title: Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution.
abstract: 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 basis of this unusual trait, we isolated a 6.8-kilobase fragment spanning exon 3 from individuals expressing GHRfl. Sequence analysis revealed the existence of two 99% identical retroelements flanking this exon. Unexpectedly, individuals expressing GHRd3 displayed a 2.7-kilobase deletion involving exon 3, which most likely results from an ancestral homologous recombination between the two retroelements. The lineage of these retroelements during primate evolution revealed the species specificity of the GHRd3 allele. These findings led us to propose a model underlying the existence of the sole GHRfl allele in most species. Such a retrovirus-mediated alternative splice mimicry, which clears up several as yet unexplained phenomena (i.e. the above-mentioned expression data, the Mendelian inheritance of GHR expression patterns, and the deletion of nonconsecutive exons in growth hormone resistant patients), represents a novel physiological mechanism accounting for protein diversity between and within species.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 468, Hôpital Henri Mondor, 94010 Créteil Cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Pantel
authors.forename: K
authors.initials: K
authors.lastname: Machinis
authors.forename: M L
authors.initials: ML
authors.lastname: Sobrier
authors.forename: P
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: S
authors.initials: S
authors.lastname: Amselem
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D005091:Exons; D006801:Humans; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010802:Phylogeny; D011323:Primates / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000235:genetics*; D018626:Retroelements; D012190:Retroviridae / Q000235:genetics; D013045:Species Specificity
chemical_list: D011986:Receptors, Somatotropin; D018626:Retroelements