Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty

Disclosures

Diabetes. 2006;55(12):3201-3213. 

In This Article

Insulin Genes

A preliminary evaluation of the relatedness of homologues can be generated from the number and relative position of introns, and these are shown in Fig. 3.[34] There are minor variations in the sizes of the introns among mammals while large dissimilarities are witnessed in the introns of chicken and zebrafish. The insulin 1 genes of rat and mouse have lost the second intron and also contain the remnant of a polydeoxyadenylate acid tract preceding the downstream direct repeat. Together, these structural features have led to the suggestion that the insulin 1 gene is a functional transposon [14] that was generated by an RNA-mediated duplication-transposition event involving a transcript of insulin 2 gene that was initiated upstream from the normal capping site. This duplication-transposition event clearly preceded separation of rat and mouse 15 million years ago. Along this evolutionary road, additional divergence has taken place resulting in rat having the two insulin genes residing about 55 Mbp apart on chromosome 1, whereas in the mouse they lie on different chromosomes, namely 6 and 7.

Figure 3.

Insulin gene intron sizes in studied species. The intron sizes (bp) are listed for all the reviewed insulin genes. The corresponding regions of the insulin protein are displayed above the exons. A, peptide A; B, peptide B; C, peptide C; P, preproinsulin leader peptide; U, untranslated. Figure is modified from ref.34.

Synteny (i.e., the preserved order of genes between organisms) provides an expedient higher-level assessment of the association between homologues. The identification and annotation of genes in most genomes remains fragmentary; however, it is clear from currently available data that all of the studied insulin genes display remarkable synteny extending all the way back to zebrafish, which diverged from humans 450 million years ago. Not only are the immediate upstream and downstream flanking genes of tyrosine hydroxylase (TH) and insulin-like growth factor 2 (IGF-2) retained, but inspection of ~500 Mbp confirms extensive maintenance of synteny of many important genes including syt8, lsp1, tnnt3, mrpL23, cd81, and tssc4. While gene order and direction of transcription are preserved, the spacing between specific genes can vary. This is most dramatically illustrated with the insulin and TH genes, which are separated by 2–22 kbp in all species except mouse and rat, where the insulin 2 gene lies ~210 and 230 kbp distant from the TH gene, respectively. Despite evidence of different rates of insertion and deletion mutation within the insulin gene region, maintenance of synteny across vast evolutionary timescales points to a common and vital function for the insulin gene product, which is wholly consistent with the high degree of insulin protein conservation.

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