ENHANCED DEVELOPMENT OF THE XIPHOPHORUS MODEL SYSTEM

描述（由申请人提供）： 60 多年来，剑尾鱼一直被用作基础生物医学研究的脊椎动物实验模型。该 R24 提案概述了资源和研究组成部分，旨在维护和加强剑尾鱼遗传资源中心 (XGSC)，该中心自 1930 年代以来一直在美国运营，使其成为全球最古老的活体动物资源中心之一，也是国家科学瑰宝。 XGSC 拥有 60 多个纯种遗传系，代表 1,400 多个水族馆中的 25 个剑尾鱼物种。 XGSC 已向代表 11 个国家的 30 多个实验室的研究人员提供了纯种鱼类和材料。剑尾龙实验模型的传统优势在于对完整动物内复杂表型相关的遗传模式进行无偏见评估。例如，在纯剑尾属菌株和选择的种间杂种中，已记录了肿瘤易感性的遗传控制，可用于多种自发性和诱导性肿瘤，包括几种遗传上不同的黑色素瘤。 我们的初步研究首次对两种脊椎动物和 F1 杂交种中物种特异性等位基因表达的相对丰度进行了全球比较。在这项初步研究中，我们能够识别出种间杂种遗传背景中亲本等位基因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，导致 F1 杂种相对于亲本的基因表达显着抑制。这些初步实验采用 RNAseq 跟踪 F1 种间杂种中的等位基因特异性基因表达，作为剑尾模型的示例，可用于揭示有关基因相互作用机制、发育程序的遗传基础、复杂行为以及疾病发生和进展的分子过程的新知识。如果该提案的目标得以实现，则可以对剑尾鱼种间混合黑色素瘤模型进行机械解剖，并且收集的结果将对人类肿瘤发生具有转化意义。

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.