Uncover the “secret” of evolution in the snake’s “venom” gene

Silver Ring Snake Photographed by Wang Yufan

Recently, based on a variety of high-throughput sequencing techniques, the research team of Li Jiatang, Chengdu Institute of Biology, Chinese Academy of Sciences, assembled the silver ring snake reference genome at the chromosome level, and combined with the multi-tissue transcriptome, conducted an in-depth exploration of the composition of the silver ring snake toxin gene family, and further analyzed the evolution of one of the important toxin components in the venom of the cobra family, the three-fingered venom family. The relevant research results were published in the Cell Report under the title of “New Discoveries of the Three-Fingered Poison Subfamily and Its Differentiation of Structure and Function”.

Why is the silver ring snake toxin gene family targeted? It is understood that the silver ring snake is a highly venomous snake of the cobra family ring snake, its venom has a strong neurotoxicity, can destroy the transmission of neurotransmitters between neuromusculars, after being bitten by the silver ring snake, the patient’s wound is usually not red, swollen and painful, and only slightly itchy or slight numbness, generally after 1 to 6 hours of systemic symptoms, including chest tightness, fatigue, blurred vision, eyelid drooping, difficulty breathing and even stop. Different studies have documented different fatalities from silver ring snake bites, with mortality rates as high as 100% in the absence of timely treatment. Antivenom is the main drug for the treatment of silver ring snake bite poisoning, but traditional antivenoms are prone to batch differences and may lead to severe allergies. The design and development of a safer and more reliable next-generation antivenom drug relies on comprehensive family sequence information on the silver ring snake toxin gene.

The reporter learned that the study found a total of 118 silver ring snake toxin gene copies, belonging to 17 toxin families, including three-finger toxin (3FTX), type I phospholipase A2 toxin family (PLA2 I) and snake venom Kunitz-type serine protease inhibitor family (snake venom Kunitz-type serine protease The number of copies of the gene in inhibitor (KUN) is 30, 9 and 31, respectively, and the transcriptional expression of these copies can account for more than 90% of the expression of all toxin genes.

Distribution and copy number of silver ring snake toxin genes on chromosomes Provided by the research team

Tridcryphalus is one of the most important and functionally differentiated toxin families in the venom of the cobra family, and its origin and evolutionary history have not yet been fully clarified due to its short sequence and large differentiation. By reconstructing the phylogeny of 3FTX and its underlying ancestral proteins, combined with collinear information from 3FTX gene clusters of different snake species, it was found that the 3FTX family was most likely produced by neofunctionalization of its LY6E ancestors on its side, and that two subfamilies (defined as MKA-3FTX and MKT-3FTX subfamilies, respectively) had differentiated before the emergence of cobra species. MKT-3FTX undergoes a large number of replication differentiation within the cobra family and becomes the main toxin effector in the venom of snakes of this family.

In contrast, the MKA-3FTX subfamily has more copies in the non-venomous banded snake (Thamnophis elegans), while there are only 4 gene copies in the genomes of the silver ring snake and the Indian cobra.

3FTX phylogeny and collinear relationship. (A) 3FTX phylogenetic maximum likelihood tree. (B) 3FTX gene family clusters of 8 snake species and their collateral conserved anchor genes. Courtesy of the research team

According to the phylogenetic relationship, the silver ring snake MKT-3FTX can be further divided into 11 subtypes. Such a high degree of differentiation may be related to the phylogenetic diversity of silver-ringed snake prey (including loach, frogs, stone dragons, other snakes, and mice) as a result of adaptation to changes in 3FTX receptors in different prey. In addition, one of the MKT-3FTX subtypes, type II alpha nerve venom (i.e., alpha ring snake venom), has a large number of gene copies, high expression and very similar sequences, suggesting the role of the dose effect behind its expansion. Unlike the MKT-3FTX gene, which is heavily expressed in the venom glands, only 1 of the 4 silver ring snake MKA-3FTX copies are actively expressed in the venom glands, and the remaining 3 gene copies are relatively more expressed in the kidneys.

In addition, compared with other MKA-3FTX paralogous homologies, MKA-3FTX expressed in the toxic glands has an additional beta sheet layer on the secondary structure, which further indicates the functional differentiation of the subfamily.

3FTX sequence alignment and protein structure prediction. (A) 3FTX protein sequence comparison and protein structure comparison. (B) Comparison of MKA-3FTX protein structure. Courtesy of the research team

Expression profiles of the 3FTX subfamily in different silver-ringed snake tissues. Courtesy of the research team

Combining high-quality genomes and multi-tissue transcriptomes, the study obtained comprehensive silver ring snake toxin gene sequence information and further elucidated the evolution of the 3FTX family based on this. This study provides a valuable data resource for the study of snake venom evolution and structural function, and has important application value for the development of safe and reliable antivenoms and drug candidates.

It is reported that this research has been funded by the Strategic Pilot Science and Technology Special Project of the Chinese Academy of Sciences, the Frontier Science Key Research Program of the Chinese Academy of Sciences, and the National Natural Science Foundation of China. (Source: China Science Daily Yang Chen)

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