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）对人类健康领先有深远的影响 在子宫先天性缺陷中，幼儿发展缺陷和事件以及 慢性成人疾病的进展。除了成为整体健康伯恩的主要贡献者， 环境污染物的异质分布导致健康分布 不同的组。但是，环境暴露对个人和 这种变异的很大一部分是由于遗传作用引起的。通过研究这些“基因x 环境”（GXE）效果，既可以量化表型变化，又可以提高 机械，分子理解涉及污染物的生物学途径 回答。这种理解反过来可以为环境中的治疗和政策提供信息 健康。为了改变我们对GXE互动的理解，我们组装了一个 国际，多学科的团队探索独特的资源 Medaka（日本米粉）鱼的面板。该面板是由来自111个近交系的 单人口（在Kiyosu镇附近被捕），近交至几乎同性恋，每个人都 基因组测序。在此提案中，我们试图筛选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， 关于心脏生理，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）的最佳功能 和果蝇参考基因组面板。与CC相似，Kiyosu面板在模型中 具有广泛遗传学能力的脊椎动物。但是，对CC的批评是相对 缺乏建立遗传多样性，并且创始人的多样性并不代表 野生人口。这里的kiyosu面板类似于源自单一多样的DRGP 野生人口并捕获其大部分遗传多样性。初步数据证明了 选定化学物质对Medaka子集中心跳表型的可重复GXE影响 线条，仔细的统计能力分析提供了信心，我们可以绘制单个基因座 使用定向的F2交叉策略。可以使用高维表型来利用 现代，可扩展的多特征技术。发现了单个GXE基因座的基因座 在该脊椎动物中，差异污染物反应，我们将使用分子表征该基因座 深度表型，CRISPR遗传工具和RNASEQ。所有数据和结果将被制作 社区公开可用，可以通过开放的MTA访问面板。我们也会 将信息与其他Killifish环境模型（地属杂志）相结合 鼠标（协作十字架）和人类（英国生物银行，alspac）资源来利用这一点 与社区有关的信息，并将见解转化为人类环境。

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