Species-specific alternative splice mimicry at the growth hormone receptorlocus revealed by the lineage of retroelements during primate evolution - A novel mechanism accounting for protein diversity between and within species

In humans, growth hormone receptor (GHR) transcripts exist in two isoforms differing by the retention (GHRfl) or exclusion (GHRd3) of exon 3, whereas in mice GHRfl is solely expressed. This species-specific expression pattern is believed to result from an alternative splice event that, on the basis of conflicting data obtained in humans, has been considered to be tissue-, developmentally, and/or individual-specific, To decipher the molecular basi s of this unusual trait, we isolated a 6.8-kilobase fragment spanning exon 3 from individuals expressing GHRfl. Sequence analysis revealed the existen ce of two 99% identical retroelements flanking this exon, Unexpectedly, ind ividuals expressing GHRd3 displayed a 2.7-kilobase deletion involving exon 3, which most likely results from an ancestral homologous recombination bet ween the two retroelements, The lineage of these retroelements during prima te evolution revealed the species specificity of the GHRd3 allele. These fi ndings led us to propose a model underlying the existence of the sole GHRfl allele in most species, Such a retrovirus-mediated alternative splice mimi cry, which clears up several as yet unexplained phenomena (i.e. the above-m entioned expression data, the Mendelian inheritance of GHR expression patte rns, and the deletion of nonconsecutive exons in growth hormone resistant p atients), represents a novel physiological mechanism accounting for protein diversity between and within species.