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POEM: Identifying Joint Additive Effects on Regulatory Circuits.

Botzman M, Nachshon A, Brodt A, Gat-Viks I - Front Genet (2016)

Bottom Line: POEM is specifically designed to achieve high performance in the case of additive joint effects.Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network.These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.

ABSTRACT

Motivation: Expression Quantitative Trait Locus (eQTL) mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress toward a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such "modularization" approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic) effects.

Results: Here we present POEM (Pairwise effect On Expression Modules), a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.

Availability: The software described in this article is available at csgi.tau.ac.il/POEM/.

No MeSH data available.


A high-level organization of pairwise additive effects in murine dendritic cells. The graph presents poeModules (squares, middle) connected to their primary eQTLs (gray circles, top) and secondary eQTLs (white circles, bottom). On this graph we marked the identifier of the poeModules (M1−M28) and the genomic position peak of each eQTL (see full genomic intervals in Supplementary Table 3). Whereas, most poeModules are trans-acting and additive (standard squares), several poeModules are either epistatic (gray squares) or cis-acting (bold squares). Notably, whereas some poeModules do not have overlapping primary and secondary eQTLs (“singletons,” A), others generate two multi-poeModule structures—the multifurcating (B) and composite (C) architectures.
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Figure 4: A high-level organization of pairwise additive effects in murine dendritic cells. The graph presents poeModules (squares, middle) connected to their primary eQTLs (gray circles, top) and secondary eQTLs (white circles, bottom). On this graph we marked the identifier of the poeModules (M1−M28) and the genomic position peak of each eQTL (see full genomic intervals in Supplementary Table 3). Whereas, most poeModules are trans-acting and additive (standard squares), several poeModules are either epistatic (gray squares) or cis-acting (bold squares). Notably, whereas some poeModules do not have overlapping primary and secondary eQTLs (“singletons,” A), others generate two multi-poeModule structures—the multifurcating (B) and composite (C) architectures.

Mentions: We next used only 28 of the 33 resulting poeModules (denoted M1-M28) since the remaining modules were nested within them (Supplementary Tables 1-3). In 25 out of 28 poeModules, at least 66% of the expression traits were affected by two trans-acting eQTLs (Supplementary Table 1); such modules are denoted “trans-acting poeModules.” In total, 122 of 133 (91%) of the traits in the poeModules were affected by two trans-acting eQTLs (Figure 3B). In addition, 27 of the 28 poeModules presented non-epistatic effects: 27 poeModules did not attain significant interaction terms in any of their traits, while module M26 showed significant interactions in four of its traits (FDR < 0.01; Supplementary Tables 1, 2 and Figure 3B; Section Materials and Methods). Overall, POEM mainly identified trans-acting, additive poeModules (24 of 28 poeModules; Figure 4), consisting of 118 (9.8%) expression traits that are affected by a pair of trans-acting eQTLs carrying a joint additive effect (Supplementary Table 2). These results demonstrate the high prevalence of non-epistatic trans-acting pairwise effects and the ability of POEM to reveal them.


POEM: Identifying Joint Additive Effects on Regulatory Circuits.

Botzman M, Nachshon A, Brodt A, Gat-Viks I - Front Genet (2016)

A high-level organization of pairwise additive effects in murine dendritic cells. The graph presents poeModules (squares, middle) connected to their primary eQTLs (gray circles, top) and secondary eQTLs (white circles, bottom). On this graph we marked the identifier of the poeModules (M1−M28) and the genomic position peak of each eQTL (see full genomic intervals in Supplementary Table 3). Whereas, most poeModules are trans-acting and additive (standard squares), several poeModules are either epistatic (gray squares) or cis-acting (bold squares). Notably, whereas some poeModules do not have overlapping primary and secondary eQTLs (“singletons,” A), others generate two multi-poeModule structures—the multifurcating (B) and composite (C) architectures.
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Related In: Results  -  Collection

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Figure 4: A high-level organization of pairwise additive effects in murine dendritic cells. The graph presents poeModules (squares, middle) connected to their primary eQTLs (gray circles, top) and secondary eQTLs (white circles, bottom). On this graph we marked the identifier of the poeModules (M1−M28) and the genomic position peak of each eQTL (see full genomic intervals in Supplementary Table 3). Whereas, most poeModules are trans-acting and additive (standard squares), several poeModules are either epistatic (gray squares) or cis-acting (bold squares). Notably, whereas some poeModules do not have overlapping primary and secondary eQTLs (“singletons,” A), others generate two multi-poeModule structures—the multifurcating (B) and composite (C) architectures.
Mentions: We next used only 28 of the 33 resulting poeModules (denoted M1-M28) since the remaining modules were nested within them (Supplementary Tables 1-3). In 25 out of 28 poeModules, at least 66% of the expression traits were affected by two trans-acting eQTLs (Supplementary Table 1); such modules are denoted “trans-acting poeModules.” In total, 122 of 133 (91%) of the traits in the poeModules were affected by two trans-acting eQTLs (Figure 3B). In addition, 27 of the 28 poeModules presented non-epistatic effects: 27 poeModules did not attain significant interaction terms in any of their traits, while module M26 showed significant interactions in four of its traits (FDR < 0.01; Supplementary Tables 1, 2 and Figure 3B; Section Materials and Methods). Overall, POEM mainly identified trans-acting, additive poeModules (24 of 28 poeModules; Figure 4), consisting of 118 (9.8%) expression traits that are affected by a pair of trans-acting eQTLs carrying a joint additive effect (Supplementary Table 2). These results demonstrate the high prevalence of non-epistatic trans-acting pairwise effects and the ability of POEM to reveal them.

Bottom Line: POEM is specifically designed to achieve high performance in the case of additive joint effects.Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network.These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.

ABSTRACT

Motivation: Expression Quantitative Trait Locus (eQTL) mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress toward a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such "modularization" approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic) effects.

Results: Here we present POEM (Pairwise effect On Expression Modules), a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.

Availability: The software described in this article is available at csgi.tau.ac.il/POEM/.

No MeSH data available.