Detection and Characterization of Copy Number Variations and Complex Genomic Rearrangements in Human Subjects Using Nanochannel Genome Mapping Technology

Alterations of genomic DNA, ranging from simple copy-number variations to complex genomic rearrangements, often induce anomalous phenotypes. The ability to observe DNA molecules long enough to span the affected genomic regions is essential for fully realizing the diagnostic potential of these structural variants. Irys, a high-throughput genome analysis platform based on Nanochannel Array technology, is uniquely suited for such task as it linearizes extremely long (hundreds of kilobases in size) DNA molecules for direct imaging. The detected molecules are used to assemble high-resolution de novo consensus genome maps, enabling detection of long-range genomic structural rearrangements. In addition, copynumber variations are analyzed by aligning the observed single molecules of genomic DNA to the reference and by normalizing the resulting coverage profile. By combining the structural variations found in human de novo assemblies with the features detected in the corresponding normalized copy-number profiles, we were able to comprehensively characterize whole chromosome aneuploidies, microdeletions, intra- and  nterchromosomal translocations, and inversions. The results are illustrated in cancer samples and in euploid subjects.