ENHANCED DEVELOPMENT OF THE XIPHOPHORUS MODEL SYSTEM

描述（申请人提供）：剑尾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。R24提案概述了资源和研究组成部分，旨在维护和加强自20世纪30年代以来在美国运营的剑尾鱼遗传资源中心（XGSC），使其成为世界上最古老的活动物资源中心之一和国家科学宝藏。XGSC拥有超过60个血统遗传系，代表1，400多个水族馆中的25种剑尾鱼。XGSC为代表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。剑尾鱼实验模型的传统优势包括对与完整动物内复杂表型相关的遗传遗传模式进行无偏倚评估。例如，在纯剑尾鱼品系和选择的种间杂交种中，对于各种自发性和诱导性肿瘤（包括几种遗传上不同的黑色素瘤），都记录了肿瘤易感性的遗传控制。 我们的初步研究代表了两种脊椎动物物种和F1杂种中物种特异性等位基因表达的相对丰度的第一次全球比较。在这项初步研究中，我们能够确定在种间杂种遗传背景中亲本等位基因的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，其导致相对于任一亲本在F1杂种中基本上抑制基因表达。这些最初的实验，采用RNAseq跟踪F1种间杂种中的等位基因特异性基因表达，作为剑尾鱼模型的实例，可用于揭示关于基因相互作用的机制、发育程序的遗传基础、复杂行为以及疾病起始和进展的分子过程的新知识。如果这一建议的目标得以实现，剑尾鱼种间杂交黑色素瘤模型的机械解剖可能会接近，收集的结果将对人类肿瘤发生具有翻译意义。 公共卫生相关性（由申请人提供）：如果实现了本提案的目标，则可以对剑尾鱼种间杂交黑色素瘤模型进行机械解剖，因为两种亲本种属的基因组和转录组序列将允许评估产生易患黑色素瘤个体的遗传调控变化。这些结果将对人类肿瘤发生具有直接的翻译意义。

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. PUBLIC HEALTH RELEVANCE (provided by applicant): If the goals of this proposal are realized, mechanistic dissection of Xiphophorus interspecies hybrid melanoma models may be approached since genome and transcriptome sequences of both parental species will allow assessment of genetic regulatory changes that produce an individual that is predisposed to melanoma. These results will have direct translational significance to tumorigenesis in humans.