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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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A genetic variant acting on the timing of response of the poor nitrogen-source degradation pathway (module no. 5-II).(A) The genomic interval underlying module no. 5-II residing in Chr2: 533–562 kb. Shown are DyVER scores (y-axis) across the genomic positions in chromosome 2 (x-axis) for seven associated genes (color coded; the module includes only those six genes that cross the FDR 6% threshold). Positions of two potential causal variants, RPB5 and CNS1, are marked below. (B) Genetic effects, relative to non-stimulated genetic effects (y-axis, log-scaled) for different associated genes from A (color coded) at six time points (x-axis). The plot depicts the short impulse of high genetic effect in all associated genes. (C) Module genes, in the context of the poor nitrogen-source degradation pathway. Enzymes are shown as color-coded rectangles (bold-pink/module genes, pink/associated genes, white/non-associated genes). The pathways show the uptake of poor nitrogen sources (allantoate, allantoin, and GABA) and their degradation into ammonium. (D) A representative gene. Expression profiles (left) and genetic effects (right, y-axis) of DAL80, a gene in module no 5-II, during response to rapamycin (x-axis). Shown as in Fig. 4B but using a marker near the RPB5 gene (marked in A).
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pcbi-1003984-g006: A genetic variant acting on the timing of response of the poor nitrogen-source degradation pathway (module no. 5-II).(A) The genomic interval underlying module no. 5-II residing in Chr2: 533–562 kb. Shown are DyVER scores (y-axis) across the genomic positions in chromosome 2 (x-axis) for seven associated genes (color coded; the module includes only those six genes that cross the FDR 6% threshold). Positions of two potential causal variants, RPB5 and CNS1, are marked below. (B) Genetic effects, relative to non-stimulated genetic effects (y-axis, log-scaled) for different associated genes from A (color coded) at six time points (x-axis). The plot depicts the short impulse of high genetic effect in all associated genes. (C) Module genes, in the context of the poor nitrogen-source degradation pathway. Enzymes are shown as color-coded rectangles (bold-pink/module genes, pink/associated genes, white/non-associated genes). The pathways show the uptake of poor nitrogen sources (allantoate, allantoin, and GABA) and their degradation into ammonium. (D) A representative gene. Expression profiles (left) and genetic effects (right, y-axis) of DAL80, a gene in module no 5-II, during response to rapamycin (x-axis). Shown as in Fig. 4B but using a marker near the RPB5 gene (marked in A).

Mentions: The poor nitrogen source degradation system (module no. 5-II) demonstrates the ability of our method to reveal novel associations acting on the timing of response and affecting an entire cellular pathway (Figs. 5,6). During growth on relatively poor nitrogen sources (allantoate, allantoin, and GABA), yeast cells activate premeases responsible for uptake of nitrogen sources and further increase the expression of enzymes that participate in degradation of poor nitrogen sources for the generation of ammonia. Exposure to the TOR inhibitor rapamycin also leads to the same nitrogen-regulated response [31]. Module no. 5-II consists of six of the twelve genes in the allantoin, allantoate and GABA degradation pathways, with all six genes having a significant impulse effect pattern (DAL1, 2, 4, 7, 80 and UGA4; Fig. 6A–C). An additional gene in these pathways, DAL5, is weakly associated using the same impulse pattern at the same genomic position (Fig. 6A–C).


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

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

A genetic variant acting on the timing of response of the poor nitrogen-source degradation pathway (module no. 5-II).(A) The genomic interval underlying module no. 5-II residing in Chr2: 533–562 kb. Shown are DyVER scores (y-axis) across the genomic positions in chromosome 2 (x-axis) for seven associated genes (color coded; the module includes only those six genes that cross the FDR 6% threshold). Positions of two potential causal variants, RPB5 and CNS1, are marked below. (B) Genetic effects, relative to non-stimulated genetic effects (y-axis, log-scaled) for different associated genes from A (color coded) at six time points (x-axis). The plot depicts the short impulse of high genetic effect in all associated genes. (C) Module genes, in the context of the poor nitrogen-source degradation pathway. Enzymes are shown as color-coded rectangles (bold-pink/module genes, pink/associated genes, white/non-associated genes). The pathways show the uptake of poor nitrogen sources (allantoate, allantoin, and GABA) and their degradation into ammonium. (D) A representative gene. Expression profiles (left) and genetic effects (right, y-axis) of DAL80, a gene in module no 5-II, during response to rapamycin (x-axis). Shown as in Fig. 4B but using a marker near the RPB5 gene (marked in A).
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pcbi-1003984-g006: A genetic variant acting on the timing of response of the poor nitrogen-source degradation pathway (module no. 5-II).(A) The genomic interval underlying module no. 5-II residing in Chr2: 533–562 kb. Shown are DyVER scores (y-axis) across the genomic positions in chromosome 2 (x-axis) for seven associated genes (color coded; the module includes only those six genes that cross the FDR 6% threshold). Positions of two potential causal variants, RPB5 and CNS1, are marked below. (B) Genetic effects, relative to non-stimulated genetic effects (y-axis, log-scaled) for different associated genes from A (color coded) at six time points (x-axis). The plot depicts the short impulse of high genetic effect in all associated genes. (C) Module genes, in the context of the poor nitrogen-source degradation pathway. Enzymes are shown as color-coded rectangles (bold-pink/module genes, pink/associated genes, white/non-associated genes). The pathways show the uptake of poor nitrogen sources (allantoate, allantoin, and GABA) and their degradation into ammonium. (D) A representative gene. Expression profiles (left) and genetic effects (right, y-axis) of DAL80, a gene in module no 5-II, during response to rapamycin (x-axis). Shown as in Fig. 4B but using a marker near the RPB5 gene (marked in A).
Mentions: The poor nitrogen source degradation system (module no. 5-II) demonstrates the ability of our method to reveal novel associations acting on the timing of response and affecting an entire cellular pathway (Figs. 5,6). During growth on relatively poor nitrogen sources (allantoate, allantoin, and GABA), yeast cells activate premeases responsible for uptake of nitrogen sources and further increase the expression of enzymes that participate in degradation of poor nitrogen sources for the generation of ammonia. Exposure to the TOR inhibitor rapamycin also leads to the same nitrogen-regulated response [31]. Module no. 5-II consists of six of the twelve genes in the allantoin, allantoate and GABA degradation pathways, with all six genes having a significant impulse effect pattern (DAL1, 2, 4, 7, 80 and UGA4; Fig. 6A–C). An additional gene in these pathways, DAL5, is weakly associated using the same impulse pattern at the same genomic position (Fig. 6A–C).

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