Evolution of the Complex Growth Hormone Gene Cluster in Macaques

In higher primates, unlike other mammals, the GH gene locus is complex, comprising several GH-like genes, resulting from gene duplication and divergent evolution, expressed in pituitary and placenta. There are 5 genes in this GH gene cluster in human and 5 to 7 in apes and most Old-World monkeys, but in macaques the cluster has expanded further. Here the nature and evolution of the GH locus in this important primate genus is explored. Analysis of genomic data for Macaca fascicularis (crab-eating macaque) revealed that the GH gene cluster in this species is variable, with at least 5 different haplotypes, comprising 11 to 14 GH-like genes. Gene-number heterozygosity was also detected in Macaca mulatta (rhesus macaque) with 9 to 13 genes. Analysis of genomic data for other macaque species revealed GH gene clusters containing 8 to 14 GH-like genes, but gene-number heterozygosity was not detected. Expression of GH-like genes in pituitary and placenta was examined for Macaca fascicularis. This analysis has established that the complexity of the GH gene cluster increased during the evolution of macaques, by gene duplication and divergent evolution, and that these processes continue within at least 2 extant species. Analysis of rate of sequence change, and distribution of substitutions within the 3D structure, shows that for at least 1 GH-like gene (GH2), the changes reflect positive selection, implying adaptive biological change. Whether this involves changes in physiological (endocrine) function or response to viral or other pathogenic challenge is not yet clear.