Zebell Sophia G, Martí-Gómez Carlos, Fitzgerald Blaine, Pinto Da Cunha Camila, Lach Michael, Seman Brooke M, Hendelman Anat, Sretenovic Simon, Qi Yiping, Bartlett Madelaine, Eshed Yuval, McCandlish David M, Lippman Zachary B
bioRxiv. 2025 Feb 25:2025.02.23.639722. doi: 10.1101/2025.02.23.639722.
Cryptic genetic variants exert minimal or no phenotypic effects alone but have long been hypothesized to form a vast, hidden reservoir of genetic diversity that drives trait evolvability through epistatic interactions. This classical theory has been reinvigorated by pan-genome sequencing, which has revealed pervasive variation within gene families and regulatory networks, including extensive cis-regulatory changes, gene duplication, and divergence between paralogs. Nevertheless, empirical testing of cryptic variation's capacity to fuel phenotypic diversification has been hindered by intractable genetics, limited allelic diversity, and inadequate phenotypic resolution. Here, guided by natural and engineered cis-regulatory cryptic variants in a recently evolved paralogous gene pair, we identified an additional pair of redundant trans regulators, establishing a regulatory network that controls tomato inflorescence architecture. By combining coding mutations with a cis-regulatory allelic series in populations segregating for all four network genes, we systematically constructed a collection of 216 genotypes spanning the full spectrum of inflorescence complexity and quantified branching in over 27,000 inflorescences. Analysis of the resulting high-resolution genotype-phenotype map revealed a layer of dose-dependent interactions within paralog pairs that enhances branching, culminating in strong, synergistic effects. However, we also uncovered an unexpected layer of antagonism between paralog pairs, where accumulating mutations in one pair progressively diminished the effects of mutations in the other. Our results demonstrate how gene regulatory network architecture and complex dosage effects from paralog diversification converge to shape phenotypic space under a hierarchical model of epistatic interactions. Given the prevalence of paralog evolution in genomes, we propose that paralogous cryptic variation within regulatory networks elicits hierarchies of epistatic interactions, catalyzing bursts of phenotypic change. cryptic mutations, paralogs, redundancy, cis-regulatory, tomato, inflorescence, gene regulatory network, modeling, epistasis.
隐秘遗传变异单独作用时产生的表型效应极小或无表型效应，但长期以来一直被认为形成了一个巨大的、隐藏的遗传多样性库，通过上位性相互作用推动性状的可进化性。泛基因组测序使这一经典理论得以复兴，该测序揭示了基因家族和调控网络中普遍存在的变异，包括广泛的顺式调控变化、基因复制以及旁系同源基因之间的差异。然而，隐秘变异推动表型多样化能力的实证检验一直受到棘手的遗传学问题、有限的等位基因多样性和不足的表型分辨率的阻碍。在这里，以一个最近进化的旁系同源基因对中的天然和工程化顺式调控隐秘变异为指导，我们鉴定出另外一对冗余的反式调节因子，建立了一个控制番茄花序结构的调控网络。通过在分离所有四个网络基因的群体中将编码突变与顺式调控等位基因系列相结合，我们系统地构建了一个包含216种基因型的集合，涵盖了花序复杂性的全谱，并对超过27000个花序的分支进行了量化。对由此产生的高分辨率基因型 - 表型图谱的分析揭示了旁系同源基因对内存在一层剂量依赖性相互作用，这种相互作用增强了分支，最终产生强烈的协同效应。然而，我们还发现了旁系同源基因对之间意想不到的拮抗作用层，其中一对中积累的突变会逐渐减弱另一对中突变的效应。我们的结果表明，基因调控网络结构和旁系同源基因多样化产生的复杂剂量效应如何在一个上位性相互作用的层次模型下汇聚以塑造表型空间。鉴于旁系同源基因进化在基因组中的普遍性，我们提出调控网络内的旁系同源隐秘变异引发上位性相互作用层次，催化表型变化爆发。隐秘突变、旁系同源基因、冗余、顺式调控、番茄、花序、基因调控网络、建模、上位性
