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Atul Kakrana, Joshua W K Ho, Blake C Meyers, David C Beebe, Cathy H Wu, Abhyudai Singh, Salil Anil Lachke; Integration of temporal lens gene expression datasets to expand the gene discovery tool iSyTE. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5037.
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© ARVO (1962-2015); The Authors (2016-present)
We recently developed the first version of the gene discovery tool iSyTE (http://bioinformatics.udel.edu/Research/iSyTE) based on enriched gene expression analysis on three mouse lens embryonic stages. Although successful in identifying several new cataract-associated genes, this version did not efficiently identify three genes previously linked to isolated congenital cataract. To increase iSyTE’s efficacy for predicting cataract genes, we performed a meta-analysis on microarray datasets from a comprehensive range of embryonic and postnatal mouse lens stages and integrated the in silico-subtracted expression datasets to expand this web-based resource.
Microarray gene expression datasets on Affymetrix Mouse Genome 430 2.0 or Illumina MouseWG-6 v2.0 from twelve mouse lens stages were obtained from NCBI-GEO. Additionally, new microarray datasets were generated for five postnatal lens stages. Lens-enriched profiles were obtained by in silico subtraction with WB and integrated to develop iSyTE 2.0.
Expansion of iSyTE to include ‘enriched-expression’ profiles based on seventeen different embryonic and postnatal stages of mouse lens (E10.5, E11.5, E12.5, E16.5, E17.5, E19.5, P0, P2, P4, P8, P12, P20, P28, P30, P42, P52, P56) significantly improved the priority rank of isolated congenital cataract-associated genes (n=24) within mapped intervals. For these linkage intervals (mean length, 12.2 MB), iSyTE 2.0 now ranks the correct mutant gene as top 1 candidate in 92% cases compared to 71% in the earlier version, and within the top 4 candidates in 100% cases. Specifically, known cataract genes that were poorly ranked by iSyTE 1.0 exhibit significant improvement: FYCO1 (rank 21 to 1), GCNT2 (rank 7 to 3), and CHMP4B (rank 34 to 4). Color-coded iSyTE 2.0 tracks based on lens-enrichment ranks for these stages will be accessible through the UCSC browser. Finally, analysis of co-expressed gene clusters allowed us to identify a signature set of genes (n=47) that exhibit lens-specific enrichment across embryonic and postnatal stages.
iSyTE 2.0 has significantly improved capability to identify candidate genes associated with lens development, homeostasis and cataract. We anticipate that the comprehensive lens-enriched gene expression information in iSyTE 2.0 will contribute to the construction of gene regulatory networks involved in the formation and maintenance of lens transparency.
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