O estudo fornece a primeira evidência de todo o genoma para a importa¢ncia funcional de estruturas incomuns de DNA
Algumas regiaµes do genoma humano onde o DNA pode se dobrar em estruturas tridimensionais incomuns chamadas G-quadruplexes (G4s) mostram sinais de que foram preservadas pela selea§a£o natural.
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)
Ilustração que mostra tendaªncias nos naveis de seleção de purificação (roxo) e termoestabilidade (verde) em G-quadruplexes (G4s) - sequaªncias no genoma humano que podem se dobrar em estruturas tridimensionais incomuns - em diferentes regiaµes do genoma (mostrado na parte inferior ) Um novo estudo de todo o genoma mostra maior seleção e estabilidade de G4s em regiaµes regulata³rias de genes e sugere que as estruturas incomuns devem ser adicionadas a lista de elementos funcionais do genoma. Crédito: Kateryna Makova e Dani Zemba, Penn State
Algumas regiaµes do genoma humano onde o DNA pode se dobrar em estruturas tridimensionais incomuns chamadas G-quadruplexes (G4s) mostram sinais de que foram preservadas pela seleção natural. Quando G4s estãolocalizados nas sequaªncias regulata³rias que controlam como os genes são expressos, ou em outras regiaµes codificantes funcionais, mas não proteicas do genoma, eles são mantidos por seleção, são mais comuns e suas estruturas incomuns são mais esta¡veis, de acordo com um novo estudo. Por outro lado, as estruturas são menos comuns, menos esta¡veis ​​e evoluem de forma neutra fora dessas regiaµes, incluindo dentro das regiaµes codificadoras de proteanas dos pra³prios genes.
Juntas, essas linhas de evidência sugerem que os elementos G4 devem ser adicionados a lista de elementos funcionais do genoma junto com genes, sequaªncias regulata³rias e RNAs não codificadores de proteanas, entre outros. Um artigo descrevendo o estudo, feito por uma equipe de pesquisadores liderada por cientistas da Penn State, foi publicado nesta tera§a-feira, 29, na revista Genome Research .
"Houve apenas um punhado de estudos que forneceram evidaªncias experimentais para elementos individuais do G4 desempenhando papanãis funcionais", disse Wilfried Guiblet, primeiro autor do artigo, um estudante de graduação na Penn State no momento da pesquisa e agora um pa³s-doutorado em o Instituto Nacional do Ca¢ncer. "Nosso estudo éo primeiro a olhar para G4s em todo o genoma para ver se eles mostram as caracteristicas dos elementos funcionais como regra geral."
Tanto quanto 1% do genoma pode dobrar em G4s, ao invanãs da tapica dupla hanãlice (em comparação, os genes codificadores de proteanas ocupam aproximadamente 1,5% do genoma). G4s são uma das várias formas não cana´nicas nas quais o DNA pode se dobrar, conhecidas coletivamente como "DNA não B". A estrutura G4 forma-se em sequaªncias de DNA ricas no nucleotadeo guanina, o "G" do alfabeto ACGT do genoma. Os G4s foram implicados em vários processos celulares importantes e foi sugerido que desempenham um papel em várias doenças humanas, incluindo distúrbios neurola³gicos e ca¢ncer.
Para entender melhor a função dos G4s em uma escala ampla do genoma, a equipe de pesquisa analisou sua distribuição no genoma, sua termoestabilidade e se eles mostravam ou não sinais de estarem sob a influaªncia da seleção natural, tudo em relação a outros elementos do genoma. Eles confirmaram que, via de regra, os G4s são mais comuns em regiaµes do genoma conhecidas por terem funções celulares importantes e que os G4s nessas regiaµes são mais esta¡veis ​​do que em outras partes do genoma.
"A estrutura tridimensional do G4s pode se formar temporariamente e quanto esta¡vel ésua estrutura depende de sua sequaªncia de DNA subjacente e de outros fatores", disse Guilbet. "Descobrimos que normalmente, G4s localizados dentro de regiaµes funcionais do genoma tendem a ser mais esta¡veis. Em outras palavras, émais prova¡vel que o DNA seja dobrado em um G4 a qualquer momento e, portanto, émais prova¡vel que o G4 esteja la¡ para uma razãofuncional. "
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As regiaµes funcionais do genoma são geralmente mantidas por um tipo de seleção natural chamada seleção purificadora. Mutações nessas regiaµes podem interromper sua função e ser prejudiciais ao organismo. As mutações, portanto, são geralmente eliminadas por seleção purificadora, que mantanãm a sequaªncia de DNA relativamente inalterada ao longo do tempo. Em regiaµes não funcionais do genoma, uma mutação pode não ter impacto e pode persistir no genoma sem quaisquer consequaªncias. Diz-se que essas regiaµes do genoma evoluem de forma neutra. Onde os G4s se enquadram neste espectro depende de sua localização no genoma.
"Podemos observar os padraµes de mudança em uma sequaªncia de DNA entre indivíduos humanos e entre humanos e nossos parentes primatas pra³ximos como um teste de seleção natural e então usar a seleção como um indicador de função", disse Yi-Fei Huang, professor assistente de biologia na Penn State e lider da equipe de pesquisa. "Nossos testes mostram que G4s localizados dentro de regiaµes funcionais do genoma parecem estar sob seleções de purificação, o que émais uma evidência de que G4s devem ser considerados como elementos funcionais. A única exceção a este padrãoforam as regiaµes codificadoras de proteanas dos genes, onde G4s são relativamente incomum, bastante insta¡vel e não evoluem sob seleção purificadora. G4s em regiaµes de genes que codificam proteanas podem ser não funcionais e de manutenção dispendiosa. "
A equipe de pesquisa mostrou recentemente que G4s, junto com outros tipos de DNA não-B, aumentaram as taxas de mutação. O fato de que G4s localizados fora das regiaµes codificadoras de proteanas são mantidos por seleção purificadora, apesar de seu alto potencial mutagaªnico, acrescenta mais peso a evidência para classificar G4s como elementos funcionais.
"Achamos que estamos vendo evidaªncias de uma mudança de paradigma de como os cientistas definem a função no genoma", disse Kateryna Makova, presidente de Ciências da Vida da Verne M. Willaman na Penn State e lider da equipe de pesquisa. "Primeiro, os geneticistas se concentraram quase exclusivamente em genes codificadores de proteanas, então ficamos cientes de muitos elementos não codificantes funcionais e agora temos G4s e possivelmente outros elementos de DNA não B. A estrutura tridimensional pode ser tão importante para definir funcionar como a sequaªncia de DNA subjacente. "
"Definir o complemento total dos elementos do genoma funcional écrucial para interpretar as possaveis consequaªncias da doena§a, não apenas de variantes genanãticas herdadas, mas também de mutações que surgem nos tecidos ao longo da vida dos indivaduos", disse Kristin Eckert, professora de patologia do Penn State College of Medicine, coautor do artigo e membro da equipe de pesquisa. "A identificação dos G4s como novos elementos funcionais dentro do genoma humano éa chave para o avanço do uso da genanãtica na medicina de precisão."