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Regulation of gene expression in the mammalian eye and its relevance to eye disease Todd Scheetz et al. Presented by John MC Ma Aims • To determine loci related to genes expressed in rat eye by expression quantitative trait loci (eQTL) • To verify certain undescribed genes by r2 correlations on members of its gene groups Background: QTL • Quantitative trait locus • Statistically links a certain genetic locus to a quantitative trait and seeks association – Phenotype QTL: The trait is a phenotype, eg blood pressure, blood sucrose – Expression QTL: The trait is the expression of a gene. • Expression QTL is used in this paper Methods: Choosing rat strains • Several criteria – Highly inbred – Readily available – Completely genotyped – Diverse origins between strains – Phenotypically normal • SR/JrHsd and SHRSP were chosen Methods: Rat breeding and Genotyping • SR/JrHsd males and SHRSP females were mated to produce F1; F1 was interbred to produce 120 F2. • RNA was extracted from eye of 12-weekold F2 and is analyzed on Affymetrix Rat 230 Rat version 2 microarray • Rats were genotyped using 399 sets of short tandem-repeat polymorphisms with PCR and gel electrophoresis Methods: eQTL Analysis • 18,976 eye-expressed probes out of the over 31,000 probe sets of the microarray was selected • Expression of probe sets analyzed: – ANOVA for linkage; – Permutation test and q-value for multiple testing correction; – Bonferroni correction for gene-level analysis Results of eQTL • 1,330 genes linked to at least one locus • False discovery rate is 1.4% Reading the dot plot (1) • X-axis refers to the genetic marker by location, where Y-axis refers to the genes by location. • A: original data for genes in chr 4 • B: A, corrected for adjacent assuming all adjacent hits is one hit Reading the dot plot (2) • Right: genome-wide dot plot • Diagonal: Neighbourhood effects • Vertical: One locus affects multiple genes • Horizontal: One gene affects multiple loci Neighbourhood effects • Most of the significant linkages falls within 50cM of the gene concerned • Although it is usually due to cis-acting regulatory regions, some are due to trans-action Gene-linking locus • 278 markers shown significant linkage to 2+ genes • Largest amount of linkage is marker D20Rat2: 33 genes, but within 10mb – This area has a high gene density and the genes are in the same family related to immune response Gene-linking locus (2) • The locus having most of noncontiguous is D9Rat46, linked to 21 genes Locus-linking genes • Statistical limitations limit how many genes can be statistically linked to a single locus – Single expression value is used to calculate all the influences to its expression • Only 2 genes are seen with larger level of regulation Linkages to retinal disease genes • 114 retinal disease genes from RetNet were investigated; 62 are adequately expressed in the rats • 7 has contiguous-only linkages, 11 are noncontiguous-only, and 7 has both kinds Case of Abca4 • Example of contiguous-linkage-only gene • Associated to Stargardt disease, an inheritable, juvenile kind of macular dystrophy • Log odds score highest at marker closest to gene • Sequencing shown the insertion of cREL promotion factor 6.6k upstream Case of Opn1sw • Example of non-contiguous-linkage-only gene • Codes an opsin most sensitive to blue light • Linked to markers D10RAT27 and D15MIT2 D10Rat27 D15Mit2 Case of Opn1sw (Cont’d) • D15MIT2 contains Thrb, known to determine fate of optic cones • Sequencing found a mutation (Ser56Asn) that decreases expression of this gene by 30% if homozygous Correlating gene expressions • Pearson’s r2 statistics was used to calculate the correlation between different class of genes, compared to randomly selected groups • Increased, but statistically insignificant increase in r2 in functional groups Correlating Bardet-Biedl Syndrome - Background • Rare genetic disease that cause multiple syndromes like: – Retinitis pigmentosa – Obesity – Polydactyly • Autosomal recessive • Several genes have seen linkage, but they only account for about half of cases Correlating Bardet-Biedl Syndrome • Hypothesis: Expression of known Bardet-Biedl syndrome-related genes are highly correlated • Result: Rat orthologs of BBS genes are strongly positively correlated Bardet-Biedl Syndrome: the Case of BBS9 • The investigators previously identified BBS9 through comparative genomics • Hypothesis: BBS9 correlates well with other BBS genes • Result: hypothesis confirmed Bardet-Biedl Syndrome: the Case of BBS11 • Investigators also previously identified BBS11 through SNP genotyping • BBS11 is also found to be corerelated to other BBS genes through pairwise r2 tests Discussion • Previous eQTL analyses has shown that gene regulation is more complex than expected • In this investigation: – Changes in expression are can be traced to inheritable factors – Multiple loci controls one gene • Experience on Abca4 and Opn1sw shown eQTL is effective method for determining role of gene regulation in diseases Discussion (Cont’d) • Regulatory relativity: functionally related gene are expressionally related; genes that response to a change can be inferred to be functionally related • In this paper, recombination between the genomes became the permutation • RG is found plausible in research and useful in finding undescribed disease genes End