Abstract
Author SummaryCellular characteristics and functions are determined largely by gene expression and expression levels differ among individuals, however it is not clear how these levels are regulated. While many cis-acting DNA sequence variants in promoters and enhancers that influence gene expression have been identified, only a few polymorphic trans-regulators of human genes are known. Here, we used human B-cells from individuals belonging to large families and identified polymorphic trans-regulators for about 1,000 human genes. We validated these results by gene knockdown, metabolic perturbation studies and chromosome conformation capture assays. Although these regulatory relationships were identified in cultured B-cells, we show that some of the relationships were also found in primary fibroblasts. The large number of regulators allowed us to better understand gene expression regulation, to uncover new gene functions, and to identify their roles in disease processes. This study shows that genetic variation is a powerful tool not only for gene mapping but also to study gene interaction and regulation.
Highlights
Expression levels of genes, like many phenotypes, vary among normal individuals
These regulatory relationships were identified in cultured B-cells, we show that some of the relationships were found in primary fibroblasts
This study shows that genetic variation is a powerful tool for gene mapping and to study gene interaction and regulation
Summary
Expression levels of genes, like many phenotypes, vary among normal individuals. Since gene expression underlies cellular characteristics and functions, variation in gene expression contributes to phenotypic diversity and differences in disease susceptibility. We and others demonstrated that there is a genetic basis to individual variation in gene expression [1,2,3,4,5,6] This facilitates studies to identify sequence variants that influence expression levels of genes. GOGE studies that treated expression levels as quantitative traits in family-based linkage [3,7] and population-based association analyses [5,8,9] have uncovered polymorphic regulatory regions that contribute to variation in human gene expression. The results allowed us to narrow the regulatory regions and identify cis- and trans-acting polymorphic regulators of ,1,000 human genes These results facilitated molecular validation and analyses of the mapping data. The end points of many human genetic studies showed genotype-phenotype connections statistically but not molecularly
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