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Abstract：
Understanding and predicting the relationships between genotype and phenotype is often challenging, largely due to the complex nature of eukaryotic gene regulation. A step towards this goal is to map how phenotypic diversity evolves through genomic changes that modify gene regulatory interactions. Using the Prairie Rattlesnake (Crotalus viridis) and related species, we integrate mRNA-seq, proteomic, ATAC-seq and whole-genome resequencing data to understand how specific evolutionary modifications to gene regulatory network components produce differences in venom gene expression. Through comparisons within and between species, we find a remarkably high degree of gene expression and regulatory network variation across even a shallow level of evolutionary divergence. We use these data to test hypotheses about the roles of specific trans-factors and cis-regulatory elements, how these roles may vary across venom genes and gene families, and how variation in regulatory systems drive diversity in venom phenotypes. Our results illustrate that differences in chromatin and genotype at regulatory elements play major roles in modulating expression. However, we also find that enhancer deletions, differences in transcription factor expression, and variation in activity of the insulator protein CTCF also likely impact venom phenotypes. Our findings provide insight into the diversity and gene-specificity of gene regulatory features and highlight the value of comparative studies to link gene regulatory network variation to phenotypic variation.
摘要：
理解和预测基因型和表型之间的关系通常是具有挑战性的。很大程度上是由于真核基因调控的复杂性。朝着这一目标迈出的一步是绘制表型多样性如何通过修改基因调控相互作用的基因组变化而演变。使用草原响尾蛇（Crotalusviridis）和相关物种，我们整合了mRNA-seq，蛋白质组学，ATAC-seq和全基因组重测序数据，以了解对基因调控网络组件的特定进化修饰如何在毒液基因表达中产生差异。通过物种内部和物种之间的比较，我们发现，即使在进化差异的浅层水平上，基因表达和调控网络的变异程度也非常高。我们使用这些数据来检验关于特定反式因子和顺式调控元件的作用的假设，这些角色如何在毒液基因和基因家族中变化，以及调节系统的变异如何驱动毒液表型的多样性。我们的结果表明，调节元件的染色质和基因型差异在调节表达中起主要作用。然而,我们还发现增强子缺失，转录因子表达的差异，绝缘子蛋白CTCF活性的变化也可能影响毒液表型。我们的发现提供了对基因调控特征的多样性和基因特异性的见解，并强调了比较研究将基因调控网络变异与表型变异联系起来的价值。
