ATHENA: A knowledge-based hybrid backpropagation-grammatical evolution neural network algorithm for discovering epistasis among quantitative trait Loci

<p>Abstract</p> <p>Background</p> <p>Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last decade, yet little heritability in highly studied complex traits has been explained by genetic variation. Non-additive gene-gene interactions, which are not often explored, are thought to be one source of this "missing" heritability.</p> <p>Methods</p> <p>Stochastic methods employing evolutionary algorithms have demonstrated promise in being able to detect and model gene-gene and gene-environment interactions that influence human traits. Here we demonstrate modifications to a neural network algorithm in ATHENA (the Analysis Tool for Heritable and Environmental Network Associations) resulting in clear performance improvements for discovering gene-gene interactions that influence human traits. We employed an alternative tree-based crossover, backpropagation for locally fitting neural network weights, and incorporation of domain knowledge obtainable from publicly accessible biological databases for initializing the search for gene-gene interactions. We tested these modifications <it>in silico </it>using simulated datasets.</p> <p>Results</p> <p>We show that the alternative tree-based crossover modification resulted in a modest increase in the sensitivity of the ATHENA algorithm for discovering gene-gene interactions. The performance increase was highly statistically significant when backpropagation was used to locally fit NN weights. We also demonstrate that using domain knowledge to initialize the search for gene-gene interactions results in a large performance increase, especially when the search space is larger than the search coverage.</p> <p>Conclusions</p> <p>We show that a hybrid optimization procedure, alternative crossover strategies, and incorporation of domain knowledge from publicly available biological databases can result in marked increases in sensitivity and performance of the ATHENA algorithm for detecting and modelling gene-gene interactions that influence a complex human trait.</p

A chromatin modifying enzyme, SDG8, is involved in morphological, gene expression, and epigenetic responses to mechanical stimulation

Thigmomorphogenesis is viewed as being a response process of acclimation to short repetitive bursts of mechanical stimulation or touch. The underlying molecular mechanisms that coordinate changes in how touch signals lead to long-term morphological changes are enigmatic. Touch responsive gene expression is rapid and transient, and no transcription factor or DNA regulatory motif has been reported that could confer a genome wide mechanical stimulus. We report here on a chromatin modifying enzyme, SDG8/ASHH2, which can regulate the expression of many touch responsive genes identified in Arabidopsis. SDG8 is required for the permissive expression of touch induced genes; and the loss of function of sdg8 perturbs the maximum levels of induction on selected touch gene targets. SDG8 is required to maintain permissive H3K4 trimethylation marks surrounding the Arabidopsis touch-inducible gene TOUCH 3 (TCH3), which encodes a calmodulin-like protein (CML12). The gene neighboring was also slightly down regulated, revealing a new target for SDG8 mediated chromatin modification. Finally, sdg8 mutants show perturbed morphological response to wind-agitated mechanical stimuli, implicating an epigenetic memory-forming process in the acclimation response of thigmomorphogenesis

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs

Incorporating genome-scale tools for studying energy homeostasis

Mammals have evolved complex regulatory systems that enable them to maintain energy homeostasis despite constant environmental challenges that limit the availability of energy inputs and their composition. Biological control relies upon intricate systems composed of multiple organs and specialized cell types that regulate energy up-take, storage, and expenditure. Because these systems simultaneously perform diverse functions and are highly integrated, they are extremely difficult to understand in terms of their individual component contributions to energy homeostasis. In order to provide improved treatments and clinical options, it is important to identify the principle genetic and molecular components, as well as the systemic features of regulation. To begin, many of these features can be discovered by integrating experimental technologies with advanced methods of analysis. This review focuses on the analysis of transcriptional data derived from microarrays and how it can complement other experimental techniques to study energy homeostasis

Genome-Wide Association Study and Pathway-Level Analysis of Kernel Color in Maize.

Rapid development and adoption of biofortified, provitamin A-dense orange maize (Zea mays L.) varieties could be facilitated by a greater understanding of the natural variation underlying kernel color, including as it relates to carotenoid biosynthesis and retention in maize grain. Greater abundance of carotenoids in maize kernels is generally accompanied by deeper orange color, useful for distinguishing provitamin A-dense varieties to consumers. While kernel color can be scored and selected with high-throughput, low-cost phenotypic methods within breeding selection programs, it remains to be well established as to what would be the logical genetic loci to target for selection for kernel color. We conducted a genome-wide association study of maize kernel color, as determined by colorimetry, in 1,651 yellow and orange inbreds from the Ames maize inbred panel. Associations were found with y1, encoding the first committed step in carotenoid biosynthesis, and with dxs2, which encodes the enzyme responsible for the first committed step in the biosynthesis of the isoprenoid precursors of carotenoids. These genes logically could contribute to overall carotenoid abundance and thus kernel color. The lcyE and zep1 genes, which can affect carotenoid composition, were also found to be associated with colorimeter values. A pathway-level analysis, focused on genes with a priori evidence of involvement in carotenoid biosynthesis and retention, revealed associations for dxs3 and dmes1, involved in isoprenoid biosynthesis; ps1 and vp5, within the core carotenoid pathway; and vp14, involved in cleavage of carotenoids. Collectively, these identified genes appear relevant to the accumulation of kernel color

An unbiased approach elucidates variation in (S)-(+)-linalool, a context-specific mediator of a tri-trophic interaction in wild tobacco

Plant volatile organic compounds (VOCs) mediate many interactions, and the function of common VOCs is especially likely to depend on ecological context. We used a genetic mapping population of wild tobacco, Nicotiana attenuata, originating from a cross of 2 natural accessions from Arizona and Utah, separated by the Grand Canyon, to dissect genetic variation controlling VOCs. Herbivory-induced leaf terpenoid emissions varied substantially, while green leaf volatile emissions were similar. In a field experiment, only emissions of linalool, a common VOC, correlated significantly with predation of the herbivore Manduca sexta by native predators. Using quantitative trait locus mapping and genome mining,we identified an (S)-(+)-linalool synthase (NaLIS). Genome resequencing, gene cloning, and activity assays revealed that the presence/absence of a 766-bp sequence in NaLIS underlies the variation of linalool emissions in 26 natural accessions. We manipulated linalool emissions and composition by ectopically expressing linalool synthases for both enantiomers, (S)-(+)- and (R)-(−)-linalool, reported to oppositely affect M. sexta oviposition, in the Arizona and Utah accessions.We used these lines to test ovipositingmoths in increasingly complex environments. The enantiomers had opposite effects on oviposition preference, but themagnitude of the effect depended strongly both on plant genetic background, and complexity of the bioassay environment. Our study reveals that the emission of linalool, a common VOC, differs by orders-of-magnitude among geographically interspersed conspecific plants due to allelic variation in a linalool synthase, and that the response of a specialist herbivore to linalool depends on enantiomer, plant genotype, and environmental complexity