RESUMO
The molecular evolution of pituitary growth hormone and prolactin in mammals shows two unusual features: episodes of markedly accelerated evolution and, in some species, complex families of related proteins expressed in placenta and resulting from multiple gene duplications. Explanations of these phenomena in terms of physiological adaptations seem unconvincing. Here, I propose an alternative explanation, namely that these evolutionary features reflect the use of the hormones (and their receptors) as viral receptors. Episodes of rapid evolution can then be explained as due to "arms races" in which changes in the hormone lead to reduced interaction with the virus, and subsequent changes in the virus counteract this. Placental paralogues of the hormones could provide decoys that bind viruses, and protect the foetus against infection. The hypothesis implies that the extensive changes introduced into growth hormone, prolactin and their receptors during the course of mammalian evolution reflect viral interactions, not endocrine adaptations.
Assuntos
Lactogênio Placentário , Vírus , Animais , Feminino , Hormônio do Crescimento/genética , Placenta , Lactogênio Placentário/genética , Gravidez , Prolactina/genéticaRESUMO
The POU1F1 (Pit-1) transcription factor is important in regulating expression of growth hormone, prolactin and TSH ß-subunit, and controlling development of the anterior pituitary cells in which these hormones are produced. POU1F1 is a conserved protein comprising three main domains, an N-terminal transcription activation domain (TAD), a POU-specific domain and a C-terminal homeodomain. Within the TAD, a ß-domain can be inserted by alternative splicing, giving an extended 'ß-variant' with altered properties. Here sequence data from over 100 species were used to assess the variability of POU1F1 in mammals. This showed that the POU-specific domain and homeodomain are very strongly conserved, and that the TAD is somewhat less conserved, as are linker and hinge regions between these main domains. On the other hand, the ß-domain is very variable, apparently evolving at a rate not significantly different from that expected for unconstrained, neutral evolution. In several species stop and/or frameshift mutations within the ß-domain would prevent expression of the ß-variant as a functional protein. In most species expression of the ß-variant is low (<5% of total POU1F1 expression). The rate of evolution of POU1F1 in mammals shows little variation, though the lineage leading to dog does show an episode of accelerated change. This comparative genomics study suggests that in most mammalian species POU1F1 variants produced by alternative splicing may have little physiological significance.
Assuntos
Processamento Alternativo/genética , Evolução Molecular , Mamíferos/genética , Fator de Transcrição Pit-1/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Cães , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Humanos , Mamíferos/metabolismo , Filogenia , Prolactina/genética , Prolactina/metabolismo , Ligação Proteica , Domínios Proteicos/genética , Alinhamento de Sequência , Tireotropina Subunidade beta/genética , Tireotropina Subunidade beta/metabolismo , Fator de Transcrição Pit-1/química , Fator de Transcrição Pit-1/metabolismoRESUMO
Pituitary prolactin (PRL) shows an episodic pattern of evolution in mammals, with a slow underlying rate (near stasis) and periods of rapid change in some groups. PRL evolution in bats, the second most speciose mammalian order, has not previously been studied, and is examined here. Slow basal evolution of PRL is seen in some bats, particularly megabats, but in most microbat groups evolution of PRL is more rapid. Accelerated evolution of PRL is particularly notable in the family Vespertilionidae, where analysis of nonsynonymous and synonymous substitutions indicates that it reflects adaptive evolution/positive selection. Remarkably, vespertilionid bats also show a large sequence insertion, of variable length, into exon 4 of PRL, giving a protein sequence 18-60 amino acids longer than normal, with the longest insertions in bats of the genus Myotis. An equivalent insertion has not been reported in PRL of any other vertebrate group. In the 3-dimensional structure of the complex between PRL and the extracellular domain (ecd) of its receptor (PRL:PRLR2) the inserted sequence is seen to be introduced in the short loop between helices 2 and 3 of PRL; it is far removed from the receptor-binding sites, and may not interfere with binding. The ecd of the receptor also shows variable rates of evolution, with a higher rate in the Vespertilionidae, but this is much less marked than for the hormone. The distribution of substitutions introduced into PRL during vespertilionid evolution appears to be non-random, and this and the evidence for positive selection suggests that the rapid evolution and insert sequence introduction were associated with a significant change in the biological properties of the hormone.
Assuntos
Quirópteros/genética , Evolução Molecular , Mutagênese Insercional/genética , Prolactina/genética , Sequência de Aminoácidos , Animais , Modelos Moleculares , Filogenia , Prolactina/química , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Transcrição GênicaRESUMO
In primates, the unigenic growth hormone (GH) locus of prosimians expressed primarily in the anterior pituitary, evolved by gene duplications, independently in New World Monkeys (NWM) and Old World Monkeys (OWMs)/apes, to give complex clusters of genes expressed in the pituitary and placenta. In human and chimpanzee, the GH locus comprises five genes, GH-N being expressed as pituitary GH, whereas GH-V (placental GH) and CSHs (chorionic somatomammotropins) are expressed (in human and probably chimpanzee) in the placenta; the CSHs comprise CSH-A, CSH-B and the aberrant CSH-L (possibly a pseudogene) in human, and CSH-A1, CSH-A2 and CSH-B in chimpanzee. Here, the GH locus in two additional great apes, gorilla (Gorilla gorilla gorilla) and orangutan (Pongo abelii), is shown to contain six and four GH-like genes, respectively. The gorilla locus possesses six potentially expressed genes, gGH-N, gGH-V and four gCSHs, whereas the orangutan locus has just three functional genes, oGH-N, oGH-V and oCSH-B, plus a pseudogene, oCSH-L. Analysis of regulatory sequences, including promoter, enhancer and P-elements, shows significant variation; in particular the proximal Pit-1 element of GH-V genes differs markedly from that of other genes in the cluster. Phylogenetic analysis shows that the initial gene duplication led to distinct GH-like and CSH-like genes and that a second duplication provided separate GH-N and GH-V. However, evolution of the CSH-like genes remains unclear. Rapid adaptive evolution gave rise to the distinct CSHs, after the first duplication, and to GH-V after the second duplication. Analysis of transcriptomic databases derived from gorilla tissues establishes that the gGH-N, gGH-V and several gCSH genes are expressed, but the significance of the many CSH genes in gorilla remains unclear.
Assuntos
Gorilla gorilla/genética , Hormônio do Crescimento/genética , Pongo/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Evolução Molecular , Conversão Gênica , Duplicação Gênica , Expressão Gênica , Loci Gênicos , Hormônio do Crescimento/metabolismo , Humanos , Masculino , Filogenia , Hipófise/metabolismo , Regiões Promotoras Genéticas , Pseudogenes , Análise de Sequência de DNARESUMO
Precise spatio-temporal expression of genes in organogenesis is regulated by the coordinated interplay of DNA elements such as promoter and enhancers present in the regulatory region of a given locus. POU1F1 transcription factor plays a crucial role in the development of somatotrophs, lactotrophs and thyrotrophs in the anterior pituitary gland, and in maintaining high expression of growth hormone, prolactin and TSH. In mouse, expression of POU1F1 is controlled by a region fenced by two CTCF sites, containing 5 upstream enhancer elements, designated E-A (5' to 3'). Elements C, B and A correspond to elements shown previously to play a role in pituitary development and hormonal expression; functional roles for elements E and D have not been reported. We performed comparative sequence analysis of this regulatory region and discovered that three elements, B, C and E, are present in all vertebrate groups except Agnatha. One very long (>2 kb) element (A) is unique to mammals suggesting a specific change in regulation of the gene in this group. Using DNA accessibility assay (ATAC-seq) we showed that conserved elements in anterior pituitary of four non-mammals are open, suggesting functionality as regulatory elements. We showed that, in many non-mammalian vertebrates, an additional upstream exon closely follows element E, leading to alternatively spliced transcripts. Here, element E functions as an alternative promoter, but in mammals this feature is lost, suggesting conversion of alternative promoter to enhancer. Our work shows that regulation of POU1F1 changed markedly during the course of vertebrate evolution, use of a low number of enhancer elements combined with alternative promoters in non-mammalian vertebrates being replaced by use of a unique combination of regulatory units in mammals. Most importantly, our work suggests that evolutionary conversion of alternate promoter to enhancer could be one of the evolutionary mechanisms of enhancer birth.
RESUMO
In most mammals the growth hormone (GH) locus comprises a single gene expressed primarily in the anterior pituitary gland. However, in higher primates multiple duplications of the GH gene gave rise to a complex locus containing several genes. In man this locus comprises five genes, including GH-N (expressed in pituitary) and four genes expressed in the placenta, but in other species the number and organization of these genes vary. The situation in chimpanzee has been unclear, with suggestions of up to seven GH-like genes. We have re-examined the GH locus in chimpanzee and have deduced the complete sequence. The locus includes five genes apparently organized in a fashion similar to that in human, with two of these genes encoding GH-like proteins, and three encoding chorionic somatomammotropins/placental lactogens (CSHs/PLs). There are notable differences between the human and chimpanzee loci with regard to the expressed proteins, gene regulation, and gene conversion events. In particular, one human gene (hCSH-L) has changed substantially since the chimpanzee/human split, potentially becoming a pseudogene, while the corresponding chimpanzee gene (CSH-A1) has been conserved, giving a product almost identical to the adjacent CSH-A2. Chimpanzee appears to produce two CSHs, with potentially differing biological properties, whereas human produces a single CSH. The pattern of gene conversion in human has been quite different from that in chimpanzee. The region around the GH-N gene in chimpanzee is remarkably polymorphic, unlike the corresponding region in human. The results shed new light on the complex evolution of the GH locus in higher primates.
Assuntos
Evolução Molecular , Hormônio do Crescimento/genética , Pan troglodytes/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Loci Gênicos , Hormônio do Crescimento/química , Hormônio do Crescimento Humano/genética , Humanos , Masculino , Dados de Sequência Molecular , Família Multigênica , Filogenia , Primatas/classificação , Primatas/genética , Alinhamento de SequênciaRESUMO
Among vertebrates the neurohypophysial hormones show considerable variation. However, in eutherian mammals they have been considered rather conserved, with arginine vasopressin (AVP) and oxytocin (OT) in all species except pig and some relatives, where lysine vasopressin replaces AVP. The availability of genomic data for a wide range of mammals makes it possible to assess whether these peptides and their precursors may be more variable in Eutheria than previously suspected. A survey of these data confirms that AVP and OT occur in most eutherians, but with exceptions. In a New-World monkey (marmoset, Callithrix jacchus) and in tree shrew (Tupaia belangeri), Pro(8)OT replaces OT, confirming a recent report for these species. In armadillo (Dasypus novemcinctus) Leu(3)OT replaces OT, while in tenrec (Echinops telfairi) Thr(4)AVP replaces AVP. In these two species there is also evidence for additional genes/pseudogenes, encoding much-modified forms of AVP, but in most other eutherian species there is no evidence for additional neurohypophysial hormone genes. Evolutionary analysis shows that sequences of eutherian neurohypophysial hormone precursors are generally strongly conserved, particularly those regions encoding active peptide and neurophysin. The close association between OT and VP genes has led to frequent gene conversion of sequences encoding neurophysins. A monotreme, platypus (Ornithorhynchus anatinus) has genes for OT and AVP, organized tail-to-tail as in eutherians, but in marsupials 3-4 genes are present for neurohypophysial hormones, organized tail-to-head as in lower vertebrates.
Assuntos
Evolução Molecular , Mamíferos/genética , Ocitocina/genética , Hormônios Neuro-Hipofisários/genética , Precursores de Proteínas/genética , Vasopressinas/genética , Sequência de Aminoácidos , Animais , Tatus/genética , Callithrix/genética , Eulipotyphla/genética , Conversão Gênica , Marsupiais/genética , Filogenia , Alinhamento de Sequência , Tupaiidae/genéticaRESUMO
In mammals, the large IGF-I gene comprises 6 exons, which are subject to alternative splicing. All transcripts contain exons 3 and 4, encoding mature IGF-I, but the other exons are included in various combinations, giving at least 6 possible mature mRNAs. At the 5' end, exons 1 and 2 are spliced alternatively to exon 3, giving different leader/signal sequences. It is shown in this study that in human an additional exon (designated exon 0) is present, upstream of exon 1. This can be spliced directly to exon 3 or, less frequently, into exon 1. Exon 0 is utilized in liver, in about 24% of IGF-I transcripts, to a minor extent in prostate and endometrium (<1% of transcripts), but not in any of 29 other normal human tissues examined. The exon 0 sequence includes an in-frame ATG/AUG, potentially providing a translation start point giving an IGF-I precursor with a very long signal peptide. However, this ATG is very close to the 5' end, and may not be included in all transcripts; an in-frame ATG in exon 3 could provide an alternative start point. Utilization of exon 0 was detected in other apes, and to a small extent in Old World monkeys, but not in New World monkeys, prosimians or various non-primate mammals. Exon 0 was not expressed in most human tumours, but was utilized in many prostate tumours, at levels much greater than seen in normal prostate, and in liver tumours, at a lower level than in normal liver.
Assuntos
Processamento Alternativo , Éxons/genética , Fator de Crescimento Insulin-Like I/genética , Fígado/metabolismo , Neoplasias/genética , Primatas/genética , RNA Mensageiro/genética , Animais , HumanosRESUMO
Divergence of proteins in signaling pathways requires ligand and receptor coevolution to maintain or improve binding affinity and/or specificity. In this paper we show a clear case of coevolution between the prolactin (PRL) gene and its receptor (prolactin receptor, PRLR) in mammals. First we observed episodic evolution of the extracellular and intracellular domains of the PRLR, which is closely consistent with that seen in PRL. Correlated evolution was demonstrated both between PRL and its receptor and between the two domains of the PRLR using Pearson's correlation coefficient. On comparing the ratio of the nonsynonymous substitution rate to synonymous substitution rate (omega = d(N)/d(S)) for each branch of the star phylogeny of mammalian PRLRs, separately for the extracellular domain (ECD) and the transmembrane domain/intracellular domain (TMD/ICD), we observed a lower omega ratio for ECD than TMD/ICD along those branches leading to pig, dog and rabbit but a higher ratio for ECD than TMD/ICD on the branches leading to primates, rodents and ruminants, on which bursts of rapid evolution were observed. These observations can be best explained by coevolution between PRL and its receptor and between the two domains of the PRLR.
Assuntos
Evolução Molecular , Mamíferos/genética , Prolactina/genética , Receptores da Prolactina/genética , Sequência de Aminoácidos , Animais , Humanos , Ligantes , Dados de Sequência Molecular , Filogenia , Seleção Genética , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Previous work has shown that the evolution of both insulin-like growth factor 1 (IGF1) and insulin shows an episode of accelerated change on the branch leading to New World Monkeys (NWM). Here the possibility that this is accompanied by a corresponding episode of accelerated evolution of IGF1 receptor (IGF1R), insulin receptor (IR) and/or IGF binding proteins (IGFBPs) was investigated. Analysis of receptor sequences from a range of primates and some non-primate mammals showed that accelerated evolution did indeed occur on this branch in the case of IGF1R and IR, but not for the similar insulin receptor-related receptor (IRRR) which does not bind insulin or IGF1. Marked accelerated evolution on this branch was also seen for some IGFBPs, but not the mannose 6-phosphate/IGF2 receptor or epidermal growth factor receptor. The rate of evolution slowed before divergence of the lineages leading to the NWM for which sequences are available (Callithrix and Saimiri). For the IGF1R and IR, the accelerated evolution was most marked for the extracellular domains (ectodomains). Application of the branch-site method showed dN/dS ratios significantly greater than 1.0 for both receptor ectodomains and for IGFBP1, and allowed identification of residues likely to have been subject to selection. These residues were concentrated in the N-terminal half of the IGF1R ectodomain but the C-terminal half of the IR ectodomain, which could have implications for the formation of hybrid receptors. Overall the results suggest that adaptive coevolution of IGF1, insulin and their receptors and some IGFBPs occurred during the evolution of NWM. For the most part, the residues that change on this branch could not be associated with specific functional aspects (ligand binding, receptor dimerization, glycosylation) and the physiological significance of this coevolution remains to be established.
Assuntos
Callithrix/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Insulina/genética , Receptor de Insulina/genética , Receptores de Somatomedina/genética , Saimiri/genética , Somatomedinas/genética , Animais , Evolução Molecular , Platirrinos/genéticaRESUMO
Pregnancy is a complex physiological condition, and the growth hormone (GH)-related hormones produced in the placenta, which emerged during the evolution of primates, are thought to play an important metabolic role in pregnancy that is not yet fully understood. The aim of this study was to identify the genes and transcription products of the GH family in baboon (Papio hamadryas) and to assess these in relation to the evolution of this gene family. GH-related transcripts were amplified using total RNA from placental tissue, by reverse transcription coupled to polymerase chain reaction (RT-PCR). Three different GH-related transcripts were identified in baboon placental tissue, with two encoding chorionic somatomammotropins (CSH) and one the placental variant of GH (GH-2). The CSH transcripts showed some minor allelic variation, and a splice variant of CSH-C that retains its in-frame third intron. Gene sequences for GH-1 (probably representing the GH gene expressed primarily in the pituitary gland), GH-2 and the two CSHs were identified in the baboon genomic database, together with a CSH-related pseudogene. Phylogenetic analysis of the baboon GH-related sequences, together with those of a related Old World monkey, macaque, and ape outgroup (human), showed the equivalence of the genes in baboon and macaque, and revealed evidence for several episodes of rapid adaptive evolution. Many of the substitutions seen during the evolution of these placental proteins have occurred in the receptor-binding sites, especially site 2, contrasting with the strong conservation of the hydrophobic core.
Assuntos
Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Hormônio do Crescimento/genética , Papio hamadryas/genética , Placenta/metabolismo , Sequência de Aminoácidos , Animais , Feminino , Hormônio do Crescimento/classificação , Dados de Sequência Molecular , Filogenia , Polimorfismo Genético , Gravidez , Especificidade da Espécie , Transcrição GênicaRESUMO
Pituitary prolactin shows an episodic pattern of molecular evolution, with occasional short bursts of rapid change imposed on a generally rather slow evolutionary rate. In mammals, episodes of rapid change occurred in the evolution of primates, cetartiodactyls, rodents and the elephant. The bursts of rapid evolution in cetartiodactyls and rodents were followed by duplications of the prolactin gene that gave rise to large families of prolactin-related proteins including placental lactogens, while in primates the burst was followed by corresponding duplications of the related GH gene. The position in elephant is less clear. Extensive data relating to the genomic sequences of elephant and two additional members of the group Afrotheria are now available, and have been used here to characterize the prolactin genes in these species and explore whether additional prolactin-related genes are present. The results confirm the rapid evolution of elephant (Loxodonta africana) prolactin - the sequence of elephant prolactin is substantially different from that predicted for the ancestral placental mammal. Hyrax (Procavia capensis) prolactin is even more divergent but tenrec (Echinops telfairi) prolactin is strongly conserved. No evidence was obtained from searches of public databases for additional genes encoding prolactin-like proteins in any of these species. Detailed analysis of evolutionary rates, and other factors, indicates that the episode of rapid change in hyrax, and probably elephant, was adaptive, though the nature of the associated biological change(s) is not clear.
Assuntos
Elefantes/genética , Eulipotyphla/genética , Procaviídeos/genética , Prolactina/genética , Animais , Sequência de Bases , Evolução Molecular , Genômica , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
The insulin-like growth factors (IGF-I and IGF-II) and insulin are related proteins that play an important role in regulation of metabolism and growth. In mammals these proteins are generally strongly conserved, though the sequence of insulin underwent periods of rapid change during the evolution of hystricomorph rodents and new-world monkeys (NWM). The availability of genomic sequence information for a number of mammals provides gene sequences for insulin and IGF precursors from several new species, and this has been used here to study the evolution of these proteins in primates. The sequence of insulin is strongly conserved in primates except for the branch leading to NWM - the sequence of marmoset insulin confirms the episode of rapid evolution in this lineage. Strongly conserved sequences are also seen for IGF-I and IGF-II, though for IGF-I (but not IGF-II) the marmoset sequence again shows an episode of fairly rapid evolution, paralleling the changes seen in insulin. Thus in NWM the sequences of insulin and IGF-I show a co-evolution that may reflect a coordinated change in the functional properties of these two molecules. The other components of the insulin and IGF precursors (signal peptides, E-domains of IGFs, insulin C-peptide) are much less strongly conserved, though to a variable extent. Signal peptides are generally quite variable, but the sequence encoding the N-terminal region of the unusually long signal peptide of IGF-I is strongly conserved, suggesting specific function(s), at least partly associated with nucleotide rather than protein sequence. The Ea domain of proIGF-I and the N-terminal end of the E-domain of proIGF-II are quite strongly conserved, which accords with reports of a biologically active peptide (preptin) derived from the latter. However, the C-terminal parts of the Eb and Ec domains of proIGF-I (produced by alternative splicing) are very variable, which is of interest in view of reports of peptides with important biological activities deriving from these regions.
Assuntos
Evolução Molecular , Peptídeos/genética , Primatas/genética , Somatomedinas/genética , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
Mammalian growth hormone (GH) sequences have been shown previously to display episodic evolution: the sequence is generally strongly conserved but on at least two occasions during mammalian evolution (on lineages leading to higher primates and ruminants) bursts of rapid evolution occurred. However, the number of mammalian orders studied previously has been relatively limited, and the availability of sequence data via mammalian genome projects provides the potential for extending the range of GH gene sequences examined. Complete or nearly complete GH gene sequences for six mammalian species for which no data were previously available have been extracted from the genome databases-Dasypus novemcinctus (nine-banded armadillo), Erinaceus europaeus (western European hedgehog), Myotis lucifugus (little brown bat), Procavia capensis (cape rock hyrax), Sorex araneus (European shrew), Spermophilus tridecemlineatus (13-lined ground squirrel). In addition incomplete data for several other species have been extended. Examination of the data in detail and comparison with previously available sequences has allowed assessment of the reliability of deduced sequences. Several of the new sequences differ substantially from the consensus sequence previously determined for eutherian GHs, indicating greater variability than previously recognised, and confirming the episodic pattern of evolution. The episodic pattern is not seen for signal sequences, 5' upstream sequence or synonymous substitutions-it is specific to the mature protein sequence, suggesting that it relates to the hormonal function. The substitutions accumulated during the course of GH evolution have occurred mainly on the side of the hormone facing away from the receptor, in a non-random fashion, and it is suggested that this may reflect interaction of the receptor-bound hormone with other proteins or small ligands.
Assuntos
Evolução Molecular , Hormônio do Crescimento/genética , Mamíferos/genética , Alinhamento de Sequência , Sequência de Aminoácidos , Animais , Tatus/genética , Sequência de Bases , Gatos/genética , Quirópteros/genética , Elefantes/genética , Genômica , Ouriços/genética , Procaviídeos/genética , Dados de Sequência Molecular , Gambás/genética , Sciuridae/genética , Musaranhos/genética , Especificidade da EspécieRESUMO
The GH gene cluster in marmoset, Callithrix jacchus, comprises eight GH-like genes and pseudogenes and appears to have arisen as a consequence of gene duplications occurring independently of those leading to the human GH gene cluster. We report here the complete sequence of the marmoset GH gene locus, including the intergenic regions and 5' and 3' flanking sequence, and a study of the multiple GH-like genes of an additional New World monkey (NWM), the white-fronted capuchin, Cebus albifrons. The marmoset sequence includes 945 nucleotides (nt) of 5' flanking sequence and 1596 nt of 3' flanking sequence that are "unique"; between these are eight repeat units, including the eight GH genes/pseudogenes. The breakpoints between these repeats are very similar, indicating a regular pattern of gene duplication. These breakpoints do not correspond to those found in the much less regular human GH gene cluster. This and phylogenetic analysis of the repeat units within the marmoset gene cluster strongly support the independent origin of these gene clusters, and the idea that the episode of rapid evolution that occurred during GH evolution in primates preceded the gene duplications. The marmoset GH gene cluster also differs from that of human in having fewer and more evenly distributed Alu sequences (a single pair in each repeat unit) and a "P-element" upstream of every gene/pseudogene. In human there is no P-element upstream of the gene encoding pituitary GH, and these elements have been implicated in placental expression of the other genes of the cluster. The GH gene clusters in marmoset and capuchin appear to have arisen as the consequence of a single-gene duplication event, but in capuchin there was then a remarkable expansion of the GH locus, giving at least 40 GH-like genes and pseudogenes. Thus even among NWMs the GH gene cluster is very variable.
Assuntos
Callithrix/genética , Cebus/genética , Evolução Molecular , Hormônio do Crescimento/genética , Primatas/genética , Elementos Alu , Animais , Conversão Gênica , Duplicação Gênica , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Família Multigênica , Filogenia , Análise de Sequência de DNARESUMO
In mammals, pituitary growth hormone (GH) is usually encoded by a single gene, but in some caprine ruminants there are two GH genes, and higher primates have a cluster of at least 5 GH-like genes. We have previously shown that in several artiodactyls (chevrotain, giraffe, and hippopotamus) there are two GH gene sequences, differing by 5-21 nucleotides (nt), but whether these arise from two distinct gene loci is unclear. We report here that in the red deer (Cervus elaphus) also there are two main GH gene sequences (designated A and B) differing at about 23 nt. Investigation of DNA from a number of individual animals demonstrated that this variation was due to allelic polymorphism, with individuals carrying either the A-type or the B-type sequence, or both. A- and B-type sequences showed some variation between individuals. The overall difference between the A and B sequences is substantial-greater than that between the GH gene sequences of three distinct bovine species, Bos taurus (ox), Bos indicus (zebu) and Bos grunniens (yak). The biological significance of the presence of two markedly differing GH gene sequences in red deer is not clear, but it is notable that several of the differences between the A and B sequences occur in the 5' upstream region, which may be associated with differences in gene expression.
Assuntos
Cervos/genética , Hormônio do Crescimento/genética , Polimorfismo Genético , Animais , Sequência de Bases , Perfilação da Expressão Gênica , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
In mammals growth hormone (GH) is generally a strongly conserved protein, reflecting a slow rate of molecular evolution. However, during primate and artiodactyl evolution episodes of rapid change occurred, so that the GHs of higher primates and ruminants differ markedly from those of other mammals. To extend knowledge of GH evolution in Cetartiodactyla (Artiodactyla plus Cetacea) we have previously characterized GH genes from several members of this group, including the common dolphin. Surprisingly the sequence deduced for dolphin GH differed at several residues from that described previously for another cetacean, finback whale. To investigate this anomaly we have now cloned and characterized the GH gene from finback whale. The overall organization of this gene is similar to that of dolphin, and the deduced amino acid sequence of finback whale GH differs from that of dolphin GH at only residue 47, and from that of pig GH at only residue 149. Phylogenetic analysis of the data provides further support for inclusion of Cetacea within the order Cetartiodactyla, as sister group of Hippopotamidae. The results support the idea that in Cetartiodactyla a burst of rapid evolution of GH occurred after the separation of the line leading to ruminants from other cetartiodactyls. Overall, the GH gene in cetaceans appears to be evolving more slowly than in most other cetartiodactyls.
Assuntos
Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Baleias/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
Pituitary prolactin, like growth hormone (GH) and several other protein hormones, shows an episodic pattern of molecular evolution in which sustained bursts of rapid change contrast with long periods of slow evolution. A period of rapid change occurred in the evolution of prolactin in primates, leading to marked sequence differences between human prolactin and that of nonprimate mammals. We have defined this burst more precisely by sequencing the coding regions of prolactin genes for a prosimian, the slow loris (Nycticebus pygmaeus), and a New World monkey, the marmoset (Callithrix jacchus). Slow loris prolactin is very similar in sequence to pig prolactin, so the episode of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. Marmoset prolactin is similar in sequence to human prolactin, so the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence (nonsynonymous sites) for mature prolactin and is not marked in other components of the gene sequence. This and the observations that (1) there was no apparent loss of function during the episode of rapid evolution, (2) the rate of evolution slowed toward the basal rate after this burst, and (3) the distribution of substitutions in the prolactin molecule is very uneven support the idea that this episode of rapid change was due to positive adaptive selection. In the slow loris and marmoset there is no evidence for duplication of the prolactin gene, and evidence from another New World monkey (Cebus albifrons) and from the chimpanzee and human genome sequences, suggests that this is the general position in primates, contrasting with the situation for GH genes. The chimpanzee prolactin sequence differs from that of human at two residues and comparison of human and chimpanzee prolactin gene sequences suggests that noncoding regions associated with regulating expression may be evolving differently from other noncoding regions.
Assuntos
Evolução Molecular , Filogenia , Primatas/genética , Prolactina/genética , Sequência de Aminoácidos , Animais , Composição de Bases , Sequência de Bases , Clonagem Molecular , Análise por Conglomerados , Componentes do Gene , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
Growth hormone, prolactin, the fish hormone, somatolactin, and related mammalian placental hormones, including placental lactogen, form a family of polypeptide hormones that share a common tertiary structure. They produce their biological effects by interacting with and dimerizing specific single transmembrane-domain receptors. The receptors belong to a superfamily of cytokine receptors with no intrinsic tyrosine kinase, which use the Jak-Stat cascade as a major signalling pathway. Hormones and receptors are thought to have arisen as a result of gene duplication and subsequent divergence early in vertebrate evolution. Mammalian growth hormone and prolactin show a slow basal evolutionary rate of change, but with episodes of accelerated evolution. These occurred for growth hormone during the evolution of the primates and artiodactyls and for prolactin in lineages leading to rodents, elephants, ruminants, and man. Placental lactogen has probably evolved independently on three occasions, from prolactin in rodents and ruminants and from growth hormone in man. Receptor sequences also show variable rates of evolution, corresponding partly, but not completely, with changes in the ligand. A principal biological role of growth hormone, the control of postnatal growth, has remained quite consistent throughout vertebrate evolution and is largely mediated by insulin-like growth factors. Prolactin has many and diverse roles. In relation to lactation, the relative roles of growth hormone and prolactin vary between species. Correlation between the molecular and functional evolution of these hormones is very incomplete, and it is likely that many important functional adaptations involved changes in regulatory elements, for example, altering tissue of origin or posttranscriptional processing, rather than change of the structures of the proteins themselves.
Assuntos
Evolução Molecular , Hormônio do Crescimento/fisiologia , Prolactina/fisiologia , Animais , Humanos , Lactação , Receptores de Superfície Celular/fisiologiaRESUMO
The sequence of growth hormone (GH) is generally strongly conserved in mammals, but episodes of rapid change occurred during the evolution of primates and artiodactyls, when the rate of GH evolution apparently increased substantially. As a result the sequences of higher primate and ruminant GHs differ markedly from sequences of other mammalian GHs. In order to increase knowledge of GH evolution in Cetartiodactyla (Artiodactyla plus Cetacea) we have cloned and characterized GH genes from camel (Camelus dromedarius), hippopotamus (Hippopotamus amphibius), and giraffe (Giraffa camelopardalis), using genomic DNA and a polymerase chain reaction technique. As in other mammals, these GH genes comprise five exons and four introns. Two very similar GH gene sequences (encoding identical proteins) were found in each of hippopotamus and giraffe. The deduced sequence for the mature hippopotamus GH is identical to that of dolphin, in accord with current ideas of a close relationship between Cetacea and Hippopotamidae. The sequence of camel GH is identical to that reported previously for alpaca GH. The sequence of giraffe GH is very similar to that of other ruminants but differs from that of nonruminant cetartiodactyls at about 18 residues. The results demonstrate that the apparent burst of rapid evolution of GH occurred largely after the separation of the line leading to ruminants from other cetartiodactyls.