Evolución génica: estudios en biología computacional
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2011
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es
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Universidad Andrés Bello
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Resumen
En este trabajo de tesis realizado en el Centro de Bioinformática y Biología Genómica de la Fundación Ciencia Para La Vida, cuatro investigaciones relativas a evolución génica fueron llevadas a cabo desde la perspectiva de la biología computacional.
El campo de la biología computacional emergió hace unos quince años y ya se ha consolidado entre las ciencias biológicas. Investigaciones llevadas a cabo enteramente in sillico sobre datos biológicos a gran escala están ya presente en artículos peer-reviewed y engloban tópicos como evolución génica, genómica comparativa, identificación de genes, análisis filogenético y estudios de expresión génica. Nada de esto hubiese sido posible sin el poder de cómputo disponible sólo recientemente. En este contexto, se realizó cuatro investigaciones.
Específicamente, en esta tesis el poder computacional permitió, por ejemplo, realizar millones de búsquedas por similitud de secuencia para estudiar un nuevo modelo de evolución génica, o para procesar datos de splicing alternativo para millones de transcritos, al analizar el fenómeno globalmente. Enfoques similares han permitido a otros autores estudiar tópicos relacionados, como splicing alternativo vs. duplicación génica, o la historia de la ganancia-pérdida de intrones durante la evolución de los eucariontes.
Para esta tesis, cuatro investigaciones fueron llevadas a cabo. En la primera de ellas, fue estudiada la prevalencia de marcos de lectura abiertos (ORFs) alternativos, encontrándose que son significativamente frecuentes en genomas, especialmente en los que el G+C codificante es alto. Por esta razón, también se mostró que constituyen una fuente considerable de errores de anotación, cuando se consigna como gen el ORF alternativo y no la secuencia que realmente es la codificante. Finalmente, se exploró la posibilidad de que, durante la evolución, genes conteniendo un ORF alternativo hayan podido duplicarse y un nuevo gen haber emergido a través de la captura del ORF.
Hasta este momento no se encontró evidencia genómica para tal mecanismo.
En la segunda, se mostró que las regiones codificantes de los organismos termófilos e hipertermófilos (todos procariontes) presentan una fracción significativamente mayor de codones NTN, que codifican para aminoácidos hidrófobos. Este resultado fortalece la hipótesis de que las interacciones hidrofóbicas en las proteínas son un mecanismo importante para conferir termoestabilidad en términos estructurales y funcionales.
La tercera investigación consistió en proponer una medida de presión selectiva para los 20 aminoácidos estándar de un modo no-sitio específico, calculable a partir de las secuencias codificantes de genes de interés. La comparación entre aminoácidos en términos de la medida propuesta calculada resultó consistente con criterios biológicos, y se muestra especialmente útil para identificar residuos aminoacídicos relevantes en nichos ecológicos que ejercen fuerte presión selectiva de algún tipo.
Finalmente, se estudió el splicing alternativo en términos de la disimilitud composicional aminoacídica entre los exones del gen eucarionte. Se encontró correlaciones entre la frecuencia individual de exones, coocurrencia de pares de exones, entre otras variables, con la disimilitud composicional.
In this thesis work carried out in the Center tor Biontormatics and Genome Biology of the Fundación Ciencia Para La Vida, tour investigations relative to gene evolution were performed from the perspective of computational biology. The field of computational biology emerged sorne fifteen years ago and has already consolidated in the life sciences. Research carried out entirely in silico on high throughput biological data is now present in peer-reviewed articles and encompasses tapies such as gene evolution, comparative genomics, gene finding, phylogenetic analysis, and gene expression studies. None of these could be accomplished without the computing power only available recently. Specifically in this thesis work, computer power permitted, tor instance, to perform millions of sequence similarity searches tor studying a novel model of gene evolution, or to process alternative splicing data tor millions of transcripts, when analyzing the phenomenon globally. Similar approaches have permitted other authors to study related tapies, such as alternative splicing vs. gene duplication, or the history of intron gain-loss through eukaryote evolution. For this thesis, tour investigations were carried out. In the first of them, the prevalence of alternate open reading trames (ORFs) was studied, finding it to be significantly frequent in genomes, especially in those where the coding G+C is high. For this very reason, it was also shown that they constitute a considerable source of annotation errors, when the alternate ORF is annotated as a gene and not the real coding sequence. Finally, the possibility that during evolution genes containing a significant alternate ORF could have duplicated and then a new gene could have arisen through the capture of the alternate ORFs was explored. So far, no genomic evidence was tound tor such mechanism. In the second investigation, it was shown that coding regions in genomes of thermophilic and hyperthermophilic prokaryotes display a significantly larger fraction of NTN codons, that code tor hydrophobic amino acids. This result strengthens the hypothesis of hydrophobic interactions in proteins as an important mechanism to confer thermic stability in structural and functional terms. The third investigation consisted in proposing a measure of selective pressure tor the 20 standard amino acids in a non site-specific manner, calculable from the coding regions of genes of interest. The comparison between amino acids in terms of the proposed measure turned out to be consistent with biological criteria, and it appears especially useful for identifying relevant amino acid residues in ecological niches that exert strong selective pressure of sorne type. Finally, alternative splicing was studied in terms of amino acidic compositional dissimilarity between the exons in the eukaryotic gene. Correlations were found between individual exon frequency, pairwise exon co-occurrence in relationship, among other variables, with compositional dissimilarity
In this thesis work carried out in the Center tor Biontormatics and Genome Biology of the Fundación Ciencia Para La Vida, tour investigations relative to gene evolution were performed from the perspective of computational biology. The field of computational biology emerged sorne fifteen years ago and has already consolidated in the life sciences. Research carried out entirely in silico on high throughput biological data is now present in peer-reviewed articles and encompasses tapies such as gene evolution, comparative genomics, gene finding, phylogenetic analysis, and gene expression studies. None of these could be accomplished without the computing power only available recently. Specifically in this thesis work, computer power permitted, tor instance, to perform millions of sequence similarity searches tor studying a novel model of gene evolution, or to process alternative splicing data tor millions of transcripts, when analyzing the phenomenon globally. Similar approaches have permitted other authors to study related tapies, such as alternative splicing vs. gene duplication, or the history of intron gain-loss through eukaryote evolution. For this thesis, tour investigations were carried out. In the first of them, the prevalence of alternate open reading trames (ORFs) was studied, finding it to be significantly frequent in genomes, especially in those where the coding G+C is high. For this very reason, it was also shown that they constitute a considerable source of annotation errors, when the alternate ORF is annotated as a gene and not the real coding sequence. Finally, the possibility that during evolution genes containing a significant alternate ORF could have duplicated and then a new gene could have arisen through the capture of the alternate ORFs was explored. So far, no genomic evidence was tound tor such mechanism. In the second investigation, it was shown that coding regions in genomes of thermophilic and hyperthermophilic prokaryotes display a significantly larger fraction of NTN codons, that code tor hydrophobic amino acids. This result strengthens the hypothesis of hydrophobic interactions in proteins as an important mechanism to confer thermic stability in structural and functional terms. The third investigation consisted in proposing a measure of selective pressure tor the 20 standard amino acids in a non site-specific manner, calculable from the coding regions of genes of interest. The comparison between amino acids in terms of the proposed measure turned out to be consistent with biological criteria, and it appears especially useful for identifying relevant amino acid residues in ecological niches that exert strong selective pressure of sorne type. Finally, alternative splicing was studied in terms of amino acidic compositional dissimilarity between the exons in the eukaryotic gene. Correlations were found between individual exon frequency, pairwise exon co-occurrence in relationship, among other variables, with compositional dissimilarity
Notas
Tesis (Doctor en Biotecnología)
Palabras clave
Biología Computacional, Terapia de gen, Investigaciones genéticas, Chile