Genetic dissection of complex traits in C. elegans

线虫复杂性状的遗传解剖

• 批准号: 8838844
• 负责人: LEONID KRUGLYAK
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838844
• 关键词: Agriculture; Alleles; Animal Model; Anthelmintics; Architecture; Behavior; Biological; Biological Assay; Biomedical Research; Caenorhabditis elegans; Candidate Disease Gene; Collection; Communities; Complex; DNA Markers; Diabetes Mellitus; Diagnosis; Disease; Disease susceptibility; Dissection; Environment; Fertility; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Growth; Hawaii; Health; Human; Human Biology; Inbreeding; Investigation; Malignant Neoplasms; Maps; Measures; Medical; Methods; Molecular; Mutation; Nature; Nematoda; Organism; Parents; Pathway interactions; Pesticides; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prevention; Quantitative Trait Loci; RNA Interference; Recombinants; Research; Research Design; Resistance; Resolution; Resources; Robin bird; Role; Stress; Surveys; Techniques; Transgenic Organisms; Variant; Work; Yeasts; Zinc Fingers; base; design; expectation; genetic resource; homologous recombination; human disease; improved; insight; interest; knock-down; loss of function mutation; novel strategies; nuclease; pathogen; research study; response; success; trait

DESCRIPTION (provided by applicant): The broad objective of the proposed research is the genetic dissection of a large number of complex and quantitative traits in the nematode worm and model organism C. elegans, with a focus on two classes of traits with relevance to human health: responses to pathogens and drugs. Success in understanding the genetic basis of phenotypic variation in a metazoan will provide critical guidance for the design of genotype-phenotype studies in humans and other organisms of medical, biological, and agricultural interest. The methods and resources developed will be broadly applicable to other phenotypes in C. elegans. The results will improve our understanding of the genes and pathways involved in susceptibility to pathogens, and in the mechanisms of action, resistance, and off-target effects of chemotherapeutics, anthelmintics, pesticides, and other compounds. Specifically, we will develop high-throughput quantitative phenotyping assays for these traits and apply them to genetic resources developed during the previous project period: a large set of high-resolution advanced intercross recombinant inbred lines from a cross between Bristol and Hawaii isolates, and a diverse collection of wild isolates extensively characterized for sequence variation. We will also apply these assays to new genetic resources that we will develop as part of the proposed research: we will build and genotype mapping populations from a maximally diverse subset of wild isolates. We will also develop new approaches for rapid identification of quantitative trait loci for any starting set of parent strains. We expect these efforts to produce:(i) a set of well-characterized diverse wild isolates and a broadly useful multiparent mapping population that will be shared with the C. elegans research community; (ii) new mapping methods applicable to C. elegans and other species; and (iii) a large set of loci for further investigation. We then propose to identify the genes and polymorphisms that underlie these loci, and to investigate the genetic architectures of the traits, including the population frequencies of the relevant alleles. We will confirm candidate genes and regions by using RNAi and transgenics to knock down or express genes in the appropriate strains. We will measure the frequencies of the identified alleles in the full diverse collection of wild isolates, and answer questions about rare vs. common alleles, additivity vs. dominance, and the role of genetic interactions. We expect to elucidate key principles of genetic architecture that will guide study design in C. elegans and other species. The pathways C. elegans uses to respond to biotic and abiotic stresses are conserved in humans and involved in a variety of diseases, including cancer and diabetes. Thus, we will leverage the power of the worm to better understand human biology.

描述（由申请人提供）：拟议研究的广泛目标是对线虫和模式生物C中大量复杂的数量性状进行遗传解剖。elegans，重点关注与人类健康相关的两类特征：对病原体和药物的反应。成功地理解后生动物表型变异的遗传基础将为人类和其他生物的医学，生物学和农业利益的基因型-表型研究的设计提供重要的指导。所开发的方法和资源将广泛适用于C.优雅的这些结果将提高我们对病原体易感性所涉及的基因和途径的理解，以及化学治疗剂，驱虫剂，杀虫剂和其他化合物的作用，耐药性和脱靶效应的机制。具体而言，我们将开发高通量定量表型分析这些性状，并将其应用于遗传资源开发在前一个项目期间：一个大的高分辨率先进的互交重组自交系之间的杂交布里斯托和夏威夷分离株，广泛收集野生菌株的序列变异的特点。我们还将把这些检测方法应用于我们将开发的新遗传资源，作为拟议研究的一部分：我们将从野生分离株的最大多样性子集中构建和基因型定位种群。我们还将开发新的方法，用于快速鉴定任何起始亲本菌株的数量性状基因座。我们期望这些努力能够产生：（i）一组特征良好的多样性野生分离物和一个广泛有用的多亲本作图群体，将与C。elegans研究社区;（ii）适用于C. elegans和其他物种;和（iii）一个大的一套基因座作进一步调查。然后，我们建议确定这些基因座的基因和多态性，并调查性状的遗传结构，包括群体频率， 相关的等位基因我们将通过使用RNAi和转基因技术在合适的菌株中敲低或表达基因来确认候选基因和区域。我们将测量在野生分离物的完整多样性集合中鉴定的等位基因的频率，并回答有关罕见与常见等位基因，加性与显性以及遗传相互作用的作用的问题。我们希望阐明遗传结构的关键原则，将指导研究设计在C。线虫和其他物种。途径C.线虫用于响应生物和非生物胁迫的基因在人类中是保守的，并且涉及多种疾病，包括癌症和糖尿病。因此，我们将利用蠕虫的力量来更好地了解人类生物学。

项目成果

Catecholamine receptor polymorphisms affect decision-making in C. elegans.

• DOI: 10.1038/nature09821
• 发表时间: 2011-04-21
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Bendesky, Andres;Tsunozaki, Makoto;Rockman, Matthew V.;Kruglyak, Leonid;Bargmann, Cornelia I.
• 通讯作者: Bargmann, Cornelia I.

A maternal-effect selfish genetic element in Caenorhabditis elegans.

• DOI: 10.1126/science.aan0621
• 发表时间: 2017-06-09
• 期刊: Science (New York, N.Y.)
• 作者: Ben-David E;Burga A;Kruglyak L
• 通讯作者: Kruglyak L

Recombinational landscape and population genomics of Caenorhabditis elegans.

• DOI: 10.1371/journal.pgen.1000419
• 发表时间: 2009-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Rockman MV;Kruglyak L
• 通讯作者: Kruglyak L

Full-genome evolutionary histories of selfing, splitting, and selection in Caenorhabditis.

• DOI: 10.1101/gr.187237.114
• 发表时间: 2015-05
• 期刊: Genome research
• 影响因子: 7
• 作者: Thomas CG;Wang W;Jovelin R;Ghosh R;Lomasko T;Trinh Q;Kruglyak L;Stein LD;Cutter AD
• 通讯作者: Cutter AD

Long-range regulatory polymorphisms affecting a GABA receptor constitute a quantitative trait locus (QTL) for social behavior in Caenorhabditis elegans.

• DOI: 10.1371/journal.pgen.1003157
• 发表时间: 2012
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Bendesky A;Pitts J;Rockman MV;Chen WC;Tan MW;Kruglyak L;Bargmann CI
• 通讯作者: Bargmann CI