Banca de DEFESA: ARTHUR SANT'ANNA FELTRIN

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : ARTHUR SANT'ANNA FELTRIN
DATA : 16/12/2020
HORA: 14:00
LOCAL: por participação remota em https://conferenciaweb.rnp.br/webconf/david-41
TÍTULO:

Consensual analysis of complex integrated transcriptome and methylome networks for the study of sexual dimorphism in Schizophrenia Spectrum Disorders

PÁGINAS: 205
GRANDE ÁREA: Outra
ÁREA: Multidisciplinar
RESUMO:

Schizophrenia Spectrum Disorders (SCZ) is characterized by being complex and multifactorial, affecting approximately 20 million people worldwide. Rare genetic variants - those with the lowest allele frequency (MAF) <1% in the population - contribute to SCZ. However, the susceptibility to SCZ appears to be more associated with the additive action of multiple common variants of small effect than the effect of rare variants. On the other hand, SCZ heritability varies from 50-80%, indicating that epigenetic factors play a fundamental role. However, SCZ has a clear sexual dimorphism: it is usually diagnosed in men during adolescence - and in women at a late age, from the age of 25. Additionally, men tend to have a much more severe form of this disorder. In this way, the integration of data that addresses both genetic (gene expression) and / or environmental (DNA methylation) contributions, may reflect more comprehensively the changes in important biological pathways in the context of the disease. So far, the algorithms that propose the integration of these types of data mostly use differentially expressed genes (DEG) and differentially methylated genes (DMG). However, these current proposals result in a small set of genes, which may not comprehensively reflect the altered genes and biological pathways in the disease. NERI (2015) is an algorithm capable of integrating data from PPI, seed genes and gene expression. Originally, it uses the analysis of shortest paths between all seed pairs in the network, selecting the best paths by concordance of co-expression values among the path edges and comparing these values between two different groups (subnetworks). The purpose of this study is to adapt the NERI algorithm to use, in addition to gene expression, DNA methylation (from the dorsolateral prefrontal cortex of men and women samples), creating a new integrative approach for the analysis of co-methylation and co-expression networks, not dependent on the use of differentially expressed genes or differentially methylated genes. We used 3 sets of seed genes associated with the risk for SCZ (from a genome wide association study - GWAS), expressed in the fetal brain at 3 different gestational periods. From the analysis of NERI's shortest paths, we selected the genes that had the highest concordance between the co-expression and co-methylation subnetworks in order to explore the similarities and differences of SCZ between men and women. We show that the genes with the highest concordance: I) show concordance only when analyzed in the context of co-expression and co-methylation networks - there is a low correlation between the gene expression signals and DNA methylation, when analyzed individually; II) men and women with SCZ have unique concordant genes - however, their enrichment points to similar metabolic pathways related to the transport of intracellular molecules and organization of organelles, suggesting that these genes are part of the same module in the human interactome network; III) these genes have extremely high topological importance within the human interactome network, being mostly central hubs, responsible for connecting different points in the network; IV) DEG and DMG in SCZ were located on the periphery of the interactome network (presenting low enrichment for biological pathways); V) the intersection between the most concordant NERI genes from men and women and the DEG and DMG genes in SCZ was minimal. Thus, we demonstrate that in addition to being able to integrate distinct biological data types, this new approach was able to find unique patterns of co-expression and co-methylation, pointing to central and highly important genes in the human interactome - which were not previously associated with SCZ.

MEMBROS DA BANCA:
Presidente - Interno ao Programa - 1722875 - DAVID CORREA MARTINS JUNIOR
Membro Titular - Examinador(a) Interno ao Programa - 1676367 - ALEXANDRE HIROAKI KIHARA
Membro Titular - Examinador(a) Externo ao Programa - 1732829 - ANA CAROLINA QUIRINO SIMOES
Membro Titular - Examinador(a) Externo à Instituição - ANDRÉ FUJITA - USP
Membro Titular - Examinador(a) Externo à Instituição - APUÃ CÉSAR DE MIRANDA PAQUOLA
Membro Suplente - Examinador(a) Externo à Instituição - MAURO ANTÔNIO ALVES CASTRO - UFPR
Membro Suplente - Examinador(a) Externo à Instituição - ISRAEL TOJAL DA SILVA - ACCAMARGO