The medaka Kiyosu panel: dissecting GxE effects of environmental chemicals

青鳉 Kiyosu 小组：剖析环境化学品的 GxE 效应

• 批准号: 10551993
• 负责人: Ewan Birney
• 金额: $ 41.89万
• 依托单位: EUROPEAN MOLECULAR BIOLOGY LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551993
• 关键词: Adult; Affect; Alleles; Automation; Biological; Biological Assay; Breeding; Brothers; CRISPR/Cas technology; Chemicals; Chromosome Mapping; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Congenital Abnormality; Critiques; Data; Defect; Development; Disease; Dissection; Dose; Drosophila genus; Embryo; Environment; Environmental Exposure; Environmental Health; Environmental Pollutants; Fertility; Fishes; Follow-Up Studies; Fundulus heteroclitus; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Health; Heart; Human; Image; Inbreeding; Incidence; Individual; International; Japanese; Joints; Killifishes; Knock-out; Laboratory mice; Linkage Disequilibrium; Liver; Maps; Measurement; Modeling; Modernization; Molecular; Mus; Organism; Oryziinae; Parents; Partner in relationship; Pathway interactions; Phenotype; Physiology; Policies; Population; Process; RNA; Regulation; Reproducibility; Resistance; Resources; Rice; Rodent; Sampling; Sister; Skeletal Development; Surveys; Techniques; Testing; Translating; Variant; Vertebrates; Xenobiotic Metabolism; Xenobiotics; animal resource; assay development; biobank; cardiogenesis; cohort; cost; early childhood; environmental change; environmental chemical; gene discovery; gene environment interaction; genetic analysis; genomic locus; health disparity; high dimensionality; improved; in utero; individual response; innovation; insight; model organism; multidisciplinary; power analysis; reference genome; response; screening; segregation; skeletal; synergism; tool; trait; transcriptome sequencing

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.

抽象的 环境污染物（污染物）对人类健康产生深远影响 子宫内先天性缺陷、儿童早期发育缺陷及其发生率和 慢性成人疾病的进展以及总体健康负担的一个主要因素， 环境污染物的异质分布导致不同人群之间的健康差异 然而，环境暴露对个人和群体的影响各不相同。 通过研究这些“基因 x”，这种变异的很大一部分是由于遗传效应造成的。 “环境”（GxE）效应，既可以量化表型变化，又可以显着增益 对污染物涉及的生物途径的机械、分子理解 这种理解反过来可以为环境处理和政策提供信息。 为了进一步改变我们对 GxE 交互的理解，我们组装了一个 国际多学科团队开发独特的资源，即野生自交系 Kiyosu 青鳉鱼（日本稻田鱼）组 该组由来自一条青鳉鱼的 111 个自交系组成。 单一种群（在清须镇附近捕获），近亲交配，每个种群 在本提案中，我们寻求筛选 10 种环境污染物（选择）。 因为它们的影响和化学多样性）对多个早期发育、高维度、 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 Mouse Collaborative Cross (CC) 的最佳功能 和果蝇参考基因组面板类似于 CC，Kiyosu 面板位于模型中。 然而，对 CC 的批评是相对的。 缺乏创始人遗传多样性，并且创始人的多样性并不代表 这里的 Kiyosu panel 类似于源自单一多样化的 DRGP。 野生种群并捕获其大部分遗传多样性的初步数据表明。 选定化学物质对青鳉亚群心跳表型的可重复 GxE 影响 线，仔细的统计功效分析使我们有信心绘制各个位点 使用定向 F2 杂交策略可以利用高维表型。 现代、可扩展的多性状技术已发现潜在的单个 GxE 位点。 为了区分该脊椎动物的污染物反应，我们将使用以下方法对基因座进行分子表征 深度表型分析、CRISPR 遗传工具和 RNAseq 将制作所有数据和结果。 向社区开放，并且可以通过开放的 MTA 访问该面板。 将信息与其他鳉鱼环境模型（Fundulusheteroclitus）整合， 小鼠（Collaborative Cross）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。

项目成果

Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel.

• DOI: 10.1186/s13059-022-02602-4
• 发表时间: 2022-02-21
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Leger A;Brettell I;Monahan J;Barton C;Wolf N;Kusminski N;Herder C;Aadepu N;Becker C;Gierten J;Hammouda OT;Hasel E;Lischik C;Lust K;Sokolova N;Suzuki R;Tavhelidse T;Thumberger T;Tsingos E;Watson P;Welz B;Naruse K;Loosli F;Wittbrodt J;Birney E;Fitzgerald T
• 通讯作者: Fitzgerald T

In vivo identification and validation of novel potential predictors for human cardiovascular diseases.

• DOI: 10.1371/journal.pone.0261572
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hammouda OT;Wu MY;Kaul V;Gierten J;Thumberger T;Wittbrodt J
• 通讯作者: Wittbrodt J

The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel.

• DOI: 10.1186/s13059-022-02623-z
• 发表时间: 2022-02-21
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Fitzgerald T;Brettell I;Leger A;Wolf N;Kusminski N;Monahan J;Barton C;Herder C;Aadepu N;Gierten J;Becker C;Hammouda OT;Hasel E;Lischik C;Lust K;Sokolova N;Suzuki R;Tsingos E;Tavhelidse T;Thumberger T;Watson P;Welz B;Khouja N;Naruse K;Birney E;Wittbrodt J;Loosli F
• 通讯作者: Loosli F