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Gilbert-Diamond D.,Computational Genetics Laboratory
Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] | Year: 2011

The goal of this unit is to introduce gene-gene interactions (epistasis) as a significant complicating factor in the search for disease susceptibility genes. This unit begins with an overview of gene-gene interactions and why they are likely to be common. Then, it reviews several statistical and computational methods for detecting and characterizing genes with effects that are dependent on other genes. The focus of this unit is genetic association studies of discrete and quantitative traits because most of the methods for detecting gene-gene interactions have been developed specifically for these study designs. © 2011 by John Wiley & Sons, Inc.


McAllister T.W.,Section of Neuropsychiatry | Tyler A.L.,Computational Genetics Laboratory | Flashman L.A.,Section of Neuropsychiatry | Rhodes C.H.,Section of Molecular Pathology | And 7 more authors.
Journal of Neurotrauma | Year: 2012

Brain-derived neurotrophic factor (BDNF) plays a role in cognition, as well as neural survival and plasticity. There are several common polymorphisms in the BDNF gene, one of which (rs6265) is an extensively studied non-synonymous coding polymorphism (Val66Met) which has been linked to cognitive performance in healthy controls and some clinical populations. We hypothesized that the Met allele of rs6265 would be associated with poorer cognitive performance in individuals with mild-to-moderate traumatic brain injury, and that other polymorphisms in the BDNF gene would also affect cognition. Genotype at 9 single-nucleotide polymorphisms (SNPs) in the BDNF gene, and measures of speed of information processing, learning, and memory were assessed in 75 patients with mTBI and 38 healthy subjects. Consistent with previous reports, the Met allele of rs6265 was associated with cognition (slower processing speed) in the entire group. Two other SNPs were associated with processing speed in the mTBI group, but both are in linkage disequilibrium with rs6265, and neither remained significant after adjustment for rs6265 status. Within the mTBI group, but not the controls, 4 SNPs, but not rs6265, were associated with memory measures. These associations were not affected by adjustment for rs6265 status. Polymorphisms in BDNF influence cognitive performance shortly after mTBI. The results raise the possibility that a functional polymorphism other than rs6265 may contribute to memory function after mTBI. © Mary Ann Liebert, Inc.


Darabos C.,Computational Genetics Laboratory | Di Cunto F.,University of Turin | Tomassini M.,University of Lausanne | Moore J.H.,Computational Genetics Laboratory | And 2 more authors.
PLoS ONE | Year: 2011

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate. © 2011 Darabos et al.


Zhang X.,Institute for Quantitative Biomedical science | Cowper-Sal-lari R.,Institute for Quantitative Biomedical science | Cowper-Sal-lari R.,Computational Genetics Laboratory | Bailey S.D.,Ontario Cancer Institute | And 5 more authors.
Genome Research | Year: 2012

Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The 17q24.3 locus harbors the single nucleotide polymorphism (SNP) rs1859962 that is statistically associated with prostate cancer (PCa). It defines a 130-kb linkage disequilibrium (LD) block that lies in an ∼2-Mb gene desert area. The functional biology driving the risk associated with this LD block is unknown. Here, we integrate genome-wide chromatin landscape data sets, namely, epigenomes and chromatin openness from diverse cell types. This identifies a PCa-specific enhancer within the rs1859962 risk LD block that establishes a 1-Mb chromatin loop with the SOX9 gene. The rs8072254 and rs1859961 SNPs mapping to this enhancer impose allele-specific gene expression. The variant allele of rs8072254 facilitates androgen receptor (AR) binding driving increased enhancer activity. The variant allele of rs1859961 decreases FOXA1 binding while increasing AP-1 binding. The latter is key to imposing allele-specific gene expression. The rs8072254 variant in strong LD with the rs1859962 risk SNP can account for the risk associated with this locus, while rs1859961 is a rare variant less likely to contribute to the risk associated with this LD block. Together, our results demonstrate that multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene can account for the risk associated with the PCa 17q24.3 locus. Allele-specific recruitment of the transcription factors androgen receptor (AR) and activating protein-1 (AP-1) account for the increased enhancer activity ascribed to this PCa-risk LD block. This further supports the notion that an integrative genomics approach can identify the functional biology disrupted by genetic risk variants.


Gilbert-Diamond D.,Computational Genetics Laboratory | Moore J.H.,Computational Genetics Laboratory | Moore J.H.,University of New Hampshire | Moore J.H.,University of Vermont | Moore J.H.,Dartmouth College
Current Protocols in Human Genetics | Year: 2011

The goal of this unit is to introduce gene-gene interactions (epistasis) as a significant complicating factor in the search for disease susceptibility genes. This unit begins with an overview of genegene interactions and why they are likely to be common. Then, it reviews several statistical and computational methods for detecting and characterizing genes with effects that are dependent on other genes. The focus of this unit is genetic association studies of discrete and quantitative traits because most of the methods for detecting gene-gene interactions have been developed specifically for these study designs. © 2011 by John Wiley & Sons, Inc.

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