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Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases.

ABSTRACT: Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly, to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD.

SUBMITTER: Sung MK

PROVIDER: S-EPMC4330252 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases.

Sung Min Kyung MK Bang Hyoeun H Choi Jung Kyoon JK

Genomics & informatics 20141231 4

Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases u ...[more]

PMID: 25705156

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Project description:BackgroundGenes that encode proteins associated with sperm competition, fertilization, and sexual conflicts of interest are often among the most rapidly evolving parts of animal genomes. One family of sperm-expressed genes (Zp3r, C4bpa) in the mammalian gene cluster called the regulator of complement activation (RCA) encodes proteins that bind eggs and mediate reproductive success, and are therefore expected to show high relative rates of nonsynonymous nucleotide substitution in response to sexual selection in comparison to other genes not involved in gamete binding at fertilization. We tested that working hypothesis by using phylogenetic models of codon evolution to identify episodes of diversifying positive selection. We used a comparative approach to quantify the evidence for episodic diversifying selection acting on RCA genes with known functions in fertilization (and sensitivity to sexual selection), and contrast them with other RCA genes in the same gene family that function in innate immunity (and are not sensitive to sexual selection).ResultsWe expected but did not find evidence for more episodes of positive selection on Zp3r in Glires (the rodents and lagomorphs) or on C4BPA in Primates, in comparison to other paralogous RCA genes in the same taxon, or in comparison to the same orthologous RCA gene in the other taxon. That result was not unique to RCA genes: we also found little evidence for more episodes of diversifying selection on genes that encode selective sperm-binding molecules in the egg coat or zona pellucida (Zp2, Zp3) in comparison to members of the same gene family that encode structural elements of the egg coat (Zp1, Zp4). Similarly, we found little evidence for episodic diversifying selection acting on two other recently discovered genes (Juno, Izumo1) that encode essential molecules for sperm-egg fusion.ConclusionsThese negative results help to illustrate the importance of a comparative context for this type of codon model analysis. The results may also point to other phylogenetic contexts in which the effects of selection acting on these fertilization proteins might be more readily discovered and documented in mammals and other taxa.

Project description:BACKGROUND: The deleterious effect of a mutation can be reverted by a second-site interacting residue. This is an epistatic compensatory process explaining why mutations that are deleterious in some species are tolerated in phylogenetically related lineages, rendering evident that those mutations are, by all means, only deleterious in the species-specific context. Although an extensive and refined theoretical framework on compensatory evolution does exist, the supporting evidence remains limited, especially for protein models. In this current study, we focused on the molecular mechanism underlying the epistatic compensatory process in mammalian mitochondrial OXPHOS proteins using a combination of in-depth structural and sequence analyses. RESULTS: Modeled human structures were used in this study to predict the structural impairment and recovery of deleterious mutations alone and combined with an interacting compensatory partner, respectively. In two cases, COI and COIII, intramolecular interactions between spatially linked residues restore the folding pattern impaired by the deleterious mutation. In a third case, intermolecular contact between mitochondrial CYB and nuclear CYT1 encoded components of the cytochrome bc1 complex are likely to restore protein binding. Moreover, we observed different modes of compensatory evolution that have resulted in either a quasi-simultaneous occurrence of a mutation and corresponding compensatory partner, or in independent occurrences of mutations in distinct lineages that were always preceded by the compensatory site. CONCLUSION: Epistatic interactions between individual replacements involving deleterious mutations seems to follow a parsimonious model of evolution in which genomes hold pre-compensating states that subsequently tolerate deleterious mutations. This phenomenon is likely to have been constraining the variability at coevolving sites and shaping the interaction between the mitochondrial and the nuclear genome.

Dataset Information

Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases.

Publications

Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases.

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