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Our current understanding of snake venom is highly biased towards species known to be medically significant in human envenomations. This vastly under-represents the true evolutionary and ecological breadth of snake venom, with gaps spanning entire clades and unique lifestyles. As a result, many genera of rear-fanged snakes lack well-understood venom profiles despite these taxa composing around 65% of known extant snake species. Methodological challenges associated with venom extraction have long been a key reason responsible for the lack of venom research on this group. Modern advancements in venomics technologies have allowed researchers to overcome many of these challenges and investigate the venom components of understudied genera. The genus Coniophanes (black-striped snakes) presents an ideal system for investigating venom and the venom delivery system in a rear-fanged venomous species with well-documented accounts of human envenomations. We sequenced and annotated de novo transcriptomes of the Duvernoy’s gland (DVG) for seven individuals across four species of Coniophanes (Dipsadidae) and confirmed toxin expression in representative venom proteomes. We assessed interspecific venom variation within this genus and further examined intraspecific venom variation within C. imperialis. We found that toxins account for 38.8% to 66% of the total DVG transcriptomes and that 18 toxin families are represented in this genus, with prominent expression of cystine-rich secretory proteins (CRiSPs) in three species and snake venom metalloproteinases (SVMPs) in all four species. In addition, we used diffusible iodine-based contrast-enhanced computed tomography (diceCT) to better understand the venom delivery system for C. fissidens, a widespread species within this genus, showcasing enlarged, grooved, rear fangs in close proximity to a prominent DVG. We provide the first ever characterization of the venom profiles of Coniophanes, highlight venom variation between and within species, and outline the venom delivery system of this understudied genus. 

Coevolution is common and frequently governs host–pathogen interaction outcomes. Phenotypes underlying these interactions often manifest as the combined products of the genomes of interacting species, yet traditional quantitative trait mapping approaches ignore these intergenomic interactions. Devil facial tumor disease (DFTD), an infectious cancer afflicting Tasmanian devils (Sarcophilus harrisii), has decimated devil populations due to universal host susceptibility and a fatality rate approaching 100%. Here, we used a recently developed joint genome-wide association study (i.e., co-GWAS) approach, 15 y of mark-recapture data, and 960 genomes to identify intergenomic signatures of coevolution between devils and DFTD. Using a traditional GWA approach, we found that both devil and DFTD genomes explained a substantial proportion of variance in how quickly susceptible devils became infected, although genomic architectures differed across devils and DFTD; the devil genome had fewer loci of large effect whereas the DFTD genome had a more polygenic architecture. Using a co-GWA approach, devil–DFTD intergenomic interactions explained ~3× more variation in how quickly susceptible devils became infected than either genome alone, and the top genotype-by-genotype interactions were significantly enriched for cancer genes and signatures of selection. A devil regulatory mutation was associated with differential expression of a candidate cancer gene and showed putative allele matching effects with two DFTD coding sequence variants. Our results highlight the need to account for intergenomic interactions when investigating host–pathogen (co)evolution and emphasize the importance of such interactions when considering devil management strategies. 

Developmental phenotypic changes can evolve under selection imposed by age- and size-related ecological differences. Many of these changes occur through programmed alterations to gene expression patterns, but the molecular mechanisms and gene-regulatory networks underlying these adaptive changes remain poorly understood. Many venomous snakes, including the eastern diamondback rattlesnake (Crotalus adamanteus), undergo correlated changes in diet and venom expression as snakes grow larger with age, providing models for identifying mechanisms of timed expression changes that underlie adaptive life history traits. By combining a highly contiguous, chromosome-level genome assembly with measures of expression, chromatin accessibility, and histone modifications, we identified cis-regulatory elements and trans-regulatory factors controlling venom ontogeny in the venom glands ofC. adamanteus. Ontogenetic expression changes were significantly correlated with epigenomic changes within genes, immediately adjacent to genes (e.g., promoters), and more distant from genes (e.g., enhancers). We identified 37 candidate transcription factors (TFs), with the vast majority being up-regulated in adults. The ontogenetic change is largely driven by an increase in the expression of TFs associated with growth signaling, transcriptional activation, and circadian rhythm/biological timing systems in adults with corresponding epigenomic changes near the differentially expressed venom genes. However, both expression activation and repression contributed to the composition of both adult and juvenile venoms, demonstrating the complexity and potential evolvability of gene regulation for this trait. Overall, given that age-based trait variation is common across the tree of life, we provide a framework for understanding gene-regulatory-network-driven life-history evolution more broadly. 

Abstract Beyond providing critical information to biologists, species distributions are useful for naturalists, curious citizens, and applied disciplines including conservation planning and medical intervention. Venomous snakes are one group that highlight the importance of having accurate information given their cosmopolitan distribution and medical significance. Envenomation by snakebite is considered a neglected tropical disease by the World Health Organization and venomous snake distributions are used to assess vulnerability to snakebite based on species occurrence and antivenom/healthcare accessibility. However, recent studies highlighted the need for updated fine-scale distributions of venomous snakes. Pitvipers (Viperidae: Crotalinae) are responsible for >98% of snakebites in the New World. Therefore, to begin to address the need for updated fine-scale distributions, we created VenomMaps, a database and web application containing updated distribution maps and species distribution models for all species of New World pitvipers. With these distributions, biologists can better understand the biogeography and conservation status of this group, researchers can better assess vulnerability to snakebite, and medical professionals can easily discern species found in their area. 

Abstract Understanding the joint roles of protein sequence variation and differential expression during adaptive evolution is a fundamental, yet largely unrealized goal of evolutionary biology. Here, we use phylogenetic path analysis to analyze a comprehensive venom-gland transcriptome dataset spanning three genera of pitvipers to identify the functional genetic basis of a key adaptation (venom complexity) linked to diet breadth (DB). The analysis of gene-family-specific patterns reveals that, for genes encoding two of the most important venom proteins (snake venom metalloproteases and snake venom serine proteases), there are direct, positive relationships between sequence diversity (SD), expression diversity (ED), and increased DB. Further analysis of gene-family diversification for these proteins showed no constraint on how individual lineages achieved toxin gene SD in terms of the patterns of paralog diversification. In contrast, another major venom protein family (PLA2s) showed no relationship between venom molecular diversity and DB. Additional analyses suggest that other molecular mechanisms—such as higher absolute levels of expression—are responsible for diet adaptation involving these venom proteins. Broadly, our findings argue that functional diversity generated through sequence and expression variations jointly determine adaptation in the key components of pitviper venoms, which mediate complex molecular interactions between the snakes and their prey. 

Abstract Despite the medical significance to humans and important ecological roles filled by vipers, few high-quality genomic resources exist for these snakes outside of a few genera of pitvipers. Here we sequence, assemble, and annotate the genome of Fea’s Viper (Azemiops feae). This taxon is distributed in East Asia and belongs to a monotypic subfamily, sister to the pitvipers. The newly sequenced genome resulted in a 1.56 Gb assembly, a contig N50 of 1.59 Mb, with 97.6% of the genome assembly in contigs >50 Kb, and a BUSCO completeness of 92.4%. We found that A. feae venom is primarily composed of phospholipase A2 (PLA2) proteins expressed by genes that likely arose from lineage-specific PLA2 gene duplications. Additionally, we show that renin, an enzyme associated with blood pressure regulation in mammals and known from the venoms of two viper species including A. feae, is expressed in the venom gland at comparative levels to known toxins and is present in the venom proteome. The cooption of this gene as a toxin may be more widespread in viperids than currently known. To investigate the historical population demographics of A. feae, we performed coalescent-based analyses and determined that the effective population size has remained stable over the last 100 kyr. This suggests Quaternary glacial cycles likely had minimal influence on the demographic history of A. feae. This newly assembled genome will be an important resource for studying the genomic basis of phenotypic evolution and understanding the diversification of venom toxin gene families.