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‣ Genoma funcional e análise "in silico" na caracterização e no isolamento de genes envolvidos em gliomas humanos; Caracterization and isolation of genes involved in human gliomas by functional genome and in silico anlysis

Degaki, Theri Leica
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 20/09/2006 Português
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São poucos os avanços obtidos em intervenções cirúrgicas ou terapias para melhora na qualidade de vida e/ou prognósticos dos pacientes acometidos por gliomas, que são os tumores mais comuns e fatais que acometem o sistema nervoso central. O modelo celular ST1 de glioma de rato responde ao tratamento com hormônio glicocorticóide (GC) com uma reversão fenotípica tumoral-normal in vitro e in vivo e o modelo celular P7 é resistente a este tratamento. Ambas as linhagens são utilizadas, no laboratório, como modelos de estudo de genes associados à origem de neoplasias e controle de proliferação celular, com potenciais aplicações na doença humana. Este trabalho possui dois objetivos gerais: a) clonagem e caracterização funcional do gene NRP/B de rato, previamente descrito no laboratório como sendo induzido durante o tratamento das células ST1 com GC; b) identificação de genes humanos no locus 22q13, frequentemente deletado e associado à progressão tumoral de gliomas. A identificação, clonagem e determinação da seqüência completa de NRP/B de rato, até então desconhecida, foi realizada neste trabalho e depositada no GenBank (número de acesso AY669396). Sua expressão parece ser cérebro-específica, sendo modulada positivamente durante o tratamento com GC nas células ST1. A superexpressão de NRP/B em células ST1 foi realizada para avaliar o papel do gene na reversão fenotípica tumoral-normal induzida por GC. Os resultados obtidos sugerem que NRP/B provoca diminuição da capacidade de crescimento independente de ancoragem em meio semi-sólido e do potencial tumorigênico das células ST1 em ensaios de tumorigênese in vivo. Experimentos preliminares sugerem o envolvimento da expressão de NRP/B no processo de progressão celular e em tumores humanos cerebrais e de mama. Para a identificação de genes humanos no locus 22q13 associados ao desenvolvimento de gliomas...

‣ Identificação e seleção de novos genes humanos associados a tumores a partir de dados obtidos no projeto Transcript Finishing Initiative (TFI); Identification and selection of new human genes associated with tumors from the Transcript Finishing Initiative (TFI) Project data.

Cruz, Luciana Oliveira
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 05/10/2007 Português
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Após o seqüenciamento completo do genoma humano, a busca e caracterização do conjunto completo de genes humanos constitui-se no principal desafio nesta área de investigação, sendo o passo limitante para o progresso na exploração dos dados contidos no seqüenciamento deste genoma. O projeto de transcriptoma denominado "Transcript Finishing Initiative" (TFI) surgiu neste contexto, com o objetivo principal de gerar fragmentos parciais de transcritos humanos, que não haviam sido descritos previamente e determinar sua seqüência, para iniciar a caracterização de novos genes humanos. A estratégia utilizada foi q alinhamento de todas as seqüências ORESTES e ESTs disponíveis com a seqüência pública do genoma humano e o agrupamento j c1usterização destas com base nas coordenadas deste genoma. Algumas das regiões que não eram cobertas por estas seqüências foram, então, completadas, por RT-PCR, utilizando-se primers ancorados nos clusters vizinhos. Cada par de clusters de ESTs selecionado para validação experimental foi designado como uma Unidade do "Transcript Finishing" (TFU), tendo sido validadas experimentalmente, pelo grupo TFI, Um total de 211 TFUs foram validadas, sendo que 197 seqüências consenso foram submetidas ao Genbank (CF272536-CF272733). Atualmente...

‣ Identificação in-silico de genes humanos submetidos à expressão alélica diferencial; In-silico identification of human genes submitted to allelic differential expression

Souza, Jorge Estefano Santana de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 02/12/2008 Português
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Estudos recentes demonstraram que a variação de expressão alelo-específica é mais comum do que se imaginou, podendo chegar, em humanos, a 50% dos genes. Identificar os genes submetidos ao controle de expressão alelo-específica é muito importante para o entendimento de várias doenças, incluindo o câncer. A identificação dos alvos desse tipo de regulação diferencial é difícil, principalmente devido à dificuldade de se avaliar a expressão de cada alelo individualmente. Neste trabalho, abordamos este problema com uma estratégia de análise in-silico, fundamentada na integração de dados públicos do genoma humano, dados de expressão (como cDNAs, SAGE e MPSS) e dados sobre polimorfismos (SNPs). Desenvolvemos um banco de dados de polimorfismos de base única (Single-Nucleotide Polymorphism - SNPs) associados a etiquetas alternativas de SAGE (Serial Analysis of Gene Expression) e MPSS (massively parallel signature sequencing). SAGE e MPSS são técnicas desenvolvidas para análise da expressão de genes em larga escala. Ambas as técnicas têm como princípio a produção de pequenas seqüências marcadoras (etiquetas), adjacentes aos sítios de enzimas de restrição que estiverem mais próximo da cauda poli-A do RNA mensageiro. Tais etiquetas são seqüenciadas em grande escala e a quantidade de etiquetas é usada para medir a abundância relativa dos RNAs mensageiros correspondentes. A presença de SNPs nos sítios de restrição ou nas seqüências das etiquetas pode gerar etiquetas distintas para alelos do mesmo gene...

‣ Similaridades entre o Transcriptoma Humano e Murino Focando Genes Situados em Regiões de Susceptibilidade ao Diabetes mellitus do Tipo 1; Similarities between Human and Mouse Transcriptomes Focusing Genes Positioned in Type 1 Diabetes mellitus Susceptibility Regions

Almeida, Renata dos Santos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 24/10/2012 Português
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O diabetes mellitus do tipo 1 (DM1) é uma doença autoimune que se desenvolve a partir da ação combinada de múltiplos fatores genéticos e ambientais, sendo caracterizada pela perda seletiva das células produtoras de insulina nas ilhotas pancreáticas em indivíduos geneticamente susceptíveis. O HLA de classe II, localizado no cromossomo humano 6p21.3, representa uma das regiões genômicas mais importantes associadas ao DM1, embora evidências apontem para a participação de diversos outros loci na susceptibilidade à doença. Essas regiões cromossômicas poderiam apresentar genes funcionalmente ativos com perfis transcricionais semelhantes ao camundongo Mus musculus, muito utilizado como modelo animal para o estudo de doenças humanas. Para testar esta hipótese, foi realizada análise dos perfis transcricionais de linfócitos periféricos provenientes de pacientes com DM1 e camundongos NOD (Non-obese diabetic) diabéticos, focando os genes situados em regiões de susceptibilidade. Foram utilizados dados de microarrays do genoma funcional completo da plataforma Agilent (Whole genome one-color Agilent 4x44k) de dezenove pacientes e oito controles, e de camundongos NOD pré-diabéticos e diabéticos. A linhagem NOD foi utilizada no estudo...

‣ Caracterização de novos genes humanos envolvidos no processo de regulação da expressão de genes homeóticos; Characterization of novel human genes involved in the regulation of expression of homeotic genes

Nunes, Diana Noronha
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 03/09/2004 Português
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A identidade na segmentação do corpo de diversos organismos, durante o desenvolvimento, é devida, em grande parte, à ação das proteínas homeóticas. Em especial, dois grupos de proteínas, Trithorax (trxG) e Polycomb (PcG) têm um papel fundamental na manutenção, respectivamente, da ativação e da repressão da transcrição gênica, associando-se à cromatina. A importância das PcG nos estimulou a buscar a caracterização das proteínas humanas ortólogas ao "Enhancer of Polycomb" (Epc) de Drosophila, até então não descritas no genoma humano. Para tanto, buscamos: - obter a sequência completa e mapear o cDNA do novo gene humano homólogo ao "Enhancer of Polycomb" de Drosophila; - analisar sua expressão em tecidos fetais, adultos e tumorais e fazer estudos buscando sua caracterização funcional. Encontramos, mapeamos e obtivemos a seqüência completa de dois genes humanos, ortólogos de Epc1 (10p11-22) e de Epc2 (2q21-23) de camundongo, publicando estes dados em 2001 (Camargo et al., 2001). Ambos os genes são bastante conservados entre várias espécies, sendo que o cDNA de hEPC2 humano, por exemplo, é 94% idêntico ao Epc2 de camundongo e possui 96% de identidade ao nível de proteína, sugerindo que a função do gene deve ter sido mantida durante a evolução. No entanto...

‣ The influence of the human genome on chronic viral hepatitis outcome

Andrade Júnior,Dahir Ramos de; Andrade,Dahir Ramos de
Fonte: Instituto de Medicina Tropical Publicador: Instituto de Medicina Tropical
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2004 Português
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The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future...

‣ Yeast and human genes that affect the Escherichia coli SOS response

Perkins, Edward L.; Sterling, Joan F.; Hashem, Vera I.; Resnick, Michael A.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 02/03/1999 Português
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The sequencing of the human genome has led to the identification of many genes whose functions remain to be determined. Because of conservation of genetic function, microbial systems have often been used for identification and characterization of human genes. We have investigated the use of the Escherichia coli SOS induction assay as a screen for yeast and human genes that might play a role in DNA metabolism and/or in genome stability. The SOS system has previously been used to analyze bacterial and viral genes that directly modify DNA. An initial screen of meiotically expressed yeast genes revealed several genes associated with chromosome metabolism (e.g., RAD51 and HHT1 as well as others). The SOS induction assay was then extended to the isolation of human genes. Several known human genes involved in DNA metabolism, such as the Ku70 end-binding protein and DNA ligase IV, were identified, as well as a large number of previously unknown genes. Thus, the SOS assay can be used to identify and characterize human genes, many of which may participate in chromosome metabolism.

‣ Evola: Ortholog database of all human genes in H-InvDB with manual curation of phylogenetic trees

Matsuya, Akihiro; Sakate, Ryuichi; Kawahara, Yoshihiro; Koyanagi, Kanako O.; Sato, Yoshiharu; Fujii, Yasuyuki; Yamasaki, Chisato; Habara, Takuya; Nakaoka, Hajime; Todokoro, Fusano; Yamaguchi, Kaori; Endo, Toshinori; OOta, Satoshi; Makalowski, Wojciech; Ik
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Orthologs are genes in different species that evolved from a common ancestral gene by speciation. Currently, with the rapid growth of transcriptome data of various species, more reliable orthology information is prerequisite for further studies. However, detection of orthologs could be erroneous if pairwise distance-based methods, such as reciprocal BLAST searches, are utilized. Thus, as a sub-database of H-InvDB, an integrated database of annotated human genes (http://h-invitational.jp/), we constructed a fully curated database of evolutionary features of human genes, called ‘Evola’. In the process of the ortholog detection, computational analysis based on conserved genome synteny and transcript sequence similarity was followed by manual curation by researchers examining phylogenetic trees. In total, 18 968 human genes have orthologs among 11 vertebrates (chimpanzee, mouse, cow, chicken, zebrafish, etc.), either computationally detected or manually curated orthologs. Evola provides amino acid sequence alignments and phylogenetic trees of orthologs and homologs. In ‘dN/dS view’, natural selection on genes can be analyzed between human and other species. In ‘Locus maps’, all transcript variants and their exon/intron structures can be compared among orthologous gene loci. We expect the Evola to serve as a comprehensive and reliable database to be utilized in comparative analyses for obtaining new knowledge about human genes. Evola is available at http://www.h-invitational.jp/evola/.

‣ Hotspots of Biased Nucleotide Substitutions in Human Genes

Berglund, Jonas; Pollard, Katherine S; Webster, Matthew T
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process...

‣ Clustering of Codons with Rare Cognate tRNAs in Human Genes Suggests an Extra Level of Expression Regulation

Parmley, Joanna L.; Huynen, Martijn A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate. However, there has been little evidence for a similar bias of synonymous codons in highly expressed human genes. Here, we ask instead whether there is evidence for the selection for codons associated with low abundance tRNAs. Rather than averaging the codon usage of complete genes, we scan the genes for windows with deviating codon usage. We show that there is a significant over representation of human genes that contain clusters of codons with low abundance cognate tRNAs. We name these regions, which on average have a 50% reduction in the amount of cognate tRNA available compared to the remainder of the gene, RTS (rare tRNA score) clusters. We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non–RTS cluster sequences. Overall, the genes with an RTS cluster have higher tissue specificity than the non–RTS cluster genes. Furthermore, these genes are functionally enriched for transcription regulation. As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand...

‣ Widespread establishment and regulatory impact of Alu exons in human genes

Shen, Shihao; Lin, Lan; Cai, James J.; Jiang, Peng; Kenkel, Elizabeth J.; Stroik, Mallory R.; Sato, Seiko; Davidson, Beverly L.; Xing, Yi
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNA-Seq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5′-UTR, and two-thirds (10/15) of 5′-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5′-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineage-specific evolution of translational regulation. Moreover...

‣ The Human Genome Retains Relics of Its Prokaryotic Ancestry: Human Genes of Archaebacterial and Eubacterial Origin Exhibit Remarkable Differences

Alvarez-Ponce, David; McInerney, James O.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Eukaryotes are generally thought to stem from a fusion event involving an archaebacterium and a eubacterium. As a result of this event, contemporaneous eukaryotic genomes are chimeras of genes inherited from both endosymbiotic partners. These two coexisting gene repertoires have been shown to differ in a number of ways in yeast. Here we combine genomic and functional data in order to determine if and how human genes that have been inherited from both prokaryotic ancestors remain distinguishable. We show that, despite being fewer in number, human genes of archaebacterial origin are more highly and broadly expressed across tissues, are more likely to have lethal mouse orthologs, tend to be involved in informational processes, are more selectively constrained, and encode shorter and more central proteins in the protein–protein interaction network than eubacterium-like genes. Furthermore, consistent with endosymbiotic theory, we show that proteins tend to interact with those encoded by genes of the same ancestry. Most interestingly from a human health perspective, archaebacterial genes are less likely to be involved in heritable human disease. Taken together, these results show that more than 2 billion years after eukaryogenesis, the human genome retains at least two somewhat distinct communities of genes.

‣ A Comparison of 100 Human Genes Using an Alu Element-Based Instability Model

Cook, George W.; Konkel, Miriam K.; Walker, Jerilyn A.; Bourgeois, Matthew G.; Fullerton, Mitchell L.; Fussell, John T.; Herbold, Heath D.; Batzer, Mark A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 03/06/2013 Português
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The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or “hit”. This hypothesized “two-hit” (two double-strand breaks) potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes...

‣ Manteia, a predictive data mining system for vertebrate genes and its applications to human genetic diseases

Tassy, Olivier; Pourquié, Olivier
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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The function of genes is often evolutionarily conserved, and comparing the annotation of ortholog genes in different model organisms has proved to be a powerful predictive tool to identify the function of human genes. Here, we describe Manteia, a resource available online at http://manteia.igbmc.fr. Manteia allows the comparison of embryological, expression, molecular and etiological data from human, mouse, chicken and zebrafish simultaneously to identify new functional and structural correlations and gene-disease associations. Manteia is particularly useful for the analysis of gene lists produced by high-throughput techniques such as microarrays or proteomics. Data can be easily analyzed statistically to characterize the function of groups of genes and to correlate the different aspects of their annotation. Sophisticated querying tools provide unlimited ways to merge the information contained in Manteia along with the possibility of introducing custom user-designed biological questions into the system. This allows for example to connect all the animal experimental results and annotations to the human genome, and take advantage of data not available for human to look for candidate genes responsible for genetic disorders. Here, we demonstrate the predictive and analytical power of the system to predict candidate genes responsible for human genetic diseases.

‣ Manteia, a predictive data mining system for vertebrate genes and its applications to human genetic diseases

Tassy, Olivier; Pourquié, Olivier
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
455.80273%
The function of genes is often evolutionarily conserved, and comparing the annotation of ortholog genes in different model organisms has proved to be a powerful predictive tool to identify the function of human genes. Here, we describe Manteia, a resource available online at http://manteia.igbmc.fr. Manteia allows the comparison of embryological, expression, molecular and etiological data from human, mouse, chicken and zebrafish simultaneously to identify new functional and structural correlations and gene-disease associations. Manteia is particularly useful for the analysis of gene lists produced by high-throughput techniques such as microarrays or proteomics. Data can be easily analyzed statistically to characterize the function of groups of genes and to correlate the different aspects of their annotation. Sophisticated querying tools provide unlimited ways to merge the information contained in Manteia along with the possibility of introducing custom user-designed biological questions into the system. This allows for example to connect all the animal experimental results and annotations to the human genome, and take advantage of data not available for human to look for candidate genes responsible for genetic disorders. Here, we demonstrate the predictive and analytical power of the system to predict candidate genes responsible for human genetic diseases.

‣ Analyses of the extent of shared synteny and conserved gene orders between the genome of fugu rubripes and human 20q

Smith, S.; Snell, P.; Grutzner, F.; Bench, A.; Haaf, T.; Metcalfe, J.; Green, A.; Elgar, G.
Fonte: Cold Spring Harbor Lab Press Publicador: Cold Spring Harbor Lab Press
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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Cosmid and BAC contig maps have been constructed across two Fugu genomic regions containing the orthologs of human genes mapping to human chromosome 20q. Contig gene contents have been assessed by sample sequencing and comparative database analyses. Contigs are centered around two Fugu topoisomerase1 (top1) genes that were initially identified by sequence similarity to human TOP1 (20q12). Two other genes (SNAI1 and KRML) mapping to human chromosome 20 are also duplicated in Fugu. The two contigs have been mapped to separate Fugu chromosomes. Our data indicate that these linkage groups result from the duplication of an ancestral chromosome segment containing at least 40 genes that now map to the long arm of human chromosome 20. Although there is considerable conservation of synteny, gene orders are not well conserved between Fugu and human, with only very short sections of two to three adjacent genes being maintained in both organisms. Comparative analyses have allowed this duplication event to be dated before the separation of Fugu and zebrafish. Our data (which are best explained by regional duplication, followed by substantial gene loss) support the hypothesis that there have been a large number of gene and regional duplications (and corresponding gene loss) in the fish lineage...

‣ Integrative Annotation of 21,037 Human Genes Validated by Full-Length cDNA Clones

Imanishi, Tadashi; Itoh, Takeshi; Suzuki, Yutaka; O'Donovan, Claire; Fukuchi, Satoshi; Koyanagi, Kanako O; Barrero, Roberto A; Tamura, Takuro; Yamaguchi-Kabata, Yumi; Tanino, Motohiko; Yura, Kei; Miyazaki, Satoru; Ikeo, Kazuho; Homma, Keiichi; Kasprzyk, A
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms...

‣ Preventing Dangerous Nonsense: Selection for Robustness to Transcriptional Error in Human Genes

Cusack, Brian P.; Arndt, Peter F.; Duret, Laurent; Crollius, Hugues Roest
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Nonsense Mediated Decay (NMD) degrades transcripts that contain a premature STOP codon resulting from mistranscription or missplicing. However NMD's surveillance of gene expression varies in efficiency both among and within human genes. Previous work has shown that the intron content of human genes is influenced by missplicing events invisible to NMD. Given the high rate of transcriptional errors in eukaryotes, we hypothesized that natural selection has promoted a dual strategy of “prevention and cure” to alleviate the problem of nonsense transcriptional errors. A prediction of this hypothesis is that NMD's inefficiency should leave a signature of “transcriptional robustness” in human gene sequences that reduces the frequency of nonsense transcriptional errors. For human genes we determined the usage of “fragile” codons, prone to mistranscription into STOP codons, relative to the usage of “robust” codons that do not generate nonsense errors. We observe that single-exon genes have evolved to become robust to mistranscription, because they show a significant tendency to avoid fragile codons relative to robust codons when compared to multi-exon genes. A similar depletion is evident in last exons of multi-exon genes. Histone genes are particularly depleted of fragile codons and thus highly robust to transcriptional errors. Finally...

‣ Systematic genome-wide approach to positional candidate cloning for identification of novel human disease genes

Kiyosawa, H; Kawashima, T; Silva, Diego; Petrovsky, Nikolai; Hasegawa, Y; Sakai, K; Hayashizaki, Y
Fonte: Blackwell Science Asia Publicador: Blackwell Science Asia
Tipo: Artigo de Revista Científica
Português
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Background: Recent large-scale genome projects afford a unique opportunity to identify many novel disease genes and thereby better understand the genetic basis of human disease. Functional Annotation of Mouse (FANTOM) 2, the largest mouse transcriptome project yet, provides a wealth of data on novel genes, splice variants and non-coding RNA, and provides a unique opportunity to identify novel human disease genes. Aims: To demonstrate the power of combining the FANTOM 2 cDNA dataset with a positional candidate approach and bioinformatics analysis to identify genes underlying human genetic disease. Results: By mapping all FANTOM 2 cDNA to the human genome, we were able to identify mouse clones that co-localised on the human genome with mapped but uncloned human disease loci. By this method we identified mouse and corresponding human genes mapping within the loci of 100 different human genetic diseases (mapped interval of <5 cM). Of particular interest was the elucidation through FANTOM 2 novel mouse gene data of candidate human genes for the following: (i) developmental disorders: neural tube defect, Meckel syndrome, Wolf-Hirschhorn syndrome and keratosis follicularis spinulosa decalvans cum ophiasi; (ii) neurological disorders: benign familial infantile convulsions 3...

‣ A influência do genoma humano no curso das hepatites virais crônicas; The influence of the human genome on chronic viral hepatitis outcome

Andrade Júnior, Dahir Ramos de; Andrade, Dahir Ramos de
Fonte: Universidade de São Paulo. Instituto de Medicina Tropical de São Paulo Publicador: Universidade de São Paulo. Instituto de Medicina Tropical de São Paulo
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; Formato: application/pdf
Publicado em 01/06/2004 Português
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Os mecanismos que determinam o clearance ou a persistência da infecção viral nas hepatites virais crônicas não estão ainda bem identificados. O progresso no conhecimento sobre as ferramentas genéticas moleculares tem permitido detectar variações na resposta imune, que freqüentemente são associadas com polimorfismos do genoma humano. As diferenças na susceptibilidade do hospedeiro para as doenças infecciosas e a intensidade das doenças não podem ser atribuídas apenas à virulência do agente microbiano. Neste artigo são discutidos vários avanços recentes no conhecimento sobre a influência dos genes humanos nas hepatites crônicas B e C, a saber: a) As associações entre os polimorfismos HLA e a susceptibilidade ou resistência às doenças hepáticas virais; b) Alelos protetores influenciando as hepatites virais B (HVB) e C (HVC); c) Alelos prejudiciais influenciando HVB e HVC; d) Genes candidatos associados com a evolução clínica de HVB e HVC (genes que influenciam as células estreladas do fígado, a produção de TGF-beta1 e TNF-alfa, os depósitos de ferro hepáticos, a produção de angiotensina II, entre outros). O conhecimento das associações genéticas com as hepatites virais crônicas pode fornecer indícios para o pleno entendimento de como se desenvolvem as suas complicações terminais...