Multiple FGF4 Retrocopies Recently Derived within Canids

Abstract

Two transcribed retrocopies of the fibroblast growth factor 4 (FGF4) gene have previously been described in the domestic dog. An FGF4 retrocopy on chr18 is associated with disproportionate dwarfism, while an FGF4 retrocopy on chr12 is associated with both disproportionate dwarfism and intervertebral disc disease (IVDD). In this study, whole-genome sequencing data were queried to identify other FGF4 retrocopies that could be contributing to phenotypic diversity in canids. Additionally, dogs with surgically confirmed IVDD were assayed for novel FGF4 retrocopies. Five additional and distinct FGF4 retrocopies were identified in canids including a copy unique to red wolves (Canis rufus). The FGF4 retrocopies identified in domestic dogs were identical to domestic dog FGF4 haplotypes, which are distinct from modern wolf FGF4 haplotypes, indicating that these retrotransposition events likely occurred after domestication. The identification of multiple, full length FGF4 retrocopies with open reading frames in canids indicates that gene retrotransposition events occur much more frequently than previously thought and provide a mechanism for continued genetic and phenotypic diversity in canids.

Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study

“…Although exact limb length data was not available in the current study, a chondrodystrophy variable was incorporated, as a way of attaining published data about which breeds carry polygenic inheritance of short limb length. The best characterised genetic mutation used as a robust marker of chondrodystrophy is an autosomal dominant fibroblast growth factor (FGF) 4 mutation in chromosome 12 (FGF4L2) that was identified in GWAS of canine limb dysplasia [ 42 ]. Breeds in which the FGF4L2 mutation is fixed exhibit a phenotype of extremely short long bones, and intervertebral disc disease [ 27 ].…”

“…Breeds in which the FGF4L2 mutation is fixed exhibit a phenotype of extremely short long bones, and intervertebral disc disease [ 27 ]. Although 5 other FGF4 retrogenes have been sequenced in dogs, and are also known to affect limb morphology, their frequency of carriage in various canine breeds has not yet been studied therefore chondrodystrophic breeds in the current study were defined as those with published, high-frequency carriage of the FGF4L2 gene [ 42 ].…”

The Effects of FGF4 Retrogenes on Canine Morphology

“…The two described FGF4 retrogene insertions lead to semi-dominant gain of function alleles [ 1 , 2 ]. The resulting phenotypic differences are most likely due to the specific expression control based on the insertion sites [ 1 , 2 , 6 ]. Further evidence for this is seen in the distinct phenotype differences seen in dogs with different FGF4L1 and FGF4L2 genotype combinations [ 16 ].…”

“…The exact mechanism linking FGF4 retrogene expression and skeletal dysplasia is not defined; limited data are available relating to temporal and spatial expression of FGF4 retrogenes and although FGF4 protein overexpression acting through FGFR3 is an intriguing comparative model, FGF ligands are known to bind to multiple receptors [ 1 , 2 , 5 ]. We identified five additional FGF4 retrogenes in canids leading to the corrected nomenclature of the retrogenes as L for “like”, followed by a number representing the order in which they were discovered [ 6 ].…”

Special Issue: A Tale of Genes and Genomes

“…Batcher and colleagues successfully used whole-genome sequence data to identify novel polymorphic retrocopies of the FGF4 gene in canids [8]. Gene retrocopies, often referred to as processed pseudogenes, often go unidentified or misidentified by common variant calling methods.…”