ENHANCED DEVELOPMENT OF THE XIPHOPHORUS MODEL SYSTEM

描述(申请人提供)：剑鱼作为脊椎动物实验模型用于基础生物医学研究已有60多年的历史。这份R24提案概述了资源和研究部分，旨在维护和加强剑鱼遗传资源中心(XGSC)，该中心自1930年S以来一直在美国运营，使其成为世界上最古老的活动物资源中心之一，也是国家科学瑰宝。XGSC拥有60多个谱系遗传系，代表1400多个水族箱中的25个剑鱼物种。XGSC已经向代表11个国家的30多个实验室的研究人员提供了纯种鱼和材料。剑鱼实验模型的传统优势包括对与完整动物的复杂表型相关的遗传遗传模式进行无偏见的评估。例如，对于各种自发和诱发的肿瘤，包括几个遗传上不同的黑色素瘤，在纯剑尾鱼品系和精选种间杂交中都有关于肿瘤易感性的基因控制的文献。 我们的初步研究首次在全球范围内比较了两个脊椎动物物种和F1杂交种的物种特异性等位基因表达的相对丰度。在最初的研究中，我们能够确定在种间杂交遗传背景下亲本等位基因表达水平的实质性变化。我们还发现了一类新的遗传相互作用，这些相互作用导致F1杂种相对于任何一个亲本的基因表达受到显著抑制。这些初步实验利用RNAseq来跟踪F1种间杂交中的等位基因特异性基因表达，作为Xphophorus模型的例子，可以用来揭示关于基因相互作用的机制、发育程序的遗传基础、复杂行为以及疾病发生和发展的分子过程的新知识。如果这一建议的目标得以实现，剑尾蛇种间杂交黑色素瘤模型的机制解剖可能会接近，所收集的结果将对人类肿瘤的发生具有翻译意义。

DESCRIPTION (provided by applicant): Xiphophorus fishes have been used as a vertebrate experimental model for fundamental biomedical research for over 60 years. This R24 proposal outlines both resource and research components designed to maintain and enhance the Xiphophorus Genetic Stock Center (XGSC) that has operated within the United States since the 1930's making it one of the oldest live animal resources centers worldwide and a national scientific treasure. The XGSC houses over 60 pedigreed genetic lines representing 25 Xiphophorus species in over 1,400 aquaria. The XGSC has provided pedigreed fish and materials to researchers in over 30 laboratories representing 11 countries. The traditional strength of the Xiphophorus experimental model involves the non-biased assessment of genetic inheritance patterns associated with complex phenotypes within intact animals. For example, genetic control of tumor susceptibility has been documented in both pure Xiphophorus strains and select interspecies hybrids, for a variety of spontaneous and induced neoplasms including several genetically distinct melanomas. Our preliminary studies represent a first global comparison of the relative abundance of species-specific allele expression in two vertebrate species and Fl hybrids. In this initial study we were able to identify substantial changes in gene expression levels for parental alleles in the interspecies hybrid genetic background. We also found a new class of genetic interactions that lead to substantially suppressed gene expression in Fl hybrids relative to either parent. These initial experiments, employing RNAseq to follow allele specific gene expression in Fl interspecies hybrids, serve as examples of the Xiphophorus model may be used to uncover new knowledge regarding the mechanics of gene interactions, the genetic basis of developmental programs, complex behaviors, and the molecular processes underlying disease initiation and progression. If the goals of this proposal are realized, mechanistic dissection of Xiphophorus interspecies hybrid melanoma models may be approached and the results gleaned will have translational significance to tumorigenesis in humans.