Integrated approaches for the analysis of complex human genomic sequence variation and its correlation to complex phenotypes

Alexander Urban
Yale University

We have been pursuing the development of enhanced genomics analytical tools that are based on novel experimental methodologies. In order to make full use of such novel technologies it is imperative that experimentalists and theoreticians work closely together, with the goal of creating an integrated procedure. This procedure is continually refined in an iterative cycle between experiment and computational data analysis. Once stabilized one can move to apply the methodology to create large datasets to uncover biological meaning. At this level there is again a need for interplay between data analysis and experimental validation of predictions.
These concepts will be illustrated by the example of developing and using advanced tools for the analysis of copy-number and structural variation (CNV/SV) in the human genome. We have developed High-Resolution Comparative Genomic Hybridization (HR-CGH) based on high-density oligonucleotide tiling microarrays, which allows us to scan entire chromosomes for CNV at exon-level resolution. We have also developed 454-Paired-End-Sequencing which takes advantage of the newly available next-generation sequencing technology and a cloning-free sample-preparation approach to scan for SV genome wide at 2-3 kb resolution.
We have applied those methods to samples and cohorts of samples from healthy subjects as well as, in the case of HR-CGH, samples from patients with various genomic disorders and complex disease phenotypes. Once the data is finely grained enough one can begin correlating the complex genotypes to those complex phenotypes.

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