Evidence for gene conversion in the generation of extensive polymorphism in the promoter of the growth hormone gene

Abstract

The human growth hormone gene (GH-N) is located in a cluster of five highly homologous genes that are coordinately expressed in pituitary (GH-N) and in placental tissues (the chorionic-somatomammotropin-like gene, the GH-variant gene and the two chorionic somatomammotropin genes). Sequence analysis from position –162 to position +100 of the GH-N gene has revealed eight nucleotide polymorphisms with no significant difference in frequency between patients affected by isolated growth hormone deficiency and controls. Remarkably, all these variations are located at positions where the GH-N differs from at least one of the other four homologous genes. The analysis of the twelve GH-N haplotypes originating from the combinations of the eight polymorphisms has revealed that not only single variations, but also nucleotide combinations are identical to those of the other placental genes. These findings suggest that whole stretches of the GH-N gene promoter have been replaced by homologous DNA stretches copied from one of the other four loci by repeated gene-conversion-like events, where the GH-N gene has acted as the recipient and the placental genes as donors of the converted sequences. The presence of a Chi-like element also indicates that the GH-N promoter represents a hot spot of gene conversion. Three of these variations cause, in addition, an amino-acid substitution in the GH-gene-derived transcriptional activator gene whose coding sequence overlaps the GH-N promoter. Thus, a DNA region that serves two distintic functions representing the proximal promoter of a gene and the 5′ coding region of another gene displays an unusually high degree of polymorphism that has probably arisen because of gene conversion.