Background: The Na + /Cl --dependent serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathways. We have shown that neuronal A3 adenosine receptor activation leads to enhanced presynaptic 5-HT transport in vitro and an increased rate of SERT-mediated 5-HT clearance in vivo. SERT stimulation by A3 adenosine receptors derives from an elevation of cGMP and subsequent activation of both cGMP-dependent protein kinase (PKG) and p38 mitogen-activated protein kinase. PKG activators such as 8-Br-cGMP are known to lead to transporter phosphorylation, though how this modification supports SERT regulation is unclear.

BackgroundSince publication of the human genome in 2003, geneticists have been interested in risk variant associations to resolve the etiology of traits and complex diseases. The International HapMap Consortium undertook an effort to catalog all common variation across the genome (variants with a minor allele frequency (MAF) of at least 5% in one or more ethnic groups). HapMap along with advances in genotyping technology led to genome-wide association studies which have identified common variants associated with many traits and diseases. In 2008 the 1000 Genomes Project aimed to sequence 2500 individuals and identify rare variants and 99% of variants with a MAF of <1%.MethodsTo determine whether the 1000 Genomes Project includes all the variants in HapMap, we examined the overlap between single nucleotide polymorphisms (SNPs) genotyped in the two resources using merged phase II/III HapMap data and low coverage pilot data from 1000 Genomes.ResultsComparison of the two data sets showed that approximately 72% of HapMap SNPs were also found in 1000 Genomes Project pilot data. After filtering out HapMap variants with a MAF of <5% (separately for each population), 99% of HapMap SNPs were found in 1000 Genomes data.ConclusionsNot all variants cataloged in HapMap are also cataloged in 1000 Genomes. This could affect decisions about which resource to use for SNP queries, rare variant validation, or imputation. Both the HapMap and 1000 Genomes Project databases are useful resources for human genetics, but it is important to understand the assumptions made and filtering strategies employed by these projects.

Recent advances in genotyping technology have led to the generation of an enormous quantity of genetic data. Traditional methods of statistical analysis have proved insufficient in extracting all of the information about the genetic components of common, complex human diseases. A contributing factor to the problem of analysis is that amongst the small main effects of each single gene on disease susceptibility, there are non-linear, gene-gene interactions that can be difficult for traditional, parametric analyses to detect. In addition, exhaustively searching all multi-locus combinations has proved computationally impractical. Novel strategies for analysis have been developed to address these issues. The Analysis Tool for Heritable and Environmental Network Associations (ATHENA) is an analytical tool that incorporates grammatical evolution neural networks (GENN) to detect interactions among genetic factors. Initial parameters define how the evolutionary process will be implemented. This research addresses how different parameter settings affect detection of disease models involving interactions. In the current study, we iterate over multiple parameter values to determine which combinations appear optimal for detecting interactions in simulated data for multiple genetic models. Our results indicate that the factors that have the greatest influence on detection are: input variable encoding, population size, and parallel computation.

To three very important educators and mentors, my mother, grandmother, and sister.Thanks for your unwavering support and love.iii