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E.E. Geisert, B. Haik, Y. Jiao, W. Gu, L. Lu, R.W. Williams; Genetic Covariance with Rod–Specific Transcripts Defines Candidates for Eight Uncloned Human Retinal Disease Loci . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4584.
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We measured whole eye mRNA expression in a genetic reference panel of highly diverse strains of mice to identify candidate genes that may cause human retinal disease. We report the production of a first draft of the Hamilton Eye Institute Mouse Eye Database (HEIMED) at www.genenetwork.org/search3.html and the initial use of HEIMED to define candidate genes for uncloned human retinal diseases.
Affymetrix M430 2.0 arrays were used to estimate mRNA expression in whole eyes of more than 65 strains, including over 50 BXD strains and 15 highly diverse isogenic lines. Many of these strains are pigmentation mutants, several develop glaucoma, and two have early onset photoreceptor degeneration. Pooled RNA from young adults of both sexes were processed separately using Bioconductor RMA. Pearson and Spearman correlations were used to rank candidates with expression tightly (r>0.8) coupled with rhodopsin (1425172_at) across all strains. Genomic locations of candidates were converted to human chromosome locations. We extracted sets of uncloned human retinal disease loci and aligned them with murine candidates using RetNet (www.sph.uth.tmc.edu/Retnet/disease.htm).
Twelve of the top 30 covariates with rhodopsin are currently associated with retinal disease in humans. For example Rdh12 (r = 0.95 with rhodopsin) has a well characterized associated with a Leber's congenital amaurosis (LCA3). We have been able to generate strong biological candidates for eight uncloned human disease loci. For example, Wdr17 is a superb candidate for RP29 (4q34).
Using the HEIMED in combination with GeneNetwork we are able to efficiently nominate eight candidates genes for human retinal diseases and mutations.
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