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Dissecting dynamic genetic variation that controls temporal gene response in yeast.

Brodt A, Botzman M, David E, Gat-Viks I - PLoS Comput. Biol. (2014)

Bottom Line: Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells.We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern.Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Inter-individual variation in regulatory circuits controlling gene expression is a powerful source of functional information. The study of associations among genetic variants and gene expression provides important insights about cell circuitry but cannot specify whether and when potential variants dynamically alter their genetic effect during the course of response. Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells. We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern. The temporal genetic effects of some modules represented a single state-transitioning pattern; for example, at 10-30 minutes following stimulation, genetic effects in the phosphate utilization module attained a characteristic transition to a new steady state. In contrast, another module showed an impulse pattern of genetic effects; for example, in the poor nitrogen sources utilization module, a spike up of a genetic effect at 10-20 minutes following stimulation reflected inter-individual variation in the timing (rather than magnitude) of response. Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module. Our methodology provides a quantitative genetic approach to studying the molecular mechanisms that shape dynamic changes in transcriptional responses.

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Co-associated genes typically share a similar pattern of genetic effects over time.(A) Six gene modules (column 1), constructed on the basis of a shared trans-associated genetic variant (a genomic interval; column 2), are listed together with their known causal gene, if available (column 3; †-cis-associated causal gene, references are in parentheses) and the number of associated genes in a module (column 4). Significant enrichments in biological processes are detailed in column 5. Significant enrichments of temporal two-state patterns in each module are presented together with the description of these enriched patterns (columns 6 and 7, respectively). (B−E) Gene expression and genetic effects in modules nos. 1 (left), 3 (middle) and 4 (right). Gene expression (B) and genetic effect (C) of representative genes, as well as genetic effects of an entire module (D); plots are shown as in Fig. 4B. (E) Average gene expression (y-axis) at six time points (x-axis) for the known causal gene of each module. For cis-associated causal genes (modules nos. 3 and 4), brown and black indicate strains carrying the RM and BY alleles, respectively. The plots demonstrate the good match between the timing of abrupt changes in causal genes (E) and the timing of alterations in the observed genetic effects of their associated target genes (D).
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pcbi-1003984-g005: Co-associated genes typically share a similar pattern of genetic effects over time.(A) Six gene modules (column 1), constructed on the basis of a shared trans-associated genetic variant (a genomic interval; column 2), are listed together with their known causal gene, if available (column 3; †-cis-associated causal gene, references are in parentheses) and the number of associated genes in a module (column 4). Significant enrichments in biological processes are detailed in column 5. Significant enrichments of temporal two-state patterns in each module are presented together with the description of these enriched patterns (columns 6 and 7, respectively). (B−E) Gene expression and genetic effects in modules nos. 1 (left), 3 (middle) and 4 (right). Gene expression (B) and genetic effect (C) of representative genes, as well as genetic effects of an entire module (D); plots are shown as in Fig. 4B. (E) Average gene expression (y-axis) at six time points (x-axis) for the known causal gene of each module. For cis-associated causal genes (modules nos. 3 and 4), brown and black indicate strains carrying the RM and BY alleles, respectively. The plots demonstrate the good match between the timing of abrupt changes in causal genes (E) and the timing of alterations in the observed genetic effects of their associated target genes (D).

Mentions: We next explored the pleiotropic trans-acting variants that arise from this analysis. Using DyVER's predictions we organized the genes into six co-association modules, each containing a group of (at least two) genes with the same trans-associated variant (Fig. 5A and B). Functional enrichment strongly related all six modules with specific biochemical pathways. For example, the entire module no. 3 consists of genes that play a role in uptake of phosphate (Pi) from extracellular sources and its accumulation in vacuoles (5 of 5 genes; Fig. 5A and B, Figure S9A). The module's validated causal gene is PHO84, a high-affinity phosphate transporter that carries a missense mutation in one of the parental strains (Figure S9B) [29], [30]. The nine genes in module no. 5 carry two distinct functionalities and are therefore treated as two distinct sub-modules, no. 5-I and no. 5-II (three daughter cell-specific genes and six poor nitrogen source degradation genes, respectively, Fig. 5A).


Dissecting dynamic genetic variation that controls temporal gene response in yeast.

Brodt A, Botzman M, David E, Gat-Viks I - PLoS Comput. Biol. (2014)

Co-associated genes typically share a similar pattern of genetic effects over time.(A) Six gene modules (column 1), constructed on the basis of a shared trans-associated genetic variant (a genomic interval; column 2), are listed together with their known causal gene, if available (column 3; †-cis-associated causal gene, references are in parentheses) and the number of associated genes in a module (column 4). Significant enrichments in biological processes are detailed in column 5. Significant enrichments of temporal two-state patterns in each module are presented together with the description of these enriched patterns (columns 6 and 7, respectively). (B−E) Gene expression and genetic effects in modules nos. 1 (left), 3 (middle) and 4 (right). Gene expression (B) and genetic effect (C) of representative genes, as well as genetic effects of an entire module (D); plots are shown as in Fig. 4B. (E) Average gene expression (y-axis) at six time points (x-axis) for the known causal gene of each module. For cis-associated causal genes (modules nos. 3 and 4), brown and black indicate strains carrying the RM and BY alleles, respectively. The plots demonstrate the good match between the timing of abrupt changes in causal genes (E) and the timing of alterations in the observed genetic effects of their associated target genes (D).
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Related In: Results  -  Collection

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pcbi-1003984-g005: Co-associated genes typically share a similar pattern of genetic effects over time.(A) Six gene modules (column 1), constructed on the basis of a shared trans-associated genetic variant (a genomic interval; column 2), are listed together with their known causal gene, if available (column 3; †-cis-associated causal gene, references are in parentheses) and the number of associated genes in a module (column 4). Significant enrichments in biological processes are detailed in column 5. Significant enrichments of temporal two-state patterns in each module are presented together with the description of these enriched patterns (columns 6 and 7, respectively). (B−E) Gene expression and genetic effects in modules nos. 1 (left), 3 (middle) and 4 (right). Gene expression (B) and genetic effect (C) of representative genes, as well as genetic effects of an entire module (D); plots are shown as in Fig. 4B. (E) Average gene expression (y-axis) at six time points (x-axis) for the known causal gene of each module. For cis-associated causal genes (modules nos. 3 and 4), brown and black indicate strains carrying the RM and BY alleles, respectively. The plots demonstrate the good match between the timing of abrupt changes in causal genes (E) and the timing of alterations in the observed genetic effects of their associated target genes (D).
Mentions: We next explored the pleiotropic trans-acting variants that arise from this analysis. Using DyVER's predictions we organized the genes into six co-association modules, each containing a group of (at least two) genes with the same trans-associated variant (Fig. 5A and B). Functional enrichment strongly related all six modules with specific biochemical pathways. For example, the entire module no. 3 consists of genes that play a role in uptake of phosphate (Pi) from extracellular sources and its accumulation in vacuoles (5 of 5 genes; Fig. 5A and B, Figure S9A). The module's validated causal gene is PHO84, a high-affinity phosphate transporter that carries a missense mutation in one of the parental strains (Figure S9B) [29], [30]. The nine genes in module no. 5 carry two distinct functionalities and are therefore treated as two distinct sub-modules, no. 5-I and no. 5-II (three daughter cell-specific genes and six poor nitrogen source degradation genes, respectively, Fig. 5A).

Bottom Line: Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells.We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern.Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Inter-individual variation in regulatory circuits controlling gene expression is a powerful source of functional information. The study of associations among genetic variants and gene expression provides important insights about cell circuitry but cannot specify whether and when potential variants dynamically alter their genetic effect during the course of response. Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells. We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern. The temporal genetic effects of some modules represented a single state-transitioning pattern; for example, at 10-30 minutes following stimulation, genetic effects in the phosphate utilization module attained a characteristic transition to a new steady state. In contrast, another module showed an impulse pattern of genetic effects; for example, in the poor nitrogen sources utilization module, a spike up of a genetic effect at 10-20 minutes following stimulation reflected inter-individual variation in the timing (rather than magnitude) of response. Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module. Our methodology provides a quantitative genetic approach to studying the molecular mechanisms that shape dynamic changes in transcriptional responses.

Show MeSH