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Doctoral Thesis
DOI
10.11606/T.41.2012.tde-15102012-105825
Document
Author
Full name
Rodrigo Fernandes Ramalho
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Meyer, Diogo (President)
Line, Sergio Roberto Peres
Matioli, Sergio Russo
Oliveira, Carla Columbano de
Silva Junior, Wilson Araújo da
Title in Portuguese
Análise dos sinais de seleção natural em reguladores de splicing exônicos do genoma humano
Keywords in Portuguese
Evolução
Reguladores de splicing
Seleção natural
Abstract in Portuguese
O splicing é o processo que resulta na remoção dos íntrons e união dos éxons nos genes eucarióticos. Nesse processo diversos elementos em cis e trans estão envolvidos. Além das sequências em cis canônicas (sítios de splicing, sítio de ramificação e trato de polipirimidina), os reguladores de splicing -- sequências curtas localizadas em éxons e íntrons - são considerados de grande importância, pois auxiliam na correta determinação das fronteiras éxons/introns. Através do splicing alternativo pode-se gerar grande diversidade de transcritos e atualmente sabe-se que no mínimo, 80% dos genes humanos apresentam variantes de splicing. A evolução dos Reguladores de Splicing Exônicos (ESRs) foi principalmente analisada através de abordagens filogenéticas. Embora esses estudos tenham revelado resultados consistentes (por exemplo, evidências de seleção negativa contra mudanças sinônimas que afetam ESRs) outros ainda parecem contraditórios, como a maior conservação filogenética e a maior taxa de evolução não-sinônima dos éxons alternativos em relação aos constitutivos. Nesta tese abordamos questões sobre o regime e a intensidade de seleção que atuam sobre os éxons e seus reguladores através da comparação da variação genética intra e inter-específica. Os resultados da tese demonstram que: 1. Há uma diferença na densidade e na intensidade de seleção negativa que atua sobre os ESRs de éxons constitutivos e alternativos. 2. Os inibidores de splicing tem papel principal na origem dos éxons alternativos a partir de éxons constitutivos e também nos casos de uso alternativo de sítios de splicing. 3. O nível de inclusão dos éxons está diretamente relacionado com a intensidade de seleção negativa sobre mudanças não-sinônimas
Title in English
Investigating he signature of natural selection on exonic splicing regulators of the human genome
Keywords in English
Evolution
Natural selection
Splicing regulators
Abstract in English
Splicing is the process by which introns are removed from a mRNA precursor and exons are ligated to form a mature mRNA. During this process several cis and trans factors are involved. Besides the canonical cis factors (e.g., splicing sites, branch point and polypyrimidine tract), Splicing Regulators - short sequences located in exons and introns - have an important role in assisting the spliceossome to correctly recognize exon/intron boundaries. Through alternative splicing, great transcript diversity is generated, and currently it is known that more than 80% of human genes present splicing variants. The evolution of Exonic Splicing Regulators (ESRs) has been mainly analyzed by interspecific comparisons. Although these studies have revealed consistent results (evidences of weak negative selection against synonymous variations that affect ESRs), other findings still appear inconsistent, for instance the reports on increased level of conservation and higher non-synonymous evolutionary rate in alternative than constitutive exons. The present thesis investigates the regime and intensity of natural selection on exons and their ESRs by comparing intra and interspecific genetic variation. We demonstrate that 1. ESRs from constitutive and alternative exons differ significantly in density and the intensity of negative selection. 2. The exonic splicing silencers have a major role in the origin of exons skipping from constitutive exons, and also on events of alternative usage of splicing sites. 3. There is a positive correlation between the exon inclusion level and the intensity of negative selection against non-synonymous variations
 
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Publishing Date
2013-01-28
 
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