Insulin-Like Growth Factor-Binding Proteins of Teleost Fishes

Abstract

The insulin-like growth factor (Igf) binding protein (Igfbp) family has a broad range of physiological functions and a fascinating evolutionary history. This review focuses on the Igfbps of teleost fishes, where genome duplication events have diversified gene repertoire, function, and physiological regulation-with six core Igfbps expanded into a family of over twenty genes in some lineages. In addition to briefly summarizing the current state of knowledge on teleost Igfbp evolution, function, and expression-level regulation, we highlight gaps in our understanding and promising areas for future work.

Keywords: comparative biology; gene family evolution; genome duplication; insulin-like growth factor binding protein; physiology; teleost fish.

Figure 1

Expansion of the core insulin-like growth factor (Igf) system—including Igfbps—during teleost evolution. (A) Simplified depiction of Igf system. (B) Core Igfbp system components (i.e., proteins encoded by distinct genes) in different vertebrate groups, contrasting a typical mammalian system with that of two teleost lineages. For teleosts, % identity is shown for paralogous amino acid sequences. For Atlantic salmon, the underlined % identities highlight paralog pairs residing in regions of the genome that experienced a delay in cytological rediploidization after genome duplication (24), a process required for paralogs to diverge in sequence on distinct chromosomes—hence, these genes have had less evolutionary time to diverge, leading to extremely high identity. Phylogenetic relationships of the Igfbp families from these different lineages, along with another group of teleosts that experienced a separate lineage-specific genome duplication event, are depicted in Figure 2.

Figure 2

Independent evolutionary expansions to the Igfbp family of teleosts. A phylogenetic analysis was performed, including 71 unique Igfbp amino acid sequences from a standardized set of taxa: Human Homo sapiens (“Hs”), coelacanth Latimeria chalumnae (“Lc”), zebrafish Danio rerio (“Dr’”), common carp Cyprinus carpio (“Cc”), Atlantic salmon Salmo salar (“Ss”), and northern pike Esox lucius (“El,” from a sister lineage to salmonids that did not undergo the salmonid-specific genome duplication). Accession numbers are given for all sequences, which were gathered from the NCBI RefSeq database, facilitated by BLAST analyses (32). The sequences were aligned using Mafft V.7 (33) with default settings. Alignment quality filtering was done using the Guidance2 algorithm (34) to remove the least confidently aligned regions. This led to a high-confidence alignment of 212 amino acids positions (SI file 1). The alignment was used in Bayesian phylogenetic analysis, using methods published elsewhere (35). Briefly, this was done in BEAST v. 1.8 (36) using the best-fitting amino acid substitution model (JTT+G+I), determined by maximum likelihood via the IQ-tree server (37), along with a relaxed molecular clock model (38), allowing probabilistic estimation of the trees root [consistent with previous studies (9, 16)]. The tree is annotated to show genome duplication events in teleost evolutionary history, including in the teleost ancestor (“3R”) and additional events in the salmonid and carp lineages. The nomenclature for salmonid and carp paralogs is given as described in the text. Branch support values (posterior probability) are highlighted by circles placed on nodes, with colors matching a legend. Minor inconsistencies in branching patterns in some Igfbp clades (e.g., relating to the 3R or salmonid 4R) compared to other studies (16), can be explained by the short alignment length. Nonetheless, the tree demonstrates independent expansions within the salmonid and carp Igfbp repertoire, additional to paralogs retained in many other teleosts.