RESUMEN
Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed â¼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
Asunto(s)
Proteínas Aviares , Pollos/fisiología , Evolución Molecular , Proteínas de Peces , Proteínas de Homeodominio , Red Nerviosa/fisiología , Rajidae/fisiología , Factores de Transcripción , Caminata/fisiología , Pez Cebra/fisiología , Aletas de Animales/fisiología , Animales , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Embrión de Pollo , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Músculo Esquelético/fisiología , Natación/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
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Cardiopatías Congénitas , Pez Cebra , Animales , Humanos , Polaridad Celular/genética , Células Germinativas/metabolismo , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
About 500 million years ago, a new type of adaptive immune defense emerged in basal jawed vertebrates, accompanied by morphological innovations, including the thymus. Did these evolutionary novelties arise de novo or from elaboration of ancient genetic networks? We reconstructed the genetic changes underlying thymopoiesis by comparative genome and expression analyses in chordates and basal vertebrates. The derived models of genetic networks were experimentally verified in bony fishes. Ancestral networks defining circumscribed regions of the pharyngeal epithelium of jawless vertebrates expanded in cartilaginous fishes to incorporate novel genes, notably those encoding chemokines. Correspondingly, novel networks evolved in lymphocytes of jawed vertebrates to control the expression of additional chemokine receptors. These complementary changes enabled unprecedented Delta/Notch signaling between pharyngeal epithelium and lymphoid cells that was exploited for specification to the T cell lineage. Our results provide a framework elucidating the evolution of key features of the adaptive immune system in jawed vertebrates.
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Evolución Biológica , Redes Reguladoras de Genes , Timo/inmunología , Vertebrados/genética , Vertebrados/inmunología , Animales , Quimiocinas/genética , Quimiocinas/inmunología , Cordados no Vertebrados/genética , Cordados no Vertebrados/inmunología , Peces/genética , Peces/inmunología , Humanos , Lampreas/genética , Lampreas/inmunología , Linfocitos/inmunología , Datos de Secuencia Molecular , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunologíaRESUMEN
The extant jawless vertebrates, represented by lampreys and hagfish, are the oldest group of vertebrates and provide an interesting genomic evolutionary pivot point between invertebrates and jawed vertebrates. Through genome analysis of one of these jawless vertebrates, the Japanese lamprey (Lethenteron japonicum), we identified all three members of the important p53 transcription factor family--Tp53, Tp63, and Tp73--as well as the Mdm2 and Mdm4 genes. These genes and their products are significant cellular regulators in human cancer, and further examination of their roles in this most distant vertebrate relative sheds light on their origin and coevolution. Their important role in response to DNA damage has been highlighted by the discovery of multiple copies of the Tp53 gene in elephants. Expression of lamprey p53, Mdm2, and Mdm4 proteins in mammalian cells reveals that the p53-Mdm2 interaction and the Mdm2/Mdm4 E3 ligase activity existed in the common ancestor of vertebrates and have been conserved for >500 million years of vertebrate evolution. Lamprey Mdm2 degrades human p53 with great efficiency, but this interaction is not blocked by currently available small molecule inhibitors of the human HDM2 protein, suggesting utility of lamprey Mdm2 in the study of the human p53 signaling pathway.
Asunto(s)
Lampreas/genética , Lampreas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Secuencia de Aminoácidos , Animales , Células Cultivadas , Secuencia Conservada , Genoma , Humanos , Lampreas/clasificación , Ratones , Modelos Moleculares , Filogenia , Unión Proteica , Proteolisis , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de SecuenciaRESUMEN
PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.
Asunto(s)
Proteínas de Unión al GTP , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Proteínas Portadoras , GTP Fosfohidrolasas/genética , Mamíferos/metabolismo , Trastornos del Neurodesarrollo/genética , ARN MensajeroRESUMEN
Huriez syndrome (HRZ, OMIM181600) is a rare genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma, and predisposition to cutaneous squamous cell carcinoma (cSCC). We report herein three HRZ families from Croatia, the Netherlands, and Germany. Deep sequencing followed by Sanger validation, confirmed the presence of germline causative SMARCAD1 heterozygous pathogenic variants. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed cSCC at 32 years of age. Two novel monoallelic germline mutations were identified which are predicted to disrupt the first exon-intron boundary of the skin-specific SMARCAD1 isoform. On the basis of phenotypic and genotypic convergence with Adermatoglyphia (OMIM136000) and Basan syndrome (OMIM129200), our results lend credence to the notion that these three Mendelian disorders are allelic. We propose adding Huriez syndrome to the previously suggested SMARCAD syndrome designation, which was originally invoked to describe the spectrum of monogenic disorders between Adermatoglyphia and Basan syndrome.
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Carcinoma de Células Escamosas , Queratodermia Palmoplantar , Neoplasias Cutáneas , Carcinoma de Células Escamosas/complicaciones , ADN Helicasas/genética , Displasia Ectodérmica , Humanos , Queratodermia Palmoplantar/genética , Queratosis , Uñas Malformadas , Esclerodermia Localizada , Enfermedades Cutáneas Genéticas , Neoplasias Cutáneas/etiología , SíndromeRESUMEN
Seahorses have a specialized morphology that includes a toothless tubular mouth, a body covered with bony plates, a male brood pouch, and the absence of caudal and pelvic fins. Here we report the sequencing and de novo assembly of the genome of the tiger tail seahorse, Hippocampus comes. Comparative genomic analysis identifies higher protein and nucleotide evolutionary rates in H. comes compared with other teleost fish genomes. We identified an astacin metalloprotease gene family that has undergone expansion and is highly expressed in the male brood pouch. We also find that the H. comes genome lacks enamel matrix protein-coding proline/glutamine-rich secretory calcium-binding phosphoprotein genes, which might have led to the loss of mineralized teeth. tbx4, a regulator of hindlimb development, is also not found in H. comes genome. Knockout of tbx4 in zebrafish showed a 'pelvic fin-loss' phenotype similar to that of seahorses.
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Evolución Biológica , Proteínas de Peces/genética , Genoma/genética , Smegmamorpha/anatomía & histología , Smegmamorpha/genética , Aletas de Animales/anatomía & histología , Aletas de Animales/metabolismo , Animales , Secuencia Conservada/genética , Proteínas de Peces/deficiencia , Eliminación de Gen , Genómica , Miembro Posterior/anatomía & histología , Miembro Posterior/metabolismo , Masculino , Anotación de Secuencia Molecular , Familia de Multigenes/genética , Tasa de Mutación , Filogenia , Reproducción/fisiología , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Factores de Tiempo , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genéticaRESUMEN
Multiciliated cells (MCCs) differentiate hundreds of motile cilia that beat to drive fluid movement over various kinds of epithelia. In Xenopus, mice and human, the coiled-coil containing protein Mcidas (Mci) has been shown to be a key transcriptional regulator of MCC differentiation. We have examined Mci function in the zebrafish, another model organism that is widely used to study ciliary biology. We show that zebrafish mci is expressed specifically in the developing MCCs of the kidney tubules, but surprisingly, not in those of the nasal placodes. Mci proteins lack a DNA binding domain and associate with the cell-cycle transcription factors E2f4/5 for regulating MCC-specific gene expression. We found that while the zebrafish Mci protein can complex with the E2f family members, its sequence as well as the requirement and sufficiency for MCC differentiation has diverged significantly from Mci homologues of the tetrapods. We also provide evidence that compared to Gmnc, another related coiled-coil protein that has recently been shown to regulate MCC development upstream of Mci, the Mci protein originated later within the vertebrate lineage. Based on these data, we argue that in contrast to Gmnc, which has a vital role in the genetic circuitry that drives MCC formation, the requirement of Mci, at least in the zebrafish, is not obligatory.
Asunto(s)
Cilios , Regulación del Desarrollo de la Expresión Génica , Túbulos Renales/embriología , Transducción de Señal , Factores de Transcripción , Proteínas de Pez Cebra , Pez Cebra , Animales , Ciclo Celular , Cilios/genética , Cilios/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Our understanding of phylogenetic relationships among bony fishes has been transformed by analysis of a small number of genes, but uncertainty remains around critical nodes. Genome-scale inferences so far have sampled a limited number of taxa and genes. Here we leveraged 144 genomes and 159 transcriptomes to investigate fish evolution with an unparalleled scale of data: >0.5 Mb from 1,105 orthologous exon sequences from 303 species, representing 66 out of 72 ray-finned fish orders. We apply phylogenetic tests designed to trace the effect of whole-genome duplication events on gene trees and find paralogy-free loci using a bioinformatics approach. Genome-wide data support the structure of the fish phylogeny, and hypothesis-testing procedures appropriate for phylogenomic datasets using explicit gene genealogy interrogation settle some long-standing uncertainties, such as the branching order at the base of the teleosts and among early euteleosts, and the sister lineage to the acanthomorph and percomorph radiations. Comprehensive fossil calibrations date the origin of all major fish lineages before the end of the Cretaceous.
Asunto(s)
Peces/genética , Genoma/genética , Transcriptoma/genética , Animales , Evolución Molecular , Exones/genética , Fósiles , Duplicación de Gen/genética , Genómica/métodos , Modelos Genéticos , FilogeniaRESUMEN
Cytidine deaminases of the AID/APOBEC family catalyze C-to-U nucleotide transitions in mRNA or DNA. Members of the APOBEC3 branch are involved in antiviral defense, whereas AID contributes to diversification of antibody repertoires in jawed vertebrates via somatic hypermutation, gene conversion, and class switch recombination. In the extant jawless vertebrate, the lamprey, two members of the AID/APOBEC family are implicated in the generation of somatic diversity of the variable lymphocyte receptors (VLRs). Expression studies linked CDA1 and CDA2 genes to the assembly of VLRA/C genes in T-like cells and the VLRB genes in B-like cells, respectively. Here, we identify and characterize several CDA1-like genes in the larvae of different lamprey species and demonstrate that these encode active cytidine deaminases. Structural comparisons of the CDA1 variants highlighted substantial differences in surface charge; this observation is supported by our finding that the enzymes require different conditions and substrates for optimal activity in vitro. Strikingly, we also found that the number of CDA-like genes present in individuals of the same species is variable. Nevertheless, irrespective of the number of different CDA1-like genes present, all lamprey larvae have at least one functional CDA1-related gene encoding an enzyme with predicted structural and chemical features generally comparable to jawed vertebrate AID. Our findings suggest that, similar to APOBEC3 branch expansion in jawed vertebrates, the AID/APOBEC family has undergone substantial diversification in lamprey, possibly indicative of multiple distinct biological roles.
Asunto(s)
Desaminasas APOBEC-1/genética , Citidina Desaminasa/clasificación , Citidina Desaminasa/genética , Variaciones en el Número de Copia de ADN , Lampreas/genética , Linfocitos/inmunología , Receptores de Antígenos/genética , Desaminasas APOBEC-1/química , Desaminasas APOBEC-1/inmunología , Secuencia de Aminoácidos , Animales , Citidina Desaminasa/química , Citidina Desaminasa/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , Conformación Proteica , Receptores de Antígenos/clasificación , Homología de Secuencia , Secuenciación Completa del GenomaRESUMEN
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.
Asunto(s)
Artrogriposis/genética , Proteínas de la Matriz Extracelular/genética , Mutación , Células de Schwann/metabolismo , Artrogriposis/diagnóstico , Artrogriposis/patología , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso , LinajeRESUMEN
In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.
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Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/fisiología , Discapacidades del Desarrollo/genética , Trastornos del Crecimiento/genética , Mutación , Columna Vertebral/anomalías , Columna Vertebral/patología , Animales , Ciclo Celular , Proliferación Celular , Células Cultivadas , Niño , Preescolar , Cilios/metabolismo , Cilios/patología , Discapacidades del Desarrollo/patología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Trastornos del Crecimiento/patología , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Linaje , Fosforilación , Transducción de Señal , Columna Vertebral/metabolismoRESUMEN
Shwachman-Diamond syndrome (SDS) is a rare multisystem ribosomal biogenesis disorder characterized by exocrine pancreatic insufficiency, hematologic abnormalities and bony abnormalities. About 90% of patients have biallelic mutations in SBDS gene. Three additional genes-EFL1, DNAJC21 and SRP54 have been reported in association with a SDS phenotype. However, the cause remains unknown for ~10% of patients. Herein, we report a 6-year-old Chinese boy, who presented in the neonatal period with pancytopenia, liver transaminitis with hepatosplenomegaly and developmental delay, and subsequently developed pancreatic insufficiency complicated by malabsorption and poor growth. Exome sequencing identified a novel de novo heterozygous variant in EIF6 (c.182G>T, p.Arg61Leu). EIF6 protein inhibits ribosomal maturation and is removed in the late steps of ribosomal maturation by SBDS and EFL1 protein. Given the interaction of EIF6 with SBDS and EFL1, we postulate heterozygous variants in EIF6 as a novel cause of Shwachman-Diamond-like phenotype. We compared the phenotype of our patient with those in patients with mutation in SBDS, EFL1, DNAJC21, and SRP54 genes to support this association. Identification of more cases of this novel phenotype would strengthen the association with the genetic etiology.
Asunto(s)
Factores Eucarióticos de Iniciación/genética , Predisposición Genética a la Enfermedad , Síndrome de Shwachman-Diamond/genética , Niño , Heterocigoto , Humanos , Masculino , Mutación Missense/genética , Fenotipo , Proteínas/genética , Síndrome de Shwachman-Diamond/patología , Secuenciación del ExomaRESUMEN
Among the numerous lineages of teleost fish that have independently transitioned from obligate water breathing to facultative air breathing, evolved properties of hemoglobin (Hb)-O2 transport may have been shaped by the prevalence and severity of aquatic hypoxia (which influences the extent to which fish are compelled to switch to aerial respiration) as well as the anatomical design of air-breathing structures and the cardiovascular system. Here, we examined the structure and function of Hbs in an amphibious, facultative air-breathing fish, the blue-spotted mudskipper (Boleophthalmus pectinirostris). We also characterized the genomic organization of the globin gene clusters of the species and we integrated phylogenetic and comparative genomic analyses to unravel the duplicative history of the genes that encode the subunits of structurally distinct mudskipper Hb isoforms (isoHbs). The B. pectinirostris isoHbs exhibit high intrinsic O2 affinities, similar to those of hypoxia-tolerant, water-breathing teleosts, and remarkably large Bohr effects. Genomic analysis of conserved synteny revealed that the genes that encode the α-type subunits of the two main adult isoHbs are members of paralogous gene clusters that represent products of the teleost-specific whole-genome duplication. Experiments revealed no appreciable difference in the oxygenation properties of co-expressed isoHbs in spite of extensive amino acid divergence between the alternative α-chain subunit isoforms. It therefore appears that the ability to switch between aquatic and aerial respiration does not necessarily require a division of labor between functionally distinct isoHbs with specialized oxygenation properties.
Asunto(s)
Evolución Molecular , Peces/fisiología , Hemoglobinas/química , Respiración , Animales , Isoformas de Proteínas/químicaRESUMEN
The emergence of jawed vertebrates (gnathostomes) from jawless vertebrates was accompanied by major morphological and physiological innovations, such as hinged jaws, paired fins and immunoglobulin-based adaptive immunity. Gnathostomes subsequently diverged into two groups, the cartilaginous fishes and the bony vertebrates. Here we report the whole-genome analysis of a cartilaginous fish, the elephant shark (Callorhinchus milii). We find that the C. milii genome is the slowest evolving of all known vertebrates, including the 'living fossil' coelacanth, and features extensive synteny conservation with tetrapod genomes, making it a good model for comparative analyses of gnathostome genomes. Our functional studies suggest that the lack of genes encoding secreted calcium-binding phosphoproteins in cartilaginous fishes explains the absence of bone in their endoskeleton. Furthermore, the adaptive immune system of cartilaginous fishes is unusual: it lacks the canonical CD4 co-receptor and most transcription factors, cytokines and cytokine receptors related to the CD4 lineage, despite the presence of polymorphic major histocompatibility complex class II molecules. It thus presents a new model for understanding the origin of adaptive immunity.
Asunto(s)
Evolución Molecular , Genoma/genética , Tiburones/genética , Animales , Calcio/metabolismo , Linaje de la Célula/inmunología , Proteínas de Peces/clasificación , Proteínas de Peces/genética , Eliminación de Gen , Genómica , Inmunidad Celular/genética , Anotación de Secuencia Molecular , Datos de Secuencia Molecular , Osteogénesis/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Filogenia , Estructura Terciaria de Proteína/genética , Tiburones/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Factores de Tiempo , Vertebrados/clasificación , Vertebrados/genética , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
Nuclear receptors (NRs) are key transcription factors that originated in the common ancestor of metazoans. The vast majority of NRs are triggered by binding to either endogenous (e.g. retinoic acid) or exogenous (e.g. xenobiotics) ligands, and their evolution and expansion is tightly linked to the function of endocrine systems. Importantly, they represent classic targets of physiological exploitation by endocrine disrupting chemicals. The NR gene repertoire in different lineages has been shaped by gene loss, duplication and mutation, denoting a dynamic evolutionary route. As the earliest diverging class of gnathostomes (jawed vertebrates), cartilaginous fishes offer an exceptional opportunity to address the early diversification of NR gene families and the evolution of the endocrine system in jawed vertebrates. Here we provide an exhaustive analysis into the NR gene composition in five elasmobranch (sharks and rays) and two holocephalan (chimaeras) species. For this purpose, we generated also a low coverage draft genome assembly of the chimaera small-eyed rabbitfish, Hydrolagus affinis. We show that cartilaginous fish retain an archetypal NR gene repertoire, similar to that of mammals and coincident with the two rounds of whole genome duplication that occurred in the gnathostome ancestor. Furthermore, novel gene members of the non-canonical NR0B receptors were found in the genomes of this lineage. Our findings provide an essential view into the early diversification of NRs in gnathostomes, paving the way for functional studies.
Asunto(s)
Evolución Molecular , Peces/genética , Receptores Citoplasmáticos y Nucleares/genética , Animales , Teorema de Bayes , Duplicación de Gen , Genoma , Filogenia , Factores de Transcripción/genéticaRESUMEN
ParaHox genes (Gsx, Pdx, and Cdx) are an ancient family of developmental genes closely related to the Hox genes. They play critical roles in the patterning of brain and gut. The basal chordate, amphioxus, contains a single ParaHox cluster comprising one member of each family, whereas nonteleost jawed vertebrates contain four ParaHox genomic loci with six or seven ParaHox genes. Teleosts, which have experienced an additional whole-genome duplication, contain six ParaHox genomic loci with six ParaHox genes. Jawless vertebrates, represented by lampreys and hagfish, are the most ancient group of vertebrates and are crucial for understanding the origin and evolution of vertebrate gene families. We have previously shown that lampreys contain six Hox gene loci. Here we report that lampreys contain only two ParaHox gene clusters (designated as α- and ß-clusters) bearing five ParaHox genes (Gsxα, Pdxα, Cdxα, Gsxß, and Cdxß). The order and orientation of the three genes in the α-cluster are identical to that of the single cluster in amphioxus. However, the orientation of Gsxß in the ß-cluster is inverted. Interestingly, Gsxß is expressed in the eye, unlike its homologs in jawed vertebrates, which are expressed mainly in the brain. The lamprey Pdxα is expressed in the pancreas similar to jawed vertebrate Pdx genes, indicating that the pancreatic expression of Pdx was acquired before the divergence of jawless and jawed vertebrate lineages. It is likely that the lamprey Pdxα plays a crucial role in pancreas specification and insulin production similar to the Pdx of jawed vertebrates.
Asunto(s)
Genes Homeobox/genética , Lampreas/genética , Familia de Multigenes , Vertebrados/genética , Secuencia de Aminoácidos , Animales , Evolución Molecular , Proteínas de Peces/genética , Perfilación de la Expresión Génica/métodos , Proteínas de Homeodominio/clasificación , Proteínas de Homeodominio/genética , Filogenia , Homología de Secuencia de Aminoácido , Vertebrados/clasificaciónRESUMEN
To appraise how evolutionary processes, such as gene duplication and loss, influence an organism's xenobiotic sensitivity is a critical question in toxicology. Of particular importance are gene families involved in the mediation of detoxification responses, such as members of the nuclear receptor subfamily 1 group I (NR1I), the pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). While documented in multiple vertebrate genomes, PXR and CAR display an intriguing gene distribution. PXR is absent in birds and reptiles, while CAR shows a tetrapod-specific occurrence. More elusive is the presence of PXR and CAR gene orthologs in early branching and ecologically-important Chondrichthyes (chimaeras, sharks and rays). Therefore, we investigated various genome projects and use them to provide the first identification and functional characterization of a Chondrichthyan PXR from the chimaera elephant shark (Callorhinchus milii, Holocephali). Additionally, we substantiate the targeted PXR gene loss in Elasmobranchii (sharks and rays). Compared to other vertebrate groups, the chimaera PXR ortholog displays a diverse expression pattern (skin and gills) and a unique activation profile by classical xenobiotic ligands. Our findings provide insights into the molecular landscape of detoxification mechanisms and suggest lineage-specific adaptations in response to xenobiotics in gnathostome evolution.