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. 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. growth hormone receptor full-length GHR GHR with exon 3 deleted human endogenous retrovirus long terminal repeat medium reiteration frequency sequence kilobase(s) polymerase chain reaction inverse PCR base pair(s) There is a variety of well documented mechanisms underlying the complexity and the diversity of the structure and regulation of eukaryotic nuclear genes during evolution. Several of these mechanisms result from the presence of repetitive DNA sequences that form a substantial fraction of these genomes (1.Charlesworth B. Sniegowski P. Stephan W. Nature. 1994; 371: 215-220Crossref PubMed Scopus (1257) Google Scholar), as well as from the existence, in the great majority of genes coding for proteins, of exonic and intronic sequences (2.Berget S.M. J. Biol. Chem. 1995; 270: 2411-2414Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar). Such a genomic organization accounts for several kinds of DNA rearrangements (1.Charlesworth B. Sniegowski P. Stephan W. Nature. 1994; 371: 215-220Crossref PubMed Scopus (1257) Google Scholar, 3.Kazazian Jr., H.H. Moran J.V. Nat. Genet. 1998; 19: 19-24Crossref PubMed Scopus (390) Google Scholar) and for mRNA splicing (4.Lopez A.J. Annu. Rev. Genet. 1998; 32: 279-305Crossref PubMed Scopus (534) Google Scholar). The latter corresponds to the precise excision of introns from nascent transcripts followed by the ligation of exons. Alternative splicing of primary transcripts represents a critical step in the regulation of gene expression, generating different mature mRNAs and thus different proteins from one gene (5.Maniatis T. Science. 1991; 251: 33-34Crossref PubMed Scopus (163) Google Scholar). This mechanism can be controlled in a cell type-specific manner, so that, depending on the nature and/or the developmental stages of the tissues examined, different mature mRNA species can be expressed; other alternative splice events appear to be constitutive, with different mRNA isoforms coexisting at constant ratios within the same cells (4.Lopez A.J. Annu. Rev. Genet. 1998; 32: 279-305Crossref PubMed Scopus (534) Google Scholar).The description of two different mature growth hormone receptor (GHR)1 transcripts is a particularly attractive example of an unusual phenomenon described as the result of an alternative splice event that, in humans, has been documented as being either constitutive or controlled in a cell type-specific manner (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar, J. 1994; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar, J. Google Scholar, PubMed Scopus Google Scholar). The GHR protein is an cell that, in humans, a of of an of a and a of D.W. Nature. PubMed Scopus Google Scholar). to the growth the GHR can form Science. PubMed Scopus Google Scholar) that to receptor B. J. Science. PubMed Scopus Google Scholar, P. B. J. 1994; PubMed Scopus Google Scholar), the well of growth The critical of the receptor in the of growth by the description of GHR in with a growth as an P. B. Full Text PDF PubMed Scopus Google Scholar).The human GHR gene is a gene that of the (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar, Genet. PubMed Scopus Google Scholar). coding exons and several exon for the exons the exon the and exons and the (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar). The existence of several GHR that within the coding by (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar). In one of these the exon 3 sequence of in with an alternative splice event to either the retention or the exclusion of exon 3, to the full-length GHR (GHRfl) or the exon isoforms been in several human either or In the a expression pattern of GHRfl and GHRd3 documented PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar), with GHRd3 in the PubMed Scopus Google Scholar). other that the expression of these two GHR isoforms for different tissues obtained from the same the same expression pattern J. 1995; PubMed Google Scholar, J. Google Scholar). This expression pattern of GHRfl and GHRd3 to be in long of J. Google Scholar). a of a of human and tissues that the expression pattern of GHRfl and GHRd3 be J. Google Scholar). that this alternative splice event from an unusual that is as a Mendelian and that splicing PubMed Scopus Google Scholar). the splicing of exon 3, P. B. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar), to be in mice the GHRfl is the PubMed Scopus Google decipher the molecular basis of this unusual in humans, the GHR genomic sequences exon 3 in individuals expressing or In in an to an for species in the expression of GHRd3 and in described a molecular mechanism to for the physiological expression, in humans, of two transcripts that by the of a coding exon. This which alternative results from a homologous recombination event between sequences that the exon. To of this been in this on the analysis of the GHR the species specificity of these retroelements most likely accounts for the documented species in the expression pattern of GHR is well that in GHR transcripts in two isoforms that by the retention or exclusion of exon 3, whereas in mice the GHRfl is solely expressed. that in the GHRd3 is from a GHR allele that a genomic deletion spanning exon 3, as with GHR expressing GHRfl we the of exon 3 with two flanking retroelements in the genomic DNA from individuals solely whereas DNA from individuals GHRd3 a exon These led us to that the documented between the GHRd3 and GHRfl is to a deletion that on an ancestral GHRfl allele. in the model in an recombination event most likely accounts for the of a GHRd3 allele from a GHRfl recombination between GHRfl as the basis for the exon 3 an event a with an exon 3 this gene been in the Sequence analysis of deleted the existence of a recombination within the of the In this the excision of exon 3 and flanking sequences results from a homologous recombination event between the two retroelements on the same GHRfl of an alternative splice clears up several as yet unexplained depending on the different in PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar, J. 1994; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar, J. Google Scholar, PubMed Scopus Google Scholar), the expression pattern of GHRfl and GHRd3 has been considered to be tissue-, developmentally, and/or in the of the mechanism underlying GHRfl and GHRd3 expression, conflicting results results a for the Mendelian of inheritance of GHRfl and GHRd3 expression PubMed Scopus Google Scholar). these findings a for the deletion of nonconsecutive exons involving exons 3, and in with (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google in the latter be the of a deletion of the exons and on a GHRd3 allele. the of exon 3 in DNA from human tissues expressing the GHRd3 transcripts J. Google Scholar, PubMed Scopus Google Scholar) to be with the of a genomic deletion of this exon in of the GHR of the to which other species to GHRd3 transcripts by of a mechanism identical to that in humans, we the presence of these sequences at the 3 from species from to the same at the GHR from exon 3, we that this sequence from a that in the of a of the in and this we to this thus PubMed Scopus Google Scholar, J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). the of exon 3 in the human species (i.e. the is at the same in and the of this event that the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). Several of the that the repeat from the repeat by of a these homologous sequences identical and In is the repeat of a fragment of the a of the sequence to the repeat that, by is of the of sequence between the and within species of the is with the of the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). is that the of the a sequence that is in the GHR gene of primate species so is to that this which is of exon 3 at a to the of the the of the of GHRd3 in the human species led to the of a that is identical to the repeat on GHRfl this which the of is with a homologous recombination event that during primate evolution. these data with the existence of the sole GHRfl allele in primate species the species of the and one the that in and GHRd3 by of a homologous recombination this be by the analysis of DNA from a of and model that accounts for this sequence of events during molecular evolution of the GHR is in The events to the and sequences to the from exon 3, which the of In this the latter event is followed by the of a a homologous recombination event between the and of the the of the within the of exon 3, the and and the homologous recombination between the two which at in the human and led to the GHRd3 allele. The GHR gene in species from and P. Scholar). In the GHRfl is the PubMed Scopus Google Scholar), and genomic DNA to as by PubMed Scopus Google Scholar, and data this latter molecular model a of these sequences of in the of GHRd3 Such a species-specific GHR which the existence of the sole GHRfl allele in several to the of the mechanisms by which the GHR gene to a growth protein P. B. PubMed Scopus Google P. 1998; PubMed Scopus Google Scholar), this gene a particularly model to isoforms of the model accounting for the structure of the 3 in primate species. 3 is by a the and sequences and The is in with an of in genomes as with gene expression the sequence an exon Jr., H.H. Nature. PubMed Scopus Google Scholar), whereas believed that or on gene This has been by the of sequences of that with a PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or that a of mRNA splicing J. 1995; PubMed Scopus Google Scholar, Moran J.P. 1994; PubMed Scopus Google Scholar). In with these the the existence of a retrovirus-mediated mechanism underlying the physiological expression, in humans, of two transcripts that by the of a coding exon. This as yet which alternative splicing and accounts for protein diversity between and within one of the mechanisms underlying the expression of isoforms at other There is a variety of well documented mechanisms underlying the complexity and the diversity of the structure and regulation of eukaryotic nuclear genes during evolution. Several of these mechanisms result from the presence of repetitive DNA sequences that form a substantial fraction of these genomes (1.Charlesworth B. Sniegowski P. Stephan W. Nature. 1994; 371: 215-220Crossref PubMed Scopus (1257) Google Scholar), as well as from the existence, in the great majority of genes coding for proteins, of exonic and intronic sequences (2.Berget S.M. J. Biol. Chem. 1995; 270: 2411-2414Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar). Such a genomic organization accounts for several kinds of DNA rearrangements (1.Charlesworth B. Sniegowski P. Stephan W. Nature. 1994; 371: 215-220Crossref PubMed Scopus (1257) Google Scholar, 3.Kazazian Jr., H.H. Moran J.V. Nat. Genet. 1998; 19: 19-24Crossref PubMed Scopus (390) Google Scholar) and for mRNA splicing (4.Lopez A.J. Annu. Rev. Genet. 1998; 32: 279-305Crossref PubMed Scopus (534) Google Scholar). The latter corresponds to the precise excision of introns from nascent transcripts followed by the ligation of exons. Alternative splicing of primary transcripts represents a critical step in the regulation of gene expression, generating different mature mRNAs and thus different proteins from one gene (5.Maniatis T. Science. 1991; 251: 33-34Crossref PubMed Scopus (163) Google Scholar). This mechanism can be controlled in a cell type-specific manner, so that, depending on the nature and/or the developmental stages of the tissues examined, different mature mRNA species can be expressed; other alternative splice events appear to be constitutive, with different mRNA isoforms coexisting at constant ratios within the same cells (4.Lopez A.J. Annu. Rev. Genet. 1998; 32: 279-305Crossref PubMed Scopus (534) Google Scholar). The description of two different mature growth hormone receptor (GHR)1 transcripts is a particularly attractive example of an unusual phenomenon described as the result of an alternative splice event that, in humans, has been documented as being either constitutive or controlled in a cell type-specific manner (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar, J. 1994; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar, J. Google Scholar, PubMed Scopus Google Scholar). The GHR protein is an cell that, in humans, a of of an of a and a of D.W. Nature. PubMed Scopus Google Scholar). to the growth the GHR can form Science. PubMed Scopus Google Scholar) that to receptor B. J. Science. PubMed Scopus Google Scholar, P. B. J. 1994; PubMed Scopus Google Scholar), the well of growth The critical of the receptor in the of growth by the description of GHR in with a growth as an P. B. Full Text PDF PubMed Scopus Google Scholar). The human GHR gene is a gene that of the (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar, Genet. PubMed Scopus Google Scholar). coding exons and several exon for the exons the exon the and exons and the (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar). The existence of several GHR that within the coding by (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google Scholar). In one of these the exon 3 sequence of in with an alternative splice event to either the retention or the exclusion of exon 3, to the full-length GHR (GHRfl) or the exon isoforms been in several human either or In the a expression pattern of GHRfl and GHRd3 documented PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar), with GHRd3 in the PubMed Scopus Google Scholar). other that the expression of these two GHR isoforms for different tissues obtained from the same the same expression pattern J. 1995; PubMed Google Scholar, J. Google Scholar). This expression pattern of GHRfl and GHRd3 to be in long of J. Google Scholar). a of a of human and tissues that the expression pattern of GHRfl and GHRd3 be J. Google Scholar). that this alternative splice event from an unusual that is as a Mendelian and that splicing PubMed Scopus Google Scholar). the splicing of exon 3, P. B. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar), to be in mice the GHRfl is the PubMed Scopus Google Scholar). To decipher the molecular basis of this unusual in humans, the GHR genomic sequences exon 3 in individuals expressing or In in an to an for species in the expression of GHRd3 and in species. described a molecular mechanism to for the physiological expression, in humans, of two transcripts that by the of a coding exon. This which alternative results from a homologous recombination event between sequences that the exon. To of this been in this on the analysis of the GHR the species specificity of these retroelements most likely accounts for the documented species in the expression pattern of GHR is well that in GHR transcripts in two isoforms that by the retention or exclusion of exon 3, whereas in mice the GHRfl is solely expressed. that in the GHRd3 is from a GHR allele that a genomic deletion spanning exon 3, as with GHR expressing GHRfl we the of exon 3 with two flanking retroelements in the genomic DNA from individuals solely whereas DNA from individuals GHRd3 a exon These led us to that the documented between the GHRd3 and GHRfl is to a deletion that on an ancestral GHRfl allele. in the model in an recombination event most likely accounts for the of a GHRd3 allele from a GHRfl recombination between GHRfl as the basis for the exon 3 an event a with an exon 3 this gene been in the Sequence analysis of deleted the existence of a recombination within the of the In this the excision of exon 3 and flanking sequences results from a homologous recombination event between the two retroelements on the same GHRfl of an alternative splice clears up several as yet unexplained depending on the different in PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar, J. 1994; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar, J. Google Scholar, PubMed Scopus Google Scholar), the expression pattern of GHRfl and GHRd3 has been considered to be tissue-, developmentally, and/or in the of the mechanism underlying GHRfl and GHRd3 expression, conflicting results results a for the Mendelian of inheritance of GHRfl and GHRd3 expression PubMed Scopus Google Scholar). these findings a for the deletion of nonconsecutive exons involving exons 3, and in with (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google in the latter be the of a deletion of the exons and on a GHRd3 allele. the of exon 3 in DNA from human tissues expressing the GHRd3 transcripts J. Google Scholar, PubMed Scopus Google Scholar) to be with the of a genomic deletion of this exon in of the GHR of the to which other species to GHRd3 transcripts by of a mechanism identical to that in humans, we the presence of these sequences at the 3 from species from to the same at the GHR from exon 3, we that this sequence from a that in the of a of the in and this we to this thus PubMed Scopus Google Scholar, J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). the of exon 3 in the human species (i.e. the is at the same in and the of this event that the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). Several of the that the repeat from the repeat by of a these homologous sequences identical and In is the repeat of a fragment of the a of the sequence to the repeat that, by is of the of sequence between the and within species of the is with the of the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). is that the of the a sequence that is in the GHR gene of primate species so is to that this which is of exon 3 at a to the of the the of the of GHRd3 in the human species led to the of a that is identical to the repeat on GHRfl this which the of is with a homologous recombination event that during primate evolution. these data with the existence of the sole GHRfl allele in primate species the species of the and one the that in and GHRd3 by of a homologous recombination this be by the analysis of DNA from a of and model that accounts for this sequence of events during molecular evolution of the GHR is in The events to the and sequences to the from exon 3, which the of In this the latter event is followed by the of a a homologous recombination event between the and of the the of the within the of exon 3, the and and the homologous recombination between the two which at in the human and led to the GHRd3 allele. The GHR gene in species from and P. Scholar). In the GHRfl is the PubMed Scopus Google Scholar), and genomic DNA to as by PubMed Scopus Google Scholar, and data this latter molecular model a of these sequences of in the of GHRd3 Such a species-specific GHR which the existence of the sole GHRfl allele in several to the of the mechanisms by which the GHR gene to a growth protein P. B. PubMed Scopus Google P. 1998; PubMed Scopus Google Scholar), this gene a particularly model to isoforms of in genomes as with gene expression the sequence an exon Jr., H.H. Nature. PubMed Scopus Google Scholar), whereas believed that or on gene This has been by the of sequences of that with a PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or that a of mRNA splicing J. 1995; PubMed Scopus Google Scholar, Moran J.P. 1994; PubMed Scopus Google Scholar). In with these the the existence of a retrovirus-mediated mechanism underlying the physiological expression, in humans, of two transcripts that by the of a coding exon. This as yet which alternative splicing and accounts for protein diversity between and within one of the mechanisms underlying the expression of isoforms at other described a molecular mechanism to for the physiological expression, in humans, of two transcripts that by the of a coding exon. This which alternative results from a homologous recombination event between sequences that the exon. To of this been in this on the analysis of the GHR the species specificity of these retroelements most likely accounts for the documented species in the expression pattern of GHR is well that in GHR transcripts in two isoforms that by the retention or exclusion of exon 3, whereas in mice the GHRfl is solely expressed. that in the GHRd3 is from a GHR allele that a genomic deletion spanning exon 3, as with GHR expressing GHRfl we the of exon 3 with two flanking retroelements in the genomic DNA from individuals solely whereas DNA from individuals GHRd3 a exon These led us to that the documented between the GHRd3 and GHRfl is to a deletion that on an ancestral GHRfl allele. in the model in an recombination event most likely accounts for the of a GHRd3 allele from a GHRfl recombination between GHRfl as the basis for the exon 3 an event a with an exon 3 this gene been in the Sequence analysis of deleted the existence of a recombination within the of the In this the excision of exon 3 and flanking sequences results from a homologous recombination event between the two retroelements on the same GHRfl allele. The of an alternative splice clears up several as yet unexplained depending on the different in PubMed Scopus Google Scholar, P. B. PubMed Scopus Google Scholar, J. 1994; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar, J. Google Scholar, PubMed Scopus Google Scholar), the expression pattern of GHRfl and GHRd3 has been considered to be tissue-, developmentally, and/or in the of the mechanism underlying GHRfl and GHRd3 expression, conflicting results results a for the Mendelian of inheritance of GHRfl and GHRd3 expression PubMed Scopus Google Scholar). these findings a for the deletion of nonconsecutive exons involving exons 3, and in with (6.Godowski P.J. Leung D.W. Meacham L.R. Galgani J.P. Hellmiss PubMed Scopus Google in the latter be the of a deletion of the exons and on a GHRd3 allele. the of exon 3 in DNA from human tissues expressing the GHRd3 transcripts J. Google Scholar, PubMed Scopus Google Scholar) to be with the of a genomic deletion of this exon in of the GHR of To the to which other species to GHRd3 transcripts by of a mechanism identical to that in humans, we the presence of these sequences at the 3 from species from to the same at the GHR from exon 3, we that this sequence from a that in the of a of the in and this we to this thus PubMed Scopus Google Scholar, J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). the of exon 3 in the human species (i.e. the is at the same in and the of this event that the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). Several of the that the repeat from the repeat by of a these homologous sequences identical and In is the repeat of a fragment of the a of the sequence to the repeat that, by is of the of sequence between the and within species of the is with the of the of and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). is that the of the a sequence that is in the GHR gene of primate species so is to that this which is of exon 3 at a to the of the the of the of GHRd3 in the human species led to the of a that is identical to the repeat on GHRfl this which the of is with a homologous recombination event that during primate evolution. these data with the existence of the sole GHRfl allele in primate species the species of the and one the that in and GHRd3 by of a homologous recombination this be by the analysis of DNA from a of and model that accounts for this sequence of events during molecular evolution of the GHR is in The events to the and sequences to the from exon 3, which the of In this the latter event is followed by the of a a homologous recombination event between the and of the the of the within the of exon 3, the and and the homologous recombination between the two which at in the human and led to the GHRd3 allele. The GHR gene in species from and P. Scholar). In the GHRfl is the PubMed Scopus Google Scholar), and genomic DNA to as by PubMed Scopus Google Scholar, and data this latter molecular model a of these sequences of in the of GHRd3 Such a species-specific GHR which the existence of the sole GHRfl allele in several to the of the mechanisms by which the GHR gene to a growth protein P. B. PubMed Scopus Google P. 1998; PubMed Scopus Google Scholar), this gene a particularly model to isoforms evolution. The of in genomes as with gene expression the sequence an exon Jr., H.H. Nature. PubMed Scopus Google Scholar), whereas believed that or on gene This has been by the of sequences of that with a PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or that a of mRNA splicing J. 1995; PubMed Scopus Google Scholar, Moran J.P. 1994; PubMed Scopus Google Scholar). In with these the the existence of a retrovirus-mediated mechanism underlying the physiological expression, in humans, of two transcripts that by the of a coding exon. This as yet which alternative splicing and accounts for protein diversity between and within one of the mechanisms underlying the expression of isoforms at other and for several DNA