Large-scale clustering of CAGE tag expression data

Background: Recent analyses have suggested that many genes possess multiple transcription start sites (TSSs) that are differentially utilized in different tissues and cell lines. We have identified a huge number of TSSs mapped onto the mouse genome using the cap analysis of gene expression (CAGE) method. The standard hierarchical clustering algorithm, which gives us easily understandable graphical tree images, has difficulties in processing such huge amounts of TSS data and a better method to calculate and display the results is needed. Results: We use a combination of hierarchical and non-hierarchical clustering to cluster expression profiles of TSSs based on a large amount of CAGE data to profit from the best of both methods. We processed the genome-wide expression data, including 159,075 TSSs derived from 127 RNA samples of various organs of mouse, and succeeded in categorizing them into 70-100 clusters. The clusters exhibited intriguing biological features: a cluster supergroup with a ubiquitous expression profile, tissue-specific patterns, a distinct distribution of non-coding RNA and functional TSS groups. Conclusion: Our approach succeeded in greatly reducing the calculation cost, and is an appropriate solution for analyzing large-scale TSS usage data

Indications of Linkage and Association of Gilles de la Tourette Syndrome in Two Independent Family Samples: 17q25 Is a Putative Susceptibility Region

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS