Lu Yuan, Olivas Taryn J, Boswell Mikki, Boswell William, Warren Wes C, Schartl Manfred, Walter Ronald B
Xiphophorus Genetic Stock Center, Texas State University, San Marcos, TX, United States.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT, United States.
Front Genet. 2020 Oct 6;11:562594. doi: 10.3389/fgene.2020.562594. eCollection 2020.
interspecies hybrids represent a valuable model system to study heritable tumorigenesis, and the only model system that exhibits both spontaneous and inducible tumors. Types of tumorigenesis depend on the specific pedigree of the parental species, , utilized to produce interspecies hybrids. Although the ancestors of the two currently used parental lines, Jp163 A and Jp163 B, were originally siblings produced by the same mother, backcross interspecies hybrid progeny between and Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to segregation of an oncogene and a regulator encoded by the genome, while the backcross hybrid progeny with or and Jp163 B exhibit melanoma on the flanks of their bodies, especially after treatment with ultraviolet light. Therefore, dissecting the genetic differences between these two closely related lines may lead to better understanding of functional molecular differences associated with tumorigenic mechanisms. For this purpose, comparative genomic analyses were undertaken to establish genetic variants between these two lines. Surprisingly, given the heritage of these two fish lines, we found genetic variants are clustered together in select chromosomal regions. Among these variants are non-synonymous mutations located in 381 genes. The non-random distribution of genetic variants between these two may highlight ancestral chromosomal recombination patterns that became fixed during subsequent inbreeding. Employing comparative transcriptomics, we also determined differences in the skin transcriptional landscape between the two lines. The genetic differences observed are associated with pathways highlighting fundamental cellular functions including inter-cellular and microenvironment-cellular interactions, and DNA repair. These results collectively lead to the conclusion that diverged functional genetic baselines are present between Jp163 A and B strains. Further, disruption of these fixed genetic baselines in the hybrids may give rise to spontaneous or inducible mechanisms of tumorigenesis.
种间杂种是研究遗传性肿瘤发生的宝贵模型系统，也是唯一能同时展现自发性肿瘤和诱发性肿瘤的模型系统。肿瘤发生的类型取决于用于产生种间杂种的亲本物种的特定谱系。尽管目前使用的两个亲本品系Jp163 A和Jp163 B的祖先最初是由同一母亲生育的兄弟姐妹，但Jp163 A与其他品系的回交种间杂交后代会因一个致癌基因和由该基因组编码的一个调节因子的分离，在背鳍处引发自发性黑色素瘤，而与Jp163 B进行回交的杂交后代在身体两侧出现黑色素瘤，尤其是在接受紫外线照射后。因此，剖析这两个密切相关品系之间的遗传差异可能有助于更好地理解与肿瘤发生机制相关的功能分子差异。为此，进行了比较基因组分析以确定这两个品系之间的遗传变异。令人惊讶的是，鉴于这两个鱼品系的遗传背景，我们发现遗传变异在特定染色体区域聚集在一起。在这些变异中，有位于381个基因中的非同义突变。这两个品系之间遗传变异的非随机分布可能突出了在随后的近亲繁殖过程中固定下来的祖先染色体重组模式。利用比较转录组学，我们还确定了这两个品系之间皮肤转录图谱的差异。观察到的遗传差异与突出基本细胞功能的途径有关，包括细胞间和微环境与细胞间的相互作用以及DNA修复。这些结果共同得出结论，Jp163 A和B品系之间存在不同的功能遗传基线。此外，杂种中这些固定遗传基线的破坏可能会引发肿瘤发生的自发或诱导机制。
