Genetic analysis of bone morphometry and ivory vertebrae in threespine stickleback

Previous genetic studies of skeletal variation in threespine stickleback fish ( Gasterosteus aculeatus ) have focused primarily on striking morphological differences. Here, we examine the largely unexplored genetic architecture of internal bone microstructural variation between marine and freshwater stickleback. µCT X-ray analysis revealed differences in the porosity, bone thickness, and bone volume fraction within armor plates and vertebrae from a marine and freshwater stickleback. Quantitative trait locus mapping in F2 progeny from a marine × freshwater stickleback cross identified a significant locus on chromosome 4 influencing multiple aspects of armor plate internal microstructure. This locus overlaps the well-characterized Eda region previously known to control armor plate number and size. Co-mapping of bone microstructure could be due to pleiotropic effects of Eda on multiple aspects of plate development or to changes in closely linked genes including Itm2a , which also plays a role in bone formation. Most bone microstructure traits in vertebrae showed weak or no genetic signal, consistent with a polygenic architecture. However, we identified a highly significant locus on chromosome 17 that is strongly associated with abnormally thickened “ivory vertebrae” that occurred in 8.4% of F2 offspring. This phenotype resembles Paget’s disease in humans, and the major locus region contains Tnfrsf1b , the stickleback ortholog of a human Paget’s disease susceptibility gene TNFRSF11A . Together, our findings identify genetic loci underlying natural variation in bone microstructure in wild fish and reveal a candidate gene associated with a disease-like skeletal phenotype, highlighting stickleback as a model for studying both evolutionary and pathological bone biology.