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Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

ABSTRACT: Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL-meQTL pairs likely to share a causal variant. We use partial correlation and mediation analyses to identify >400 of these pairs showing evidence of a causal relationship between expression and methylation (i.e., shared mechanism) with many additional pairs we are underpowered to detect. These co-localized pairs are enriched for SNPs showing opposite associations with expression and methylation, although many SNPs affect multiple CpGs in opposite directions. This work demonstrates the pervasiveness of co-regulated expression and methylation in the human genome. Applying this approach to other types of molecular QTLs can enhance our understanding of regulatory mechanisms.

SUBMITTER: Pierce BL

PROVIDER: S-EPMC5824840 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

Pierce Brandon L BL Tong Lin L Argos Maria M Demanelis Kathryn K Jasmine Farzana F Rakibuz-Zaman Muhammad M Sarwar Golam G Islam Md Tariqul MT Shahriar Hasan H Islam Tariqul T Rahman Mahfuzar M Yunus Md M Kibriya Muhammad G MG Chen Lin S LS Ahsan Habibul H

Nature communications 20180223 1

Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL-meQTL pairs likely to share a causal variant. We use partial correlation and mediation analyses to identify >400 ...[more]

PMID: 29476079

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Project description:BackgroundThe large influx of biological sequences poses the importance of identifying and correlating conserved regions in homologous sequences to acquire valuable biological knowledge. These conserved regions contain statistically significant residue associations as sequence patterns. Thus, patterns from two conserved regions co-occurring frequently on the same sequences are inferred to have joint functionality. A method for finding conserved regions in protein families with frequent co-occurrence patterns is proposed. The biological significance of the discovered clusters of conserved regions with co-occurrences patterns can be validated by their three-dimensional closeness of amino acids and the biological functionality found in those regions as supported by published work.MethodsUsing existing algorithms, we discovered statistically significant amino acid associations as sequence patterns. We then aligned and clustered them into Aligned Pattern Clusters (APCs) corresponding to conserved regions with amino acid conservation and variation. When one APC frequently co-occurred with another APC, the two APCs have high co-occurrence. We then clustered APCs with high co-occurrence into what we refer to as Co-occurrence APC Clusters (Co-occurrence Clusters).ResultsOur results show that for Co-occurrence Clusters, the three-dimensional distance between their amino acids is closer than average amino acid distances. For the Co-occurrence Clusters of the ubiquitin and the cytochrome c families, we observed biological significance among the residing amino acids of the APCs within the same cluster. In ubiquitin, the residues are responsible for ubiquitination as well as conventional and unconventional ubiquitin-bindings. In cytochrome c, amino acids in the first co-occurrence cluster contribute to binding of other proteins in the electron transport chain, and amino acids in the second co-occurrence cluster contribute to the stability of the axial heme ligand.ConclusionsThus, our co-occurrence clustering algorithm can efficiently find and rank conserved regions that contain patterns that frequently co-occurring on the same proteins. Co-occurring patterns are biologically significant due to their three-dimensional closeness and other evidences reported in literature. These results play an important role in drug discovery as biologists can quickly identify the target for drugs to conduct detailed preclinical studies.

Project description:BackgroundBiological invasions are major drivers of environmental change that can significantly alter ecosystem function and diversity. In plants, soil microbes play an important role in plant establishment and growth; however, relatively little is known about the role they might play in biological invasions. A first step to assess whether root microbes may be playing a role in the invasion process is to find out if invasive plants host different microbes than neighbouring native plant species.MethodsIn this study we investigated differences in root associated microbes of native sugar maple (Acer saccharum Marsh.) and exotic Norway maple (A. platanoides L.) collected from a forested reserve in eastern Canada. We used microscopy to examine root fungi and high-throughput sequencing to characterize the bacterial, fungal and arbuscular mycorrhizal communities of both maple species over one growing season.ResultsWe found differences in root associated bacterial and fungal communities between host species. Norway maple had a higher bacterial and fungal OTU (operational taxonomic units) richness compared to sugar maple, and the indicator species analysis revealed that nine fungal OTUs and three bacterial OTUs had a significant preference for sugar maple. The dominant bacterial phyla found on the roots of both maple species were Actinobacteria and Proteobacteria. The most common fungal orders associated with the Norway maple roots (in descending order) were Helotiales, Agaricales, Pleosporales, Hypocreales, Trechisporales while the Agaricales, Pleosporales, Helotiales, Capnodiales and Hypocreales were the dominant orders present in the sugar maple roots. Dark septate fungi colonization levels were higher in the sugar maple, but no differences in arbuscular mycorrhizal fungal communities and colonization rates were detected between maple species.DiscussionOur findings show that two congeneric plant species grown in close proximity can harbor distinct root microbial communities. These findings provide further support for the importance of plant species in structuring root associated microbe communities. The high colonization levels observed in Norway maple demonstrates its compatibility with arbuscular mycorrhizal fungi in the introduced range. Plant-associated microbial communities can affect host fitness and function in many ways; therefore, the observed differences suggest a possibility that biotic interactions can influence the dynamics between native and invasive species.

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Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

Publications

Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

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