Tissue-Specific Effects of Genetic and Epigenetic Variation on Gene Regulation and Splicing


In order to better understand how genetic differences between individuals can cause diseases, it is crucial to understand how genetic variants affect cellular functions in the different tissues that compose the human body. From the umbilical cord of 195 newborn babies, we previously obtained three different cell-types: fibroblasts, T-cells and immortalized B-cells. From every individual in each cell type we measured four features across the genome: 1) genetic differences, 2) DNA methylation, an epigenetic modification of DNA that can affect its functional state, 3) gene expression—the amount of gene activity, 4) alternative splicing—which of the different versions of a gene is manifested. We find thousands of genetic variants of the DNA sequence that affect methylation, gene expression, and splicing. We show that while these genetic effects often affect multiple cell-types, the strength of these effects varies between cell-types. Also epigenetic methylation marks of DNA associate to gene expression and particularly often to splicing. Since abnormalities in gene expression, DNA methylation and alternative splicing are associated to diseases, it is important to continue studying how these traits are inter-related and affected by genetic variation across cell-types.


Vyšlo v časopise: Tissue-Specific Effects of Genetic and Epigenetic Variation on Gene Regulation and Splicing. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004958
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004958

Souhrn

In order to better understand how genetic differences between individuals can cause diseases, it is crucial to understand how genetic variants affect cellular functions in the different tissues that compose the human body. From the umbilical cord of 195 newborn babies, we previously obtained three different cell-types: fibroblasts, T-cells and immortalized B-cells. From every individual in each cell type we measured four features across the genome: 1) genetic differences, 2) DNA methylation, an epigenetic modification of DNA that can affect its functional state, 3) gene expression—the amount of gene activity, 4) alternative splicing—which of the different versions of a gene is manifested. We find thousands of genetic variants of the DNA sequence that affect methylation, gene expression, and splicing. We show that while these genetic effects often affect multiple cell-types, the strength of these effects varies between cell-types. Also epigenetic methylation marks of DNA associate to gene expression and particularly often to splicing. Since abnormalities in gene expression, DNA methylation and alternative splicing are associated to diseases, it is important to continue studying how these traits are inter-related and affected by genetic variation across cell-types.


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