doi: 10.1016/j.cub.2016.07.038. Epub 2016 Sep 15.
The Deep Origin and Recent Loss of Venom Toxin Genes in Rattlesnakes
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- PMID:27641771
- PMCID: PMC5207034
- DOI: 10.1016/j.cub.2016.07.038
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The Deep Origin and Recent Loss of Venom Toxin Genes in Rattlesnakes
Noah L Dowell et al. Curr Biol..
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Abstract
The genetic origin of novel traits is a central but challenging puzzle in evolutionary biology. Among snakes, phospholipase A2 (PLA2)-related toxins have evolved in different lineages to function as potent neurotoxins, myotoxins, or hemotoxins. Here, we traced the genomic origin and evolution of PLA2 toxins by examining PLA2 gene number, organization, and expression in both neurotoxic and non-neurotoxic rattlesnakes. We found that even though most North American rattlesnakes do not produce neurotoxins, the genes of a specialized heterodimeric neurotoxin predate the origin of rattlesnakes and were present in their last common ancestor (∼22 mya). The neurotoxin genes were then deleted independently in the lineages leading to the Western Diamondback (Crotalus atrox) and Eastern Diamondback (C. adamanteus) rattlesnakes (∼6 mya), while a PLA2 myotoxin gene retained in C. atrox was deleted from the neurotoxic Mojave rattlesnake (C. scutulatus; ∼4 mya). The rapid evolution of PLA2 gene number appears to be due to transposon invasion that provided a template for non-allelic homologous recombination.
Keywords: gene duplication; gene expression; gene loss; genome sequencing; neurotoxin; novelty; phospholipase A2; rattlesnake; transposable elements; venom.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Figures
(A–C) The relative positions and orientations (denoted with arrowheads) of theC. scutulatus (A),C. atrox (B), andC. adamanteus (C) full-length PLA2 genes between the conservedOtud3 andMul1 genes are indicated. The identities of each major expressed venom gland PLA2 gene are indicated above the schematic. Below each schematic are the strand-specific coverage plots for aligned venom gland RNA-seq reads that overlap exons. Exons for each gene (color matched) are shown between the coverage plots. The predicted translation products of the expressed gene models (mapped reads) are identical (100% amino acid identity) to proteins previously detected in venom.Pla2-gB2 encodes Mojave toxin subunit B (Mtx B);Pla2-gA2 encodes Mojave toxin subunit A (Mtx A); for other gene nomenclature, see text. Note that the complement of genes differs between species and that each species expresses different major transcripts in the venom gland. See also Figures S1 and S4 and Table S1.
Trimmed species phylogeny with venom type represented as black (neurotoxic) or white (non-neurotoxic) boxes. Within this clade, the most parsimonious interpretation of the neurotoxic venom distribution is that the most recent common ancestor (MRCA) possessed neurotoxic venom and three lineages (x) have independently lost neurotoxicity. See also Figures S2–S4 and Tables S1 and S2.
(A–C) Blocks of high sequence identity that overlap the venom genes inC. scutulatus (A),C. adamanteus (B), andC. atrox (C) are shown as gray boxes linked by arcs above the PLA2 group 2 complex (drawn to scale). The duplication identifiers are to the left of each sequence pair (SD14, etc.). The duplications are ordered from top to bottom by the level of sequence divergence. Dashed arcs link duplicated regions on opposite strands. Solid arcs link duplicated regions on the same strand. (D) Model of the expansion of the PLA2 group 2 complex that gave rise to the inferred, ancestral rattlesnake complex with at least sevenPla2-g genes, based on the sequence divergence of specific duplicated regions and protein phylogeny. Genes are colored according to the naming convention of modern genes. Boxes on left are color matched to the duplicated genes. (i) The ancestral chromosome is inferred to have four distinct Pla2 group 2 family members, including a singlePla2-g gene, which is most similar to thegC gene in modern rattlesnakes. (ii) The earliest duplication gave rise togC and the basic Pla2s (SD9, SD11, SD13). (iii) Tandem duplication of basic-Pla2s (SD7). (iv) Inversion of a basic Pla2 yields the head-to-head basic:acidic (gC∷gA)Pla2 unit (SD10, 27, 40, 42). (v) A large duplication of thegC∷gA unit expanded the Pla2 complex to seven genes (SD14). See Figure S5 for evolutionary distances between duplicated sequences.
(A) All three rattlesnake species PLA2 complexes have conserved sequence blocks (boxes) that can include conserved clusters of transposable element (TE) sequences (white boxes, expanded below locus) and that share individual TE components, orientation and location. Gray boxes share high identity with gray regions of large conserved sequence blocks outside of the TE clusters. These elements may serve as permissive substrates for NAHR-mediated gene duplications and deletions.Pla2-g genes are depicted by arrows with color scheme, and abbreviations are the same as in Figure 1; the position of lineage-specific deletions is denoted by parentheses. TE abbreviations are as follows: ERV, endogenous retrovirus 1–10 Ami; hAT, DNA transposon; CR1, LINE CR1-1 element. (B) A rearrangedC. atrox PLA2 complex with a duplicatedgC1∷gA1 gene pair was discovered in one of four specimens analyzed. Orange bar indicates the novel sequence relative to the standardC.atrox chromosome. Four exons (white arrow) of anOtud3 pseudogene (ψOtud3) are betweengA1′ andgB1, while an intactOtud3 gene is still present downstream ofPla2-e.
Model depicting the evolution of the PLA2 group 2G gene complex. Significant evolutionary events are mapped onto a simplified cladogram of venomous snakes, and the PLA2 complexes of various species are shown. The complex is inferred to have expanded from a singlePla2-g gene as is present today in the elapidO. hannah (top). The number ofPla2-g genes expanded in viperids, and some gained expression in venom. Further duplication and the differentiation of distinctPla2-g types, including the components of the neurotoxic heterodimer (gA2 andgB2) and the Lys49 myotoxin (gK), occurred in the pit viper (Crotalinae) lineage (middle). The MRCA of rattlesnakes possessed at least sevenPla2-g genes, which has been reduced by unique lineage-specific losses (gray circles) in extant rattlesnakes (bottom, deleted genes denoted by faded colors in brackets). See also Figure S3 and Table S1.
Comment in
- Venom Evolution: Gene Loss Shapes Phenotypic Adaptation.Casewell NR.Casewell NR.Curr Biol. 2016 Sep 26;26(18):R849-R851. doi: 10.1016/j.cub.2016.07.082.Curr Biol. 2016.PMID:27676304
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