Aplicabilidade de redes PPI em Biologia de sistemas no contexto da síndrome de Williams-Beuren
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Data
2022-02-07
Autores
Medeiros, Priscila
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Uma microdeleção hemizigótica de 1,5Mb a 1,8Mb na região do braço longo do cromossomo 7 (7q11.23) ocasiona uma doença genética rara multigênica. Faces típicas, doenças cardiovasculares, alterações do tecido conjuntivo combinados com déficit de aprendizado e crescimento, personalidade e perfil cognitivo característicos representam o conjunto de sinais clínicos que caracteriza a síndrome de Williams-Beuren (SWB). Embora a técnica da FISH permita o diagnóstico citomolecular da síndrome, a existência de deleções de tamanhos típicos e atípicos, as quais não são evidenciadas pela FISH, acarreta em diferentes genes afetados. Por isso, o objetivo deste estudo foi investigar e caracterizar a microdeleção mediante análise por CMA (do inglês Chromosome Microarray Analysis) e analisar o impacto desta através de uma abordagem in silico utilizando redes de interação entre proteínas (PPI). Dentre os 14 indivíduos recrutados e avaliados no estudo, apenas um apresentou uma FISH negativa. Clinicamente, todos os participantes exibiram características da SWB com escore acima de 3. Uma deleção típica de 1,367,201Kb foi confirmada e caracterizada por CMA em 13 participantes do estudo e o impacto desta foi analisado em duas redes biológicas, uma representando a rede de um indivíduo sem alterações (GN) e outra representando o indivíduo acometido (PN). As proteínas codificadas pelos genes deletados foram extraídos da rede GN para simular a rede PPI do indivíduo com a deleção (PN). Análises topológicas de ambas redes foram analisadas, assim como nas redes no contexto de comunidades. Os resultados não mostraram diferenças significativas entre as redes. Pela análise de enriquecimento com termos ontológicos relacionados a processos biológicos, foi possível identificar as regiões onde houve enriquecimento dentro de cada comunidade, bem como identificar quais proteínas e termos ontológicos são compartilhados. Com isso, foi possível analisar diferenças entre as redes após a deleção e apontar diferentes proteínas até então não correlacionadas à síndrome. Embora a abordagem in silico utilizada neste estudo não tenha apresentando diferenças estatísticas, a utilização de estudos com redes biológicas além de trazer novas descobertas para o estudo da SWB, pode também ser uma ferramenta importante para esclarecer a variabilidade fenotípica e fisiopatologia da doença.
A hemizygous deletion of 1.5Mb to 1.8Mb in the long arm region of chromosome 7 (7q11.23) causes a rare multigenic genetic disorder. Typical faces, cardiovascular disease, connective tissue abnormalities combined with learning and growth deficits, a characteristic personality and cognitive profile represent the set of clinical signs that characterize Williams-Beuren syndrome (SWB). Although the FISH technique allows the diagnosis, a correct genotype-phenotype correlation is necessary since, due to the existence of typical or atypical deletions, different genes can be affected. To this end, the aim of this study was to investigate and characterize microdeletion by Chromosome Microarray Analysis (CMA) and analyze its impact through an in silico approach using protein-protein interaction networks (PPI). Among the fourteen recruited and evaluated individuals, only one had a negative FISH. Clinically, all individuals exhibited WBS characteristics with score higher than 3. A typical deletion of 1,367,201Kb in thirteen individuals was confirmed and characterized by CMA and its impact was analyzed in two biological networks, one representing the network of an unchanged individual (GN) and the other representing the affected individual (PN). The proteins encoded by the deleted genes were extracted from the GN network to simulate the PPI network of the individual with the deletion (PN). Topological analyses of both networks were analyzed, as well as networks in the context of communities. The results exhibited no significant differences among the networks. By analyzing enrichment with ontological terms related to biological processes, it was possible to identify the regions where enrichment occurred within each community, as well as to identify which proteins and ontological terms are shared. By doing so, it was possible to analyze differences between the networks after the deletion and to point out different proteins not previously correlated to the syndrome. Although the in silico approach used in this study did not show statistical differences, the use of studies with biological networks, besides bringing new discoveries for the study of WBS, can also be an important tool to clarify the phenotypic variability and pathophysiology of the disease.
A hemizygous deletion of 1.5Mb to 1.8Mb in the long arm region of chromosome 7 (7q11.23) causes a rare multigenic genetic disorder. Typical faces, cardiovascular disease, connective tissue abnormalities combined with learning and growth deficits, a characteristic personality and cognitive profile represent the set of clinical signs that characterize Williams-Beuren syndrome (SWB). Although the FISH technique allows the diagnosis, a correct genotype-phenotype correlation is necessary since, due to the existence of typical or atypical deletions, different genes can be affected. To this end, the aim of this study was to investigate and characterize microdeletion by Chromosome Microarray Analysis (CMA) and analyze its impact through an in silico approach using protein-protein interaction networks (PPI). Among the fourteen recruited and evaluated individuals, only one had a negative FISH. Clinically, all individuals exhibited WBS characteristics with score higher than 3. A typical deletion of 1,367,201Kb in thirteen individuals was confirmed and characterized by CMA and its impact was analyzed in two biological networks, one representing the network of an unchanged individual (GN) and the other representing the affected individual (PN). The proteins encoded by the deleted genes were extracted from the GN network to simulate the PPI network of the individual with the deletion (PN). Topological analyses of both networks were analyzed, as well as networks in the context of communities. The results exhibited no significant differences among the networks. By analyzing enrichment with ontological terms related to biological processes, it was possible to identify the regions where enrichment occurred within each community, as well as to identify which proteins and ontological terms are shared. By doing so, it was possible to analyze differences between the networks after the deletion and to point out different proteins not previously correlated to the syndrome. Although the in silico approach used in this study did not show statistical differences, the use of studies with biological networks, besides bringing new discoveries for the study of WBS, can also be an important tool to clarify the phenotypic variability and pathophysiology of the disease.
Descrição
Palavras-chave
7q11.23, Genética, PPI, Redes de interação proteína-proteína, Síndrome de Williams-Beuren, Mapeamento de interação e proteínas