Duplication and diversification of insulin genes in ray-finned fish

Abstract

Insulin is a key hormone for the regulation of metabolism in vertebrates. Insulin is produced by pancreatic islet cells in response to elevated glucose levels and leads to the uptake of glucose by tissues such as liver and adipose tissue to store energy. Insulin also has additional functions in regulating development. Previous work has shown that the proglucagon gene, which encodes hormones counter regulating insulin, is duplicated in teleost fish, and that the peptide hormones encoded by these genes have diversified in function. I sought to determine whether similar processes have occurred to insulin genes in these species. Searches of fish genomes revealed an unexpected diversity of insulin genes. A triplication of the insulin gene occurred at the origin of teleost fish, however one of these three genes, insc , has been lost in most teleost fish lineages. The two other insulin genes, insa and insb , have been retained but show differing levels of selective constraint suggesting that they might have diversified in function. Intriguingly, a duplicate copy of the insa gene, which I named insab , is found in many fish. The coding sequence encoded by insab genes is under weak selective constraint, with its predicted protein sequences losing their potential to be processed into a two-peptide hormone. However, these sequences have retained perfectly conserved cystine residues, suggesting that they maintain insulin’s three-dimensional structure and therefore might modulate the processing and secretion of insulin produced by the other genes.

Crocins from Crocus sativus L. in the Management of Hyperglycemia. In Vivo Evidence from Zebrafish

“…Three insulin genes have been discovered in zebrafish, namely insulin a ( insa ), insulin b ( insb ), and insulin c ( insc ). Insa and insb are expressed as early as 1 hpf indicating that both genes are maternally expressed [ 28 , 29 ]. However, insa reaches its peak at 72 hpf, a time point in which an almost mature zebrafish pancreas is established, on the contrary to insb, whose expression is restricted only during very early developmental stages.…”

“…Therefore, it has been hypothesized that insa is the prominent responsible gene for glucose homeostasis regulation [ 30 ]. Insc is quite a newly discovered gene, expressed in the gut and internal organs [ 29 ], but its exact function is still not clear. In this respect, we focused on the study of insa.…”

Evolution of the Insulin Gene: Changes in Gene Number, Sequence, and Processing

“…While some evidence for differences in the selective constraints acting on the two insulin genes has been detected (25), no evidence for different functions have been found, thus a convincing explanation has not been reached. Intriguingly, duplicated insulin genes that originated by retroposition, like the rodent Ins1 gene, have also been described in several species of bony fish through three independent origins (28). While most of the retroposed insulin-like sequences in fish appeared to be pseudogenes, the gene sequence of a potentially retroprocessed insulin gene in the Northern pike (Esox lucius) has an intact coding sequence (Figure 1C) that is potentially functional (28).…”

“…The grey box indicates the genome duplication. (D) Summary of the duplications of insulin genes in bony fish (28). A triplication of the insulin gene, yielding insa, insb, and insc genes, occurred in an early ancestor of teleost fish (the order of the duplications events yielding the insa, insb, and insc is unresolved).…”

“…Intriguingly, duplicated insulin genes that originated by retroposition, like the rodent Ins1 gene, have also been described in several species of bony fish through three independent origins (28). While most of the retroposed insulin-like sequences in fish appeared to be pseudogenes, the gene sequence of a potentially retroprocessed insulin gene in the Northern pike (Esox lucius) has an intact coding sequence (Figure 1C) that is potentially functional (28). Further study is needed to determine whether this retroposed Northern pike insulin gene is expressed and if its encoded protein has a physiological function.…”