Variation in gene regulation is ubiquitous, yet identifying the mechanisms producing such variation, especially for complex traits, is challenging. Snake venoms provide a model system for studying the phenotypic impacts of regulatory variation in complex traits because of their genetic tractability. Here, we sequence the genome of the Tiger Rattlesnake, which possesses the simplest and most toxic venom of any rattlesnake species, to determine whether the simple venom phenotype is the result of a simple genotype through gene loss or a complex genotype mediated through regulatory mechanisms. We generate the most contiguous snake-genome assembly to date and use this genome to show that gene loss, chromatin accessibility, and methylation levels all contribute to the production of the simplest, most toxic rattlesnake venom. We provide the most complete characterization of the venom gene-regulatory network to date and identify key mechanisms mediating phenotypic variation across a polygenic regulatory network.

基因调控的变异无处不在，但识别产生这种变异的机制，尤其是复杂性状，却具有挑战性。由于蛇毒的遗传易处理性，蛇毒为研究复杂性状的调控变异对表型的影响提供了一个模型系统。在这里，我们对虎响尾蛇的基因组进行了测序，虎响尾蛇拥有所有响尾蛇物种中最简单、毒性最强的毒液，以确定简单毒液表型是通过基因丢失产生的简单基因型的结果，还是通过调节机制介导的复杂基因型的结果。我们生成了迄今为止最连续的蛇基因组组装，并使用该基因组来证明基因丢失、染色质可及性和甲基化水平都有助于产生最简单、毒性最强的响尾蛇毒液。我们提供了迄今为止最完整的毒液基因调控网络特征，并确定了介导多基因调控网络表型变异的关键机制。