Abstract
Associations between the level of single transcripts and single corresponding genetic variants, expression single nucleotide polymorphisms (eSNPs), have been extensively studied and reported. However, most expression traits are complex, involving the cooperative action of multiple SNPs at different loci affecting multiple genes. Finding these cooperating eSNPs by exhaustive search has proven to be statistically challenging. In this paper we utilized availability of sequencing data with transcriptional profiles in the same cohorts to identify two kinds of usual suspects: eSNPs that alter coding sequences or eSNPs within the span of transcription factors (TFs). We utilize a computational framework for considering triplets, each comprised of a SNP and two associated genes. We examine pairs of triplets with such cooperating source eSNPs that are both associated with the same pair of target genes. We characterize such quartets through their genomic, topological and functional properties. We establish that this regulatory structure of cooperating quartets is frequent in real data, but is rarely observed in permutations. eSNP sources are mostly located on different chromosomes and away from their targets. In the majority of quartets, SNPs affect the expression of the two gene targets independently of one another, suggesting a mutually independent rather than a directionally dependent effect. Furthermore, the directions in which the minor allele count of the SNP affects gene expression within quartets are consistent, so that the two source eSNPs either both have the same effect on the target genes or both affect one gene in the opposite direction to the other. Same-effect eSNPs are observed more often than expected by chance. Cooperating quartets reported here in a human system might correspond to bi-fans, a known network motif of four nodes previously described in model organisms. Overall, our analysis offers insights regarding the fine motif structure of human regulatory networks.
Highlights
Markers associated with changes in gene expression, called expression single nucleotide polymorphisms (eSNPs) have been extensively mapped using high throughput genomic data [2,3,4,5,6,7,8,9,10]
We evaluated two categories of candidate eSNPs that reside within regions along the genome with known regulatory potential, i.e., within the span of known exons and transcription factors (TFs) (Figure S1 in Text S1; see Methods)
We aim to study quartets with cooperating eSNP sources, i.e. SNPs that carry independent information towards predicting the level of each one of the two transcripts, and no third intermediate SNP can explain the expression to either gene better (Figure 1c; see Methods)
Summary
Markers associated with changes in gene expression, called eSNPs have been extensively mapped using high throughput genomic data [2,3,4,5,6,7,8,9,10]. They allow effectively delineating regulatory associations between each eSNP source and each of its regulated target transcripts. Regulatory networks have been characterized as featuring specific motifs as their fundamental building blocks [11,12]. While previously studied networks are often derived from TF-DNA or protein-protein binding experiments, this work utilizes geneticsgenomics data to study the bi-fan motif across a human regulatory network
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