the world by the late Cretaceous period 1. During the course of their evolution, snakes lost their limbs, acquiring a serpentine body 2. Some also evolved or co-opted venom systems to help subdue, capture and digest their prey 2,3. The Colubroides clade of advanced snakes encompasses >3,000 extant species including >600 venomous species 4. The most venomous snakes include the true vipers and pit vipers, both members of the Viperidae family, and cobras, kraits, mambas and sea snakes from the Elapidae family 5. Although humans are not an intended target, accidental contact with venomous snakes can be deadly. Snakebite envenoming is a serious neglected tropical disease that affects ~5 million people worldwide annually, leading to ~400,000 amputations and >100,000 deaths 6. In India alone, the high rural population density combined with the presence of the 'big four' deadly snakes, namely the Indian cobra (Naja naja), Russell's viper (Daboia russelli), sawscaled viper (Echis carinatus) and common krait (Bungarus caeruleus), results in >46,000 snakebite-related deaths annually 7. Snake venom is a potent lethal cocktail rich in proteins and peptides, secreted by specialized venom gland cells. Venom components can be broadly classified as neurotoxic, cytotoxic, cardiotoxic or hemotoxic, and the composition can vary both between and within species 8-11. Currently, snake antivenom is the only treatment effective in the prevention or reversal of the effects of envenomation. Since 1896, antivenom has been developed by immunization of large mammals, such as the horse, with snake venom to generate a cocktail of antibodies that are used for therapy 12. Given the heterologous nature of these antibodies, they often elicit adverse immunological responses when treating snakebite victims 13. Moreover, the antivenom composition is not well defined and its ability to neutralize the venom

Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

“…A total of 295 Human ACE2 orthologs were obtained from NCBI ( Supplementary Table 3 for accession numbers). A snake ACE2 ortholog protein was obtained from the 15 published Indian cobra genome (Suryamohan et al, 2020). Multiple sequence alignment of residues surrounding the ACE2 NxT/S motif was performed using MCoffee (www.tcoffee.org).…”

Cysteine-Rich Secretory Proteins (CRISPs) from Venomous Snakes: An Overview of the Functional Diversity in a Large and Underappreciated Superfamily

“…Although 1-6 gene copies are observed for CRISPs in snake genomes [89,90], CRISP gene positions in snake genomes appear to be conserved. For genomes of both Naja naja and Crotalus viridis, svCRISP genes are located on chromosome 1 [90,91], potentially close to the centromere.…”

“…Although 1-6 gene copies are observed for CRISPs in snake genomes [89,90], CRISP gene positions in snake genomes appear to be conserved. For genomes of both Naja naja and Crotalus viridis, svCRISP genes are located on chromosome 1 [90,91], potentially close to the centromere. This genome location may promote sequence conservation and may explain why expression of some toxins varies for different snake families, such as is observed for phospholipase A 2 s and three-finger toxins, but svCRISPs are present at consistent levels in venoms of most venomous snakes.…”

“…Expression levels of toxin and non-toxin homologs of svCRISPs have been evaluated for one opisthoglyph and for proteroglyphs and solenoglyphs [89][90][91][92]. At least two CRISP genes are expressed in snake venom glands, but differences in expression levels of each are apparent.…”

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

“…Public RNA datasets from 4 tissues (heart, kidney, liver, and salivary glands) were used for comparative transcriptomic analysis (see methods). We obtained expression data for cobra tissues, including that of venom gland from (29).…”