Abstract
Xiphophorus 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, X. maculatus, utilized to produce interspecies hybrids. Although the ancestors of the two currently used X. maculatus parental lines, Jp163 A and Jp163 B, were originally siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to segregation of an oncogene and a regulator encoded by the X. maculatus genome, while the backcross hybrid progeny with X. hellerii or X. couchianus 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 X. maculatus 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.
Highlights
Melanoma is a devastating disease with continuously growing incidence despite a decreasing trend of cancer incidences for most cancer types over the past few decades
Xiphophorus maculatus (X. maculatus) JpA and JpB strains used for genome resequencing were at their 116th and 109th generation of inbreeding, respectively
Spontaneous tumor incidences of two interspecies crosses established between X. hellerii and X. maculatus JpA or JpB [i.e., X. hellerii x (JpA × X. hellerii), or scheme A; X. hellerii× (JpB × X. hellerii), or scheme B] strains were first compared
Summary
Melanoma is a devastating disease with continuously growing incidence despite a decreasing trend of cancer incidences for most cancer types over the past few decades. Animal models that produce both heritable and induced melanoma, for dissection of genetic interactions underlying different tumorigenic mechanisms, or assessment of genetic vs environmental contributions to disease, is very rare. Melanoma development in Xiphophorus is similar to that of humans at the histological, transcriptome, and signaling pathway levels (Potrony et al, 2015; Lu et al, 2018). These attributes render the Xiphophorus system as the only model wherein one may study genetic interactions underlying divergent melanomagenic mechanisms
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