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The insulin-like growth factor (IGF) receptor (IGF-IR) is necessary for IGF signalling and has essential roles in cellular growth. In teleost fish, two distinct IGF-IR duplicates are conserved called IGF-IRa and IGF-IRb. However, while a salmonid-specific whole genome duplication (ssWGD) is known to have expanded several key genes within the IGF axis, its impact on the IGF-IR repertoire remains unresolved. Using bioinformatic and phylogenetic approaches, we establish that salmonids retain two IGF-IRa paralogues from ssWGD and a single IGF-IRb copy. We measured the tissue-specific and developmental transcriptional regulation of each IGF-IR gene, revealing tight co-expression between the IGF-IRa paralogues, but expression divergence comparing IGF-IRa and IGF-IRb genes. We also examined the regulation of each IGF-IR gene in fish challenged by bacterial and viral infections, adding to recent reports that the IGF axis has roles linking growth and immunity. While whole salmonid fry showed a small upregulation of IGF-IR expression during both types of infection, bacterial challenge caused striking downregulation of IGF-IRa1 and IGF-IRa2 in head kidney and spleen of adult fish, alongside genes coding IGF hormones, highlighting a strong repression of IGF-signalling in primary immune tissues. The reported immune-responsive regulation of IGF-IR genes adds to an emerging body of evidence that supports important cross-talk between master growth and immune pathways in vertebrates.

This work was supported by the Marine Alliance for Science and Technology for Scotland pooling initiative, funded by the Scottish Funding Council (grant number HR09011) and contributing institutions. Whole genome duplication (WGD) was experienced twice by the vertebrate ancestor (2 rounds; 2R), again by the teleost fish ancestor (3R) and most recently in certain teleost lineages (4R). Consequently, vertebrate gene families are often expanded in 3R and 4R genomes. Arguably, many types of ‘functional divergence’ present across 2R gene families will exceed that between 3R/4R paralogues of genes comprising 2R families. Accordingly, 4R offers a form of replication of 2R. Examining if this concept has implications for molecular evolutionary research, we studied insulin-like growth factor (IGF) binding proteins (IGFBPs), whose six 2R family members carry IGF hormones and regulate interactions between IGFs and IGF1-receptors (IGF1Rs). Using phylogenomic approaches, we resolved the complete IGFBP repertoire of 4R-derived salmonid fishes (nineteen genes; thirteen more than human) and established evolutionary relationships/nomenclature with respect to WGDs. Traits central to IGFBP action were determined for all genes, including atomic interactions in IGFBP-IGF1/IGF2 complexes regulating IGF-IGF1R binding. Using statistical methods, we demonstrate that attributes of these protein interfaces are overwhelming a product of 2R IGFBP family membership, explain 49-68% of variation in IGFBP mRNA concentration in several different tissues and strongly predict the strength and direction of IGFBP transcriptional regulation under differing nutritional-states. The results support a model where vertebrate IGFBP family members evolved divergent structural attributes to provide distinct competition for IGFs with IGF1Rs, pre-disposing different functions in the regulation of IGF-signaling. Evolution of gene expression acted to ensure the appropriate physiological production of IGFBPs according to their structural specializations, leading to optimal IGF-signaling according to nutritional-status and the endocrine/local mode of action. This study demonstrates that relatively recent gene family expansion can facilitate inference of functional evolution within ancient genetic systems. Publisher PDF