The medaka Kiyosu panel: dissecting GxE effects of environmental chemicals

摘要 环境污染物（污染物）对人类健康有着深远的影响， 子宫内先天性缺陷、儿童早期发育缺陷的发生率和 慢性成人疾病的进展。除了是整体健康负担的主要贡献者外， 环境污染物的不均匀分布导致了 不同的群体。然而，环境暴露对个人有不同的影响， 这种差异的很大一部分是由于遗传效应。通过研究这些“X基因 环境”（GxE）的影响，人们既可以量化表型变化，重要的是获得 对污染物的生物学途径的分子机理理解 应答这种理解反过来又可以为环境保护方面的治疗和政策提供信息。 健康为了进一步改变我们对GxE相互作用的理解，我们组装了一个 国际，多学科的团队，以利用一个独特的资源，野生衍生的近交Kiyosu 一组青鳉鱼。该小组由111个近交系组成， 单个种群（在清洲镇附近捕获），近交到近纯合性，每个 基因组测序在这个建议中，我们试图筛选10种环境污染物（选择 对于它们的影响和化学多样性）对多种早期发育，高维， 心脏生理学、心脏发育和骨骼发育的定量测量。 Kiyosu面板汇集了鼠标协作交叉（CC） 和果蝇参考基因组小组。与CC类似，Kiyosu面板处于模型中 具有广泛遗传能力的脊椎动物。然而，对CC的批评是相对的， 缺乏创始遗传多样性，创始人的多样性并不代表一个 野生种群在这里，Kiyosu面板类似于DRGP，其来自单一的多样化的 野生种群并捕获其大部分遗传多样性。初步数据显示， 选择的化学物质对青鳉亚群心跳表型的重复性GxE效应 线，仔细的统计功率分析提供了信心，我们可以映射个别基因座 使用定向F2杂交策略。高维表型可以利用 现代的、可扩展的多性状技术。在发现了单个GxE基因座 在这种脊椎动物的差异污染物反应，我们将分子特征的基因座使用 深入的表型分析、CRISPR遗传工具和RNAseq。所有的数据和结果都将 该面板可通过开放的MTA访问。我们还将 将这些信息与其他鳉鱼环境模型（异基底）相结合， 小鼠（协作交叉）和人类（英国生物银行，ALSPAC）资源来利用这一点 与社区分享信息，并将见解转化为人类背景。

Abstract Environmental pollutants (contaminants) have a profound impact on human health leading to in utero congenital defects, early childhood development defects and the incidence and progression of chronic adult disease. As well as being a major contributor to health burden overall, the heterogeneous distribution of environmental contaminants leads to health disparities between different groups. However, environmental exposures have a variable impact on individuals, and a substantial part of that variation is due to genetic effects. By studying these “Gene x Environment” (GxE) effects, one can both quantify phenotypic changes and importantly gain mechanistic, molecular understanding of the biological pathways involved in contaminant responses. This understanding in turn can inform both treatment and policy in environmental health. To make a step change in our understanding of GxE interactions, we have assembled an international, multi-disciplinary team to exploit a unique resource, the wild-derived inbred Kiyosu panel of medaka (Japanese rice-paddy) fish. This panel is formed from 111 inbred lines from a single population (captured near the town of Kiyosu), inbred to near-homozygosity and each genome sequenced. In this proposal, we seek to screen 10 environmental contaminants (chosen for their impact and chemical diversity) on multiple early developmental, high dimensional, quantitative measurements on heart physiology, heart development and skeletal development. The Kiyosu panel brings together the best features of both the Mouse Collaborative Cross (CC) and the Drosophila Reference Genome Panel. Similar to the CC, the Kiyosu panel is in a model vertebrate with a broad range of genetics capabilities. However, a critique of the CC is the relative lack of founding genetic diversity, and that the diversity of the founders is not representative of a wild population. Here the Kiyosu panel is similar to the DRGP being derived from a single diverse wild population and capturing the majority of its genetic diversity. Preliminary data demonstrate reproducible GxE effects of selected chemicals on heartbeat phenotypes in a subset of medaka lines, and careful statistical power analysis provides confidence that we can map individual loci using a directed F2 cross strategy. The high dimensional phenotypes can be exploited using modern, scalable multi-trait techniques. Having discovered individual GxE loci underlying differential contaminant response in this vertebrate, we will molecularly characterize the loci using in depth phenotyping, CRISPR genetic tools, and RNAseq. All data and results will be made openly available to the community, and the panel can be accessed via an open MTA. We will also integrate the information with other killifish environmental models (Fundulus heteroclitus), the Mouse (Collaborative Cross), and human (UK BioBank, ALSPAC) resources to exploit this information with the community and translate insights to a human context.