A bioinformatics approach for the identification of developmental QTL candidate genes. A. Q. Nato1, B. Li2, F. Chen1,3, J. H. Millonig1,2,4, T. C. Matise1 1) Department of Genetics, Rutgers University, Piscataway, NJ; 2) Center for Advanced Biotechnology and Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ; 3) MedStar Health Research Institute, Washington, DC; 4) Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ.

   Neural tube defects (NTDs) occur in ~1/1,000 live births in the United States and are considered one of the most common birth defects. Approximately 20.5 million Americans over age 40 have cataract in either eye. We have formerly established a spontaneous mouse mutant, vacuolated lens (vl), as a multigenic model for cataract and NTDs. Vl arose on the C3H/HeSnJ background and exhibits cataract and NTDs with 100% penetrance. A mutation in an orphan G protein coupled receptor, Gpr161, which is expressed in the developing neural tube and lens, causes these disorders. However, the severity and incidence of the vl phenotypes are modified when the mutation is crossed to C57BL6/J, CAST/Ei, or MOLF/Ei backgrounds indicating that unlinked loci can bypass the effect of the Gpr161 mutation. Quantitative trait locus (QTL) analysis mapped the position of five modifier loci (Modifiers of vacuolated lens: Modvl1-5). Several resources are available for the identification of candidate genes for adult QTL but not for developmental QTL. For this study, we developed a bioinformatics pipeline specifically designed for the identification of developmental QTL candidate genes. In-house computer scripts were created to mine the NCBI Entrez Gene, expressed sequenced tag (EST), and Gene Expression Omnibus (GEO) databases, and to identify genes within the Modvl 95% confidence intervals expressed at particular developmental stages. We utilized the dataBase for Gene Expression Evolution (Bgee) to determine which of these developmentally expressed genes are localized to the developing CNS and eye. dbSNP data, resequencing, and bioinformatics analysis were then employed to identify coding polymorphisms in these CNS- and eye-restricted transcripts and determine whether they are predicted to be functional. Finally, we identified pathways that are most significantly associated with these developmentally restricted transcripts and may therefore be relevant to neural tube closure and lens development. We have successfully identified candidate genes for each Modvl locus through our new bioinformatics pipeline that allows EST, microarray data, spatial/temporal expression, and dbSNP data to be searched successively. This pipeline (http://compgen.rutgers.edu/devQTL) may be utilized by other investigators to identify candidate genes for developmental QTL.

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