scholarly journals Layers of epistasis: genome-wide regulatory networks and network approaches to genome-wide association studies

2010 ◽  
Vol 3 (5) ◽  
pp. 513-526 ◽  
Author(s):  
Richard Cowper-Sal·lari ◽  
Michael D. Cole ◽  
Margaret R. Karagas ◽  
Mathieu Lupien ◽  
Jason H. Moore
Keyword(s):  
Regulatory Networks ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Network Approaches

Genome-wide association studies reveal the coordinated regulatory networks underlying photosynthesis and wood formation in Populus

2021 ◽  
Author(s):  
Mingyang Quan ◽  
Xin Liu ◽  
Qingzhang Du ◽  
Liang Xiao ◽  
Wenjie Lu ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Regulatory Networks ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Wood Properties ◽  
Wood Formation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Regulatory Pathways ◽  
Genome Wide

Abstract Photosynthesis and wood formation underlie the ability of trees to provide renewable resources and perform ecosystem services; however, the genetic basis and regulatory pathways coordinating these two linked processes remain unclear. Here, we used a systems genetics strategy, integrating genome-wide association study, transcriptomic analyses, and transgenic experiments, to investigate the genetic architecture of photosynthesis and wood properties among 435 unrelated individuals of Populus tomentosa and unravel the coordinated regulatory networks causative of two trait categories. We totally detected 222 significant single-nucleotide polymorphisms, annotated to 177 candidate genes, for 10 traits of photosynthesis and wood properties. Epistasis uncovered 74 epistatic interactions for phenotypes. Strikingly, we deciphered the coordinated regulation patterns of pleiotropic genes underlying phenotypic variations for two trait categories. Furthermore, expression quantitative trait nucleotide mapping and coexpression analysis were integrated to unravel the potential transcriptional regulatory networks of candidate genes coordinating photosynthesis and wood properties. Finally, we heterologously expressed two pleiotropic genes, PtoMYB62 and PtoMYB80, in Arabidopsis thaliana, and demonstrated that they coordinate regulatory networks balancing photosynthesis and stem secondary cell wall components, respectively. Our study provides insight into the regulatory mechanisms coordinating photosynthesis and wood formation in poplar, which will accelerate the genetic breeding in trees via molecular design.

scholarly journals Type 1 diabetes mellitus-associated genetic variants contribute to overlapping immune regulatory networks

2018 ◽  
Author(s):  
Denis M. Nyaga ◽  
Mark H. Vickers ◽  
Craig Jefferies ◽  
Jo K. Perry ◽  
Justin M. O’Sullivan
Keyword(s):  
Type 1 Diabetes ◽  
Regulatory Networks ◽  
Immune Cell ◽  
Association Studies ◽  
Pancreatic Beta Cell ◽  
Three Dimensional ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractType 1 diabetes (T1D) is a chronic metabolic disorder characterised by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk loci across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue-and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 298 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, CLEC2B, TYK2, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signalling, and programmed cell death protein-1 (PD-1). These pathways have been implicated in the pancreatic beta-cell inflammation and destruction as observed in T1D. Our results demonstrate that T1D-associated variants contribute to adaptive immune signalling, and immune-cell proliferation and activation through tissue and cell-type specific regulatory networks.Author SummaryAlthough genome-wide association studies have identified risk regions across the human genome that predispose individuals to the development of type 1 diabetes (T1D), the mechanisms through which these regions contribute to disease is unclear. Here, we used population-based genetic data from genome-wide association studies (GWAS) to understand how the three-dimensional (3D) organization of the DNA contributes to the differential expression of genes involved in immune system dysregulation as observed in T1D. We identified interconnected regulatory networks that affect immune pathways (adaptive immune signalling and immune-cell proliferation and activation) in a tissue and cell-type specific manner. Some of these pathways are implicated in the pancreatic beta-cell destruction. However, we observed other regulatory changes in tissues that are not typically considered to be central to the pathology of T1D, which represents a novel insight into the disease. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic and therapeutic interventions in T1D.

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