Naturally occurring SNPs within A. gambiae immune genes have been found to be associated with parasite in fection, including TOLL5B and ILP3 as well as Sp SNAKElike and Belinostat TOLL6. Indeed, it has been pro posed that a breakdown in mosquito Inhibitors,Modulators,Libraries innate immunity is responsible for susceptibility Inhibitors,Modulators,Libraries to parasite infection, raising the possibility of undertaking studies searching for naturally occurring mutations in immune signaling genes. Most recently, Li et al. identified nonsynon ymous SNPs in A. gambiae adenosine deaminase, fibrinogen related protein 1 and fibrinogen related protein 30. RNAi mediated silencing of FREP1 resulted in a significant decrease in infection prevalence while FBN30 transcript ablation increased infection in tensity two fold relative to controls.

While these as sociation studies support the role of natural genetic variation in the control of Plasmodium development, mutations such as these have thus far been used only to identify target Inhibitors,Modulators,Libraries genes for which to query the effects of RNAi mediated silencing on infection phenotype. How ever, many immune gene products require protein protein interaction to form complexes or post translational modi fication to mediate specific cellular functions. As such, the work presented here indicates that functional SNP studies can be extended to determine the mechanisms by which coding sequence mutations specifically impact infection phenotype. Conclusion We have established proof of principle for the functional analysis of SNPs on protein function and infection sus ceptibility in A. gambiae. In particular, we have demon strated that engineered mutations in A.

gambiae MEK recapitulate the effects of small molecule inhibition of MEK ERK signaling in mosquito cells and on parasite infection. In addition to proof of principle, the interruption of MEK ERK signaling via engineered D site mutations can be translated for the development of transgenic A. gambiae that Inhibitors,Modulators,Libraries are resistant to malaria para site development and transmission. Besides genome wide association studies, the current gene expression based approaches are mainly based on the signature gene set concept, which has been perfected during the past 14 years of relentless efforts in gene expres sion profiles of cancer, cardiovascular disease, diabetes and other disease researches. The key differences of this signature gene set approach from traditional linkage based genetics study lie in two aspects.

First, the signature gene set approach can identify genomic variation, being it in SNP, DNA copy number alteration, or miss regulation of gene expression. Second, it can predict the relevant bio logical pathways, protein protein Inhibitors,Modulators,Libraries interaction networks, and gene ontology functional groups, thus identifying novel therapeutic targetsbiomarkers for drug discovery, with the hope that their variations from patient to patient could explain large portion of dosage variation, free copy resistance and efficacy of the drug.