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1.  Dissecting Dynamic Genetic Variation That Controls Temporal Gene Response in Yeast 
PLoS Computational Biology  2014;10(12):e1003984.
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.
Author Summary
Genetic variation is postulated to play a major role in transcriptional responses to stimulation. Such process involves two inter-related dynamic processes: first, the time-dependent changes in gene expression, and second, the time-dependent changes in genetic effects. Although the dynamics of gene expression has been extensively investigated, the dynamics of genetic effects yet remain poorly understood. Here we develop DyVER, a method that combines genotyping with time-series gene expression data to uncover the timing of transitions in the magnitude of genetic effects. We examine gene expression in yeast segregants during rapamycin response, finding several distinct ways of change in the magnitude of genetic effects over time. These include impulse-like and sustained transitions in genetic effects, acting both in cis and trans. Our findings suggest that associations of genes with the same genetic variant often occur via the same timing of state transition in genetic effects. Furthermore, the results uncover a previously unknown variant whose impulse-like temporal genetic effect suggests a novel molecular function for determining the timing rather than the magnitude of response. Our results show that steady-state association studies miss important genetic information, and demonstrate the power of DyVER to render a comprehensive map of dynamic changes in genetic effects.
PMCID: PMC4256076  PMID: 25474467
2.  CRISPR/Cas systems in archaea 
Mobile Genetic Elements  2012;2(1):63-64.
CRISPR (Clustered, Regularly, Interspaced, Short, Palindromic Repeats) loci have been shown to provide prokaryotes with an adaptive immunity against viruses and plasmids. CRISPR arrays are transcribed and processed into small CRISPR RNA molecules, which base-pair with invading DNA or RNA and lead to its degradation by CRISPR-associated (Cas) protein complexes. New spacers can be acquired by active CRISPR/Cas systems, and thus the sequences of these spacers provide a record of the past “infection history” of the organism. Recently we used spacer sequences from archaeal genomes to infer gene exchange events among archaeal species and genera and to demonstrate that at least in this domain of life CRISPR indeed has an anti-viral role.
PMCID: PMC3383453  PMID: 22754756
CRISPR; Lateral Gene Transfer; archaea; horizontal gene transfer; viruses
3.  CRISPR loci reveal networks of gene exchange in archaea 
Biology Direct  2011;6:65.
CRISPR (Clustered, Regularly, Interspaced, Short, Palindromic Repeats) loci provide prokaryotes with an adaptive immunity against viruses and other mobile genetic elements. CRISPR arrays can be transcribed and processed into small crRNA molecules, which are then used by the cell to target the foreign nucleic acid. Since spacers are accumulated by active CRISPR/Cas systems, the sequences of these spacers provide a record of the past "infection history" of the organism.
Here we analyzed all currently known spacers present in archaeal genomes and identified their source by DNA similarity. While nearly 50% of archaeal spacers matched mobile genetic elements, such as plasmids or viruses, several others matched chromosomal genes of other organisms, primarily other archaea. Thus, networks of gene exchange between archaeal species were revealed by the spacer analysis, including many cases of inter-genus and inter-species gene transfer events. Spacers that recognize viral sequences tend to be located further away from the leader sequence, implying that there exists a selective pressure for their retention.
CRISPR spacers provide direct evidence for extensive gene exchange in archaea, especially within genera, and support the current dogma where the primary role of the CRISPR/Cas system is anti-viral and anti-plasmid defense.
Open peer review
This article was reviewed by: Profs. W. Ford Doolittle, John van der Oost, Christa Schleper (nominated by board member Prof. J Peter Gogarten)
PMCID: PMC3285040  PMID: 22188759
CRISPR; Lateral Gene transfer; Horizontal gene transfer; viruses; archaea; competence

Results 1-3 (3)