In Silico Detection of Sequence Variations Modifying Transcriptional Regulation

Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation

Identifying Novel Genes and Pathways Correlated with Group 3 and Group 4 Medulloblastoma Metastasis to the Spine

Medulloblastoma (MB) is a cancer of the cerebellum and the most common childhood brain malignancy. For children with high-risk MB, mortality is nearly always the result of the primary tumour having metastasized to the leptomeninges. This is due to the fact that current therapy for metastatic MB is less effective than that for primary disease. This is a product of the fact that most MB research has focused on primary tumours rather than metastases, due to the low availability of metastatic MB tissues for research, and, until recently, the absence of mouse models of metastatic MB. With greater understanding of primary MB has come a more rounded foundation upon which to build a better therapy. Thus, it is exciting to note that mouse models of MB dissemination now exist, and with these models has come first glimpses of mechanisms that may be driving MB metastasis. In an effort to build upon this new body of knowledge our lab engaged in a process of repeated selection for increased metastasis propensity among spine metastases from mouse patient-derived xenograft (PDX) models of human Group 3 and Group 4 MB. By phenotypically selecting for increased metastasis propensity, we would necessarily also select for increased activity of the genes and pathways necessary and sufficient for increased metastasis propensity, some of which might represent valuable new therapeutic targets. In this manner, we have identified several long non-coding RNAs (lncRNAs) and Cancer Testis Antigen (CTA) genes increasingly transcribed in correlation with metastasis. Further, we have found that their increased transcription is followed closely by the activation of several well- known metastasis pathways. So lncRNAs and CTA genes may represent novel new components of the complex systems regulating MB metastasis.Ph.D

Remarkable sequence signatures in archaeal genomes

Complete archaeal genomes were probed for the presence of long (≥ 25 bp) oligonucleotide repeats (words). We detected the presence of many words distributed in tandem with narrow ranges of periodicity (i.e., spacer length between repeats). Similar words were not identified in genomes of non-archaeal species, namely Escherichia coli, Bacillus subtilis, Haemophilus influenzae, Mycoplasma genitalium and Mycoplasma pneumoniae. BLAST similarity searches against the GenBank nucleotide sequence database revealed that these words were archaeal species-specific, indicating that they are of a signature character. Sequence analysis and genome viewing tools showed these repeats to be restricted to non-coding regions. Thus, archaea appear to possess a non-coding genomic signature that is absent in bacterial species. The identification of a species-specific genomic signature would be of great value to archaeal genome mapping, evolutionary studies and analyses of genome complexity

PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation

PAZAR is an open-access and open-source database of transcription factor and regulatory sequence annotation with associated web interface and programming tools for data submission and extraction. Curated boutique data collections can be maintained and disseminated through the unified schema of the mall-like PAZAR repository. The Pleiades Promoter Project collection of brain-linked regulatory sequences is introduced to demonstrate the depth of annotation possible within PAZAR. PAZAR, located at http://www.pazar.info , is open for business.Other UBCMolecular Medicine and Therapeutics, Centre forMedicine, Faculty ofNon UBCReviewedFacult

Moot Court: Rumsfeld v. FAIR

The Institute of Bill of Rights Law, part of the William and Mary School of Law, marked the commencement of the new term of the United States Supreme Court with its 18th annual Supreme Court Preview conference. The Supreme Court Preview brought together leading court journalists, advocates, and legal scholars for a day and a half to discuss and analyze the Court’s upcoming term. The first session of the conference featured a moot court argument based on the Rumsfeld v. FAIR case, which was about a federal law that requires colleges and universities that receive certain types of federal aid to allow military recruiters on campus. Some universities viewed this as an intrusion into their First Amendment rights because of the “Don’t Ask, Don’t Tell” policy. Participants included Jay Sekulow of the American Center for Law and Justice representing Rumsfeld; Beth Brinkman, former Asst. to the Solicitor General in the Clinton Administration, representing FAIR (Forum for Academic & Institutional Rights); and Walter Dellinger, former Acting Solicitor General in the Clinton Administration, with an amicus brief representing Harvard Law School Representing Supreme Court Justices were Joan Biskupic, Linda Greenhouse, Charles Lane, Michael Gerhardt, David Savage, John Payton, Stuart Taylor, William Van Alstyne, and Dahlia Lithwick

Divergent clonal selection dominates medulloblastoma at recurrence

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples