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E.M. Stone, A.P. Chiang, T. Scheetz, K.A. Kim, R.E. Swiderski, D.Y. Nishimura, L.M. Affatigato, J. Huang, T.L. Casavant, V.C. Sheffield; Analysis of Correlated Gene Expression in a Large Cohort of Rats Assists the Discovery of Two New Genes Involved in Bardet Biedl Syndrome (BBS) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5919.
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To investigate the hypothesis that functionally related genes will exhibit coordinated variation of expression in response to the genetic permutation associated with a cross of distantly–related, highly–inbred rat strains.
Two inbred strains of laboratory rats (SR/JR/HSD and SHR/SP) were crossed and the resultant F1 animals were inter–crossed. At 12 weeks of age, 120 healthy males of the resulting F2 generation were euthanized. RNA was extracted from the eyes and genomic DNA was extracted from the liver of each animal. The ocular gene expression of each animal was determined using Affymetrix GeneChip Rat Genome 230 2.0 Arrays, which contain 31099 probes. Pairwise correlation of gene expression was investigated both as a marker of biological pathway membership and as a means of identifying new disease genes.
Eight genes previously known to cause BBS showed much higher correlation of expression than randomly selected expressed genes among the 120 F2 animals. When a number of candidate genes for BBS were evaluated for correlated expression with the eight known BBS genes, two new genes (B1 and TRIM32) exhibited greater correlation than the others. Screening of the coding sequences of these genes in BBS patients revealed disease–causing mutations.
As organisms evolve, there is an evolutionary advantage in linking the expression of functionally related genes to the biological situations for which their functions are needed. The evolutionary conservation of these correlated control mechanisms provides a means of detecting functional relationships among groups of genes. Thus, the analysis of gene expression in the progeny of a large genetic cross can be used to find new genes responsible for genetically heterogeneous diseases like BBS.
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