Evolution of base composition in the insulin and insulin-like growth factor genes

The genomes of homeothermic (warm-blooded) vertebrates are mosaicinterspersions of homogeneously GC-rich and GC-poor regions (isochores).Evolution of genome compartmentalization and GC-rich isochores ishypothesized to reflect either selective advantages of an elevated GCcontent or chromosome location and mutational pressure associated with thetiming of DNA replication in germ cells. To address the present controversyregarding the origins and maintenance of isochores in homeothermicvertebrates, newly obtained as well as published nucleotide sequences ofthe insulin and insulin-like growth factor (IGF) genes, members of awell-characterized gene family believed to have evolved by repeatedduplication and divergence, were utilized to examine the evolution of basecomposition in nonconstrained (flanking) and weakly constrained (intronsand fourfold degenerate sites) regions. A phylogeny derived from amino acidsequences supports a common evolutionary history for the insulin/IGF familygenes. In cold- blooded vertebrates, insulin and the IGFs were similar inbase composition. In contrast, insulin and IGF-II demonstrate dramaticincreases in GC richness in mammals, but no such trend occurred in IGF- I.Base composition of the coding portions of the insulin and IGF genes acrossvertebrates correlated (r = 0.90) with that of the introns and flankingregions. The GC content of homologous introns differed dramatically betweeninsulin/IGF-II and IGF-I genes in mammals but was similar to the GC levelof noncoding regions in neighboring genes. Our findings suggest that thebase composition of introns and flanking regions is determined bychromosomal location and the mutational pressure of the isochore in whichthe sequences are embedded. An elevated GC content at codon third positionsin the insulin and the IGF genes may reflect selective constraints on theusage of synonymous codons.