Abstract

Vertebrate sex determination and differentiation are coordinated by the activations and maintenance of reproductive transcriptional-regulatory networks (TRNs). There is considerable interest in studying the conserved design principles and functions of reproductive TRNs given that their intricate regulation is susceptible to disruption by gene mutations or exposures to exogenous endocrine disrupting chemicals (or EDCs). In this manuscript, the Boolean rules describing reproductive TRNs in humans, mice, and zebrafish, were represented as a pseudo-stoichiometric matrix model. This model mathematically described the interactions of 35 transcription factors with 21 sex determination and differentiation genes across the three species. The in silico approach of Extreme Pathway (ExPa) analysis was used to predict the extent of TRN gene activations subject to the species-specific transcriptomics data, from across various developmental life-stages. A goal of this work was to identify conserved and functional reproductive TRNs across the three species. ExPa analyses predicted the sex differentiation genes, DHH, DMRT1, and AR, to be highly active in male humans, mice, and zebrafish. Whereas FOXL2 was the most active gene in female humans and mice; and CYP19A1A in female zebrafish. These results agree with the expectation that regardless of a lack of sex determination genes in zebrafish, the TRNs responsible for canalizing male vs. female sexual differentiation are conserved with mammalian taxa. ExPa analysis therefore provides a framework with which to study the TRNs that influence the development of sexual phenotypes. And the in silico predicted conservation of sex differentiation TRNs between mammals and zebrafish identifies the piscine species as an effective in vivo model to study mammalian reproductive systems under normal or perturbed pathologies.

 抽象的

脊椎动物的性别决定和分化是通过生殖转录调控网络（TRN）的激活和维持来协调的。鉴于生殖 TRN 复杂的调控容易受到基因突变或暴露于外源内分泌干扰化学物质（或 EDC）的破坏，人们对研究生殖 TRN 的保守设计原则和功能非常感兴趣。在这份手稿中，描述人类、小鼠和斑马鱼生殖 TRN 的布尔规则被表示为伪化学计量矩阵模型。该模型以数学方式描述了三个物种中 35 个转录因子与 21 个性别决定和分化基因的相互作用。极端途径 (ExPa) 分析的计算机方法用于根据物种特异性转录组数据预测不同发育生命阶段的 TRN 基因激活程度。这项工作的目标是确定这三个物种中保守且功能性的生殖 TRN。 ExPa 分析预测性别分化基因 DHH、DMRT1 和 AR 在雄性人类、小鼠和斑马鱼中高度活跃。而 FOXL2 是女性人类和小鼠中最活跃的基因；和 CYP19A1A 在雌性斑马鱼中。这些结果与预期一致，即尽管斑马鱼缺乏性别决定基因，但负责引导雄性与雌性性别分化的 TRN 在哺乳动物类群中是保守的。因此，ExPa 分析提供了一个框架来研究影响性表型发展的 TRN。 计算机预测的哺乳动物和斑马鱼之间性别分化 TRN 的保守性将鱼类物种确定为研究正常或紊乱病理条件下哺乳动物生殖系统的有效体内模型。