Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.

BackgroundHigh serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation.MethodsGene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher’s Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network.ResultsWe measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals.ConclusionsThis study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.

SummaryLeprosy is an infectious disease in which the clinical manifestations correlate with the type of immune response mounted to the pathogen, Mycobacterium leprae. To investigate which biological pathways or gene sets are over-represented in lepromatous (L-Lep) versus tuberculoid (T-Lep) patients that might be relevant in disease pathogenesis, we compared the gene expression profiles of L-lep versus T-lep skin lesions using knowledgeguided bioinformatic analysis, incorporating data on likely biological functions, including gene ontology information and regulatory data. Analysis of probe sets comparatively increased in expression in L-lep versus T-lep revealed multiple pathways and functional groups involving B-cell genes (P values all < 0Á005) relevant to the dataset. Further pathways analysis of B-cell genes comparatively increased in expression in L-lep versus T-lep lesions revealed a potential network linking the expression of immunoglobulin M (IgM) and interleukin-5 (IL-5). Analysis of the leprosy lesions by immunohistology indicated that there was approximately 8% more IgMpositive cells in L-lep lesions than in T-lep lesions. Furthermore, IL-5 synergized in vitro with M. leprae to enhance total IgM secretion from peripheral blood mononuclear cells. This pathways analysis of leprosy in combination with our in vitro studies implicates a role for IL-5 in the increased IgM at the site of disease in leprosy.

Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by the presence of multiple lipoprotein phenotypes that increase the risk of premature coronary heart disease. In a previous study, we identiWed an intragenic microsatellite marker within the protocadherin 15 (PCDH15) gene to be associated with high triglycerides (TGs) in Finnish dyslipidemic families. In this study we analyzed all four known nonsynonymous SNPs within PCDH15 in 1,268 individuals from Finnish and Dutch multigenerational families with FCHL. Association analyses of quantitative traits for SNPs were performed using the QTDT test. The nonsynonymous SNP rs10825269 resulted in a P = 0.0006 for the quantitative TG trait. Additional evidence for association was observed with the same SNP for apolipoprotein B levels (apo-B) (P = 0.0001) and total cholesterol (TC) levels (P = 0.001). None of the other three SNPs tested showed a signiWcant association with any lipid-related trait. We investigated the expression of PCDH15 in diVerent human tissues and observed that PCDH15 is expressed in several tissues including liver and pancreas. In addition, we measured the plasma lipid levels in mice with loss-of-function mutations in Pcdh15 (Pcdh15 av-Tg and Pcdh15 av-3J ) to investigate possible abnormalities in their lipid proWle. We observed a signiWcant diVerence in plasma TG and TC concentrations for the Pcdh15 av-3J carriers when compared with the wild type (P = 0.013 and P = 0.044, respectively). Our study suggests that PCDH15 is associated with lipid abnormalities.

Objective-Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism. Methods and Results-Our data show that rs7575840 is associated with serum apoB levels (Pϭ4.85ϫ10 Ϫ10 ) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (Pϭ2ϫ10 Ϫ5 to 9ϫ10 Ϫ7 ) in the Finnish Metabolic Syndrome in Men study sample (nϭ7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (nϭ2666, Pϭ3.33ϫ10 Ϫ5 ). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (Pϭ1.13ϫ10 Ϫ10 ) and a regional noncoding RNA (BU630349) (Pϭ7.86ϫ10 Ϫ6 ) in adipose tissue. Conclusion-It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels. Key Words: gene expression Ⅲ adipose tissue Ⅲ apolipoprotein B Ⅲ association analysis Ⅲ Mexicans G enome-wide association studies (GWAS) have been successful in discovering single-nucleotide polymorphisms (SNPs) that affect low-density lipoprotein cholesterol (LDL-C) levels with low to moderate effect sizes. 1 However, many of the significantly associated SNPs are intergenic and belong to large linkage disequilibrium (LD) blocks, making it difficult to evaluate their functional relevance.The SNP rs7575840 has been implicated in a recent GWAS for LDL-C. 1 As rs7575840 resides in the apolipoprotein B (APOB) gene region, 6.5 kb upstream of the gene, we tested it for association with refined lipid phenotypes and proton nuclear magnetic resonance spectroscopy measurements of lipid particles in a white population sample, the Metabolic Syndrome in Men (METSIM) cohort (nϭ7710). Furthermore, to also explore the role of this GWAS variant in another population, we fine mapped the APOB region in a Mexican dyslipidemic case/control study sample and compared the regional LD between non-Mexican whites and Mexicans. The Mexican population has a 44% prevalence of hypercholesterolemia, defined by total cholesterol (TC) Ͼ200 mg/dL. 2 Other forms of dyslipidemias are highly common in this population as well. However, to...