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Indian Cobra Genome, Transcriptome Unearths Core Toxin Genes for Antivenom Development

NEW YORK – Members of an international team led by investigators at the SciGenom Research Foundation, MedGenome, AgriGenome Labs, Roche's Genentech, and elsewhere have established a high-quality genome assembly and transcriptome for the Indian cobra, Naja naja, using the sequence to find genes that might be amenable to targeting in the future.

The researchers used long-read sequencing, short-read sequencing, optical mapping, Hi-C mapping, single chromosome sequencing, and other approaches to assemble the 1.8 billion base genome for the Indian cobra, which produces a potent venom contributing to considerable numbers of death, disability, and amputation. By bringing in RNA sequence data from the venom gland and more than a dozen other organs, they narrowed in on 19 genes with preferential expression in the snake's venom glands, apparently contributing to the production of deadly toxins in its venom.

The findings, published online today in Nature Genetics, may eventually help to develop safe, effective antivenom against Indian cobra bites by targeting the newly detected toxins produced by these gene with synthetic human antibodies, the study's senior author Somasekar Seshagiri said in a statement.

Seshagiri is currently president of India's SciGenom Research Foundation and previously worked as a staff scientist with Genentech's molecular biology department.

For their study, Seshagiri and his colleagues used Pacific Biosciences, Oxford Nanopore, and Illumina sequencing — in combination with Chicago, Hi-C, optical mapping, 10x Genomics, and other data — to sequentially assemble an Indian cobra reference genome.

With the help of gene expression data spanning more than a dozen tissues, they subsequently annotated more than 23,200 predicted protein-coding genes, identifying informative mutations, gene family expansions, and phylogenetic insights. They also compared sequences from six Indian cobras from India or from a zoo in Kentucky to get a glimpse at the animal's genetic diversity and did proteome predictions focused on future drug development.

Along with such clues to Indian cobra biology and evolution, the researchers reasoned that the new sequence data could lead to new antivenom avenues based on synthetic, recombinant venom built from core proteins. At the moment, they explained, antivenom development hinges on antibodies raised in horses that have been injected with snake venom — an expensive and tricky approach that is not always feasible in places where venomous snake bites prevail.

When the team brought in RNA sequences from the venom gland and other organs, for example, it uncovered 12,346 gene with pronounced expression in the venom gland. The latter set included more than 100 genes from known toxin families and 19 genes classified as "venom-ome-specific toxins," or VSTs, the authors reported.

"[R]ecombinant venom proteins can be used as baits against antibody phage libraries to obtain toxin-neutralizing, activity-tested, humanized synthetic antibodies," the authors explained, adding that "[p]rimary cultures of venom gland cells or the recently developed venom gland organoid cultures … in combination with genome information, can provide an alternative, viable source of venom antigens for antivenom development."

The Indian cobra is considered one of the "big four" venomous snakes, the authors noted, which together account for millions of snakebites and tens of thousands of deaths in India and beyond. Other members of the big four include the Russell's viper, saw-scaled viper, and common krait.

"Obtaining the genomes and the venom gland genes from the other three of the 'big four' and the deadly African snakes such as the black mamba, carpet viper and spitting cobras is the logical next step," co-author Manjunatha Kini, a biological sciences researcher at the National University of Singapore, said in a statement. "It will provide a complete platform for developing a safe, universal antivenom for snakebite victims all over India, Africa and other neighbouring countries."

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