Allelic divergence in the human insulin gene provides evidence for intragenic recombination events in the non-coding regions: evidence for existence of new alleles.

Intragenic polymorphism of the human insulin gene (INS) was investigated in Korean subjects. The 1.9 kb INS sequence, including the 5' to 3' flanking regions, was amplified using the polymerase chain reaction (PCR), and analyzed by direct sequencing. All nucleotide sequences in the coding regions were the same as INS sequences previously reported, and four nucleotides, at positions +216, +1045, +1367, and +1380 in the non-coding regions, were found to be polymorphic. In addition to the previously identified polymorphic alleles alpha 1 (A-C-C-C) and beta 1 (T-G-T-A), new nucleotide arrangements were also identified and designated alpha 4 (A-C-C-A), alpha 5 (A-G-C-C), alpha 6 (A-C-T-C), and beta 2 (T-C-C-C). It was concluded that the new alleles may originate by intragenic recombination within INS during chromosomal crossing-over between the alpha 1 and beta 1 alleles. The allele alpha 1 was the predominant form in our sample; the new variant alleles, as well as allele beta 1, appeared to be much less frequent in INSs genes of the Korean subjects studied. Furthermore, the new alleles were detected only in heterozygous form. These results suggest that intragenic recombination can account for allelic divergence in INS.