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TUESDAY, MARCH 16, 2010
7:00 am Conference Registration
Sponsored by
7:30 Breakfast Presentation
CNV- Based Approaches to Gene Discovery in Brain Disorders
Jonathan Sebat, Ph.D., Chief, Beyster Center for Molecular Genomics of Neuropsychiatric Diseases, UCSD
8:30 Chairperson’s Remarks
Harris Lewin, Ph.D., Professor and Director, Institute for Genomic Biology, University of Illinois
8:35 FEATURED SPEAKER
Developing a Human CNV Map at a 500 bp Resolution for the Incorporation of Structural Genetic Variants in GWAS Studies
Charles Lee, Ph.D., Associate Professor, Brigham & Women’s Hospital
Over the past five years, it has been appreciated that the human genome harbors thousands of structural genomic variants. The largest category of currently-known structural genomic variants are copy number variants (CNVs) where segments of DNA are either lost or gained in a given genome. In an effort to better incorporate CNVs in genome wide association studies, we have developed a comprehensive CNV map at a 500 bp resolution, investigated the genomic impact of the identified CNVs, and have developed CNV targeted arrays that genotype over 20,000 common and rare CNVs in an efficient and cost-effective manner.
9:05 Building a Map of Human Copy Number Variation
Hakon Hakonarson, M.D., Ph.D., Director, Center for Applied Genomics, Children’s Hospital of Philadelphia
We have built a map of human copy number variation (CNVs) based on the analysis of 2,026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort was analyzed for CNVs in a single study using a uniform array platform and computational tools. We have catalogued and characterized over 50,000 individual CNVs, 78% of which were identified in multiple unrelated individuals. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics. We are currently expanding this effort, analyzing over 50,000 children to address rare CNVs in more depth, with the ultimate goal of comparing them to CNVs in older people to establish potential roles of pathogeneity of these CNVs that are observed in healthy children and may not express disease states until much later in life, and many of which may also be protective of common diseases.
9:35 Sensitive and Accurate Detection of Copy Number Variants using Read Depth of Coverage
Jonathan Sebat, Ph.D., Assistant Professor, Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego
Sponsored by
10:05 Association of Phenotypes to CNVs in Large Scale Multi-Platform Studies
Soheil Shams, Ph.D., President & CSO, BioDiscovery, Inc.
With massive amounts of genomic data generated from the latest high-throughput technologies, data analysis and interpretation can be a challenging task. The need is for a single streamlined application designed for the end user that can integrate data from diverse sources. BioDiscovery's Nexus family of modular software provides a custom-fit solution for each individual with easy to use interface, one click tools, and a CNV repository for maximizing collaborative work. We will demonstrate this system by showing our analysis of DNA copy number changes and mRNA expression changes in an Ovarian Cancer dataset.
10:20 Networking Coffee Break, Exhibit & Poster Viewing
11:00 Using Changes in Both the Genome and the Transcriptome to Drive towards Causal Genotypes
Thomas J. Downey, President & CEO, Partek, Inc.
Without prior knowledge of a link between a genetic element and a disease state, the analysis of changes in chromosomal copy number has been largely descriptive in nature. Especially with the high ploidy levels associated with cancer studies, it is especially difficult to infer any mechanic understanding of the disease state without looking at the genes within chromosomal segments with differing abundance. It then becomes critical to understand how the abundance of a DNA template affects its RNA expression levels to identify genes that are sensitive to changes in template abundance. The ability to measure changes in both the genome and the transcriptome within the same samples allows researchers to incorporate both technologies providing a richer analysis. Techniques to integrate both data sets will be presented as well as a discussion on how to enrich for “driver genes” which may be causal to a disease phenotype.
11:30 Evolutionary Breakpoints in Chromosomes are Hotspots of Genetic Variation
Harris Lewin, Ph.D., Professor and Director, Institute for Genomic Biology, University of Illinois
Multispecies comparisons chromosome organization are yielding vast new knowledge of how genomes evolve. There are homologous synteny blocks >30 million base pairs that are conserved for hundreds of millions of years, wheeras other chromosomal regions may undergo repeated rearrangements. We have shown that rearrangement sites, termed evolutionary breakpoint regions (EBRs), are hotspots of genetic variation, including increased density of segmental duplications, copy number variants, repeat elements, single nucleotide polymorphisms, and zinc finger proteins. In addition, we have shown that highly frequent rearrangements associated with certain cancers are associated with EBRs. The relationships between chromosome organization, genome evolution, adaptive phenotypes and cancer will be discussed.
12:00 pm Close of Morning Session
Sponsored by
12:15 Luncheon Presentation
nCounter™ Analysis System: A Complete Solution for Detecting and Counting Large Sets of Target miRNA, mRNA, and DNA Molecules in Biological Samples Using Color Coded Tags
Stephen Jackson Ph.D., Field Application Scientist, NanoString Technologies, Inc.
The nCounter Analysis System detects and counts individual nucleic acid molecules. Over 500 different nucleic acid species can be measured in a single hybridization reaction without the need for amplification. The novel molecular barcoding system provides digital counting of nucleic acid molecules in a variety of input materials including formalin-fixed paraffin-embedded (FFPE) tissues, cell lysates, and blood. These features make the nCounter Analysis System well suited to measure multi-gene expression signatures, validate transcriptional networks and detect mRNA fusion-transcript biomarkers. Current efforts to expand the platform to other applications, such as miRNA expression profiling and detecting variations in genomic copy number, will be presented.
2:00 Chairperson’s Remarks
Mansoor Mohammad, Ph.D., President & CEO, Combimatrix Molecular Diagnostics
2:05 Copy Number Alterations that Predict Metastatic Capability of Human Breast Cancer
Yi Zhang, Principal Scientist, Veridex LLC, a Johnson & Johnson Company
We have analyzed the DNA copy numbers for over 100,000 single-nucleotide polymorphism (SNP) loci across the human genome in genomic DNA from 313 lymph node-negative primary breast tumors for which genome-wide gene-expression data were also available. Combining these two data sets allowed us to identify genomic loci, and their mapped genes, having high correlation with distant metastasis. Our study demonstrates the feasibility of using copy number alterations (CNAs) to predict patient prognostic outcome. When combined with gene expression based signatures for prognosis, the copy number signature refines risk classification and can help identify those breast cancer patients who have a significantly worse outlook in prognosis and a potential differential response to chemotherapeutic drugs.
2:35 New Syndrome Identification through the Use of Microarray Analysis
Bassem A. Bejjani, M.D., CMO , Signature Genomic Laboratories
With the use of our proprietary database accessed through our software, Genoglyphix, multiple patients with over-lapping deletions has allowed for a genotype-first approach to the identification of new microdeletion syndromes and the delineation of causative genes. From these overlapping deletions, the smallest region of overlap (SRO) is delineated and candidate genes are identified. The use of the database for identifying multiple patients, including very small deletions of only one or two genes, helps implicate specific genes as causative for certain phenotypic features of these new syndromes. The design of the array and availability of clinical information on these patients is critical for delineation of the cytogenetic basis for certain phenotypes and for the identification of novel syndromes.
3:05 Clinical Implementation of Array CGH for Diagnosing Genome Copy Number Changes in Cancers
Mansoor Mohammed, Ph.D., President & CEO, Combimatrix Molecular Diagnostics
3:35 Networking Refreshment Break, Exhibit & Poster Viewing
4:15 Application of Array-based Whole Genome Scanning Technologies as a Cytogenetic Tool in Haematological Malignancies
Christine O’Keefe, Ph.D., Department of Translational Hematology and Oncology Research, Cleveland Clinic
4:45 Panel Discussion with Afternoon Speakers
5:15 Close of Day