Comparison of <i>Xiphophorus</i> and human melanoma transcriptomes reveals conserved pathway interactions

Lu, Yuan; Boswell, Mikki; Boswell, William T.; Kneitz, Susanne; Hausmann, Michael; Klotz, Barbara; Regneri, Janine; Savage, Markita; Amores, Angel; Postlethwait, John H.; Warren, Wesley C.; Schartl, Manfred; Walter, Ronald B.

doi:10.1111/pcmr.12686

Cited by 14 publications

(13 citation statements)

References 88 publications

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“…maculatus × X . hellerii ) BC 5 fish from one single batch [45–49], and skin samples from 8 X . couchianus × ( X .…”

Section: Methodsmentioning

confidence: 99%

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Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model

Boswell

et al. 2018

PLoS Genet

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Understanding the genetic mechanisms underlying segregation of phenotypic variation through successive generations is important for understanding physiological changes and disease risk. Tracing the etiology of variation in gene expression enables identification of genetic interactions, and may uncover molecular mechanisms leading to the phenotypic expression of a trait, especially when utilizing model organisms that have well-defined genetic lineages. There are a plethora of studies that describe relationships between gene expression and genotype, however, the idea that global variations in gene expression are also controlled by genotype remains novel. Despite the identification of loci that control gene expression variation, the global understanding of how genome constitution affects trait variability is unknown. To study this question, we utilized Xiphophorus fish of different, but tractable genetic backgrounds (inbred, F1 interspecies hybrids, and backcross hybrid progeny), and measured each individual’s gene expression concurrent with the degrees of inter-individual expression variation. We found, (a) F1 interspecies hybrids exhibited less variability than inbred animals, indicting gene expression variation is not affected by the fraction of heterozygous loci within an individual genome, and (b), that mixing genotypes in backcross populations led to higher levels of gene expression variability, supporting the idea that expression variability is caused by heterogeneity of genotypes of cis or trans loci. In conclusion, heterogeneity of genotype, introduced by inheritance of different alleles, accounts for the largest effects on global phenotypical variability.

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“…maculatus × X . hellerii ) BC 5 fish from one single batch [45–49], and skin samples from 8 X . couchianus × ( X .…”

Section: Methodsmentioning

confidence: 99%

“…maculatus genome (Ensembl Xmac.4.4.2) using Bowtie2 [50], and gene expression was subsequently quantified using a custom Perl script that count sequencing reads that mapped to gene models [33]. For technical details regarding gene expression assessment and genotyping, see [21,45].…”

Section: Methodsmentioning

confidence: 99%

Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model

Boswell

et al. 2018

PLoS Genet

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“…Xiphophorus also represents a relevant model as it is one of only a few animal models for which the induction of melanomas can occur by exposure to UV radiation alone, and studies in these fish were important for proving the role that solar UV-B radiation plays in the formation of cutaneous melanoma [55]. More recently, gene expression profiling of melanomas produced in these fish showed that the high-expressing Xmrk Xiphophorus melanomas share transcriptomic features and molecular functions of highly proliferative, dedifferentiated human melanoma [56].…”

Section: Fishmentioning

confidence: 99%

Spontaneously occurring melanoma in animals and their relevance to human melanoma

Weyden

Brenn

Patton

et al. 2020

The Journal of Pathology

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In contrast to other cancer types, melanoma incidence has been increasing over the last 50 years, and while it still represents less than 5% of all cutaneous malignancies, melanoma accounts for the majority of skin cancer deaths, due to its propensity to metastasise. Whilst melanoma most commonly affects the skin, it can also arise in mucosal surfaces, the eye, and the brain. For new therapies to be developed, a better understanding of the genetic landscape, signalling pathways, and tumour–microenvironmental interactions is needed. This is where animal models are of critical importance. The mouse is the foremost used model of human melanoma. Arguably this is due to its plethora of benefits as a laboratory animal; however, it is important to note that unlike humans, melanocytes are not present at the dermal–epidermal junction in mice and mice do not develop melanoma without genetic manipulation. In contrast, there are numerous reports of animals that spontaneously develop melanoma, ranging from sharks and parrots to hippos and monkeys. In addition, several domesticated and laboratory‐bred animals spontaneously develop melanoma or UV‐induced melanoma, specifically, fish, opossums, pigs, horses, cats, and dogs. In this review, we look at spontaneously occurring animal ‘models’ of melanoma and discuss their relevance to the different types of melanoma found in humans. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland..

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“…However, 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 melanoma-genic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory

Olivas

Boswell

et al. 2020

Front. Genet.

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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.

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Comparison of Xiphophorus and human melanoma transcriptomes reveals conserved pathway interactions

Cited by 14 publications

References 88 publications

Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model

Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model

Spontaneously occurring melanoma in animals and their relevance to human melanoma

Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory

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