Oncogenic allelic interaction in Xiphophorus highlights hybrid incompatibility

Abstract

Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population. Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility. Interspecies hybridization between southern platyfish and green swordtails leads to lethal melanocyte tumorigenesis. This occurs in hybrids with tumor incidence following progeny ratio that is consistent with two-locus interaction, suggesting melanoma development is a result of negative epistasis. Such observations makeXiphophorusone of the only two vertebrate hybrid incompatibility examples in which interacting genes have been identified. One of the two interacting loci has been characterized as a mutant epidermal growth factor receptor. However, the other locus has not been identified despite over five decades of active research. Here we report the localization of the melanoma regulatory locus to a single gene,rab3d, which shows all expected features of the long-sought oncogene interacting locus. Our findings provide insights into the role ofegfrregulation in regard to cancer etiology. Finally, they provide a molecular explainable example of hybrid incompatibility.

Predictability and parallelism in the contemporary evolution of hybrid genomes

“…This type of ancestral-derived incompatibility may be more likely in cases where there are biased patterns of lineage specific substitutions in particular gene classes, as appears to be the case for the X. birchmanni mitochondrially interacting proteins discussed above (Table 1). Our findings add to a handful of known cases where the same or similar genetic interactions are under selection in hybridization events across multiple species pairs [21,23,62,63]. Whether this phenomenon is widespread awaits progress mapping additional hybrid incompatibilities in related species pairs [6].…”

The genomic consequences of hybridization

“…( A ) In crosses between Xiphophorus birchmanni and Xiphophorus malinche , xmrk interacts with the gene cd97 to generate melanoma in a subset of hybrids ( Powell et al, 2020 ). ( B ) In crosses between distantly related species Xiphophorus maculatus and Xiphophorus hellerii , xmrk interacts with a different region, rab3d, to cause melanoma ( Schartl et al, 2010 ; Kazianis et al, 1998 ; Lu et al, 2020 ). Phylogenetic analyses suggest that these incompatibilities with xmrk have arisen independently ( Powell et al, 2020 ).…”

Xmrks the Spot: Fish Models for Investigating Epidermal Growth Factor Receptor Signaling in Cancer Research

“…R(Diff) was originally identified as having a genetic sequence homologous to the mammalian cyclin-dependent kinase inhibitor 2 (CDKN2) gene family [ 47 , 48 , 49 ]. More recently, it has been determined that cdkn2ab is not the R(Diff) gene but is tightly linked to it and that the R(Diff) locus is RAB3D , a Ras-related small G protein with GTPase activity that regulates exocytosis [ 50 ]. In human HCC tissues, RAB3D can interact with Golgi membrane protein 1 (GOLM1), a protein that facilitates EGFR cycling from the Golgi apparatus to the plasma membrane, causing increased downstream oncogenic kinase signaling [ 51 ].…”

“…In human HCC tissues, RAB3D can interact with Golgi membrane protein 1 (GOLM1), a protein that facilitates EGFR cycling from the Golgi apparatus to the plasma membrane, causing increased downstream oncogenic kinase signaling [ 51 ]. This recent observation suggests that RAB3D may regulate EGFR cycling, thereby reducing the number of active receptors on the cell surface, leading to decreased oncogenic EGFR signaling [ 50 ]. Further, RAB3D can modulate the secretion of matrix metalloproteinase-9 (MMP-9) from activated macrophages, facilitating migration into infected tissues [ 52 ].…”