Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Three-Dimensional Genome Architecture Predicts the Distribution of Chromosomal Alterations in Human Cancers
Over the last decade, novel technologies have exposed how cancer genomes are riddled with mutations, including everything from single nucleotide substitutions through large-scale copy-number alterations. Progress towards deciphering highly contorted cancer genomes lies in a better understanding of the forces and mutational mechanisms behind patterns of genomic alterations in cancer.
Unequivocally establishing a connection between genomic alterations and three-dimensional genome structure in cancer has up to this point been limited by our ability to measure three-dimensional structure of DNA, and the resolution with which we are able to observe genomic alterations in cancer. Fortunately, both of these have become available in the last two years. Array-based technology now allows determination of somatic copy number alterations (SCNAs) in cancer at much higher resolutions and throughput than microscopy-based methods (1). Similarly doing away with microscopy, the 3C technique and its descendants (2), use a biochemical approach for high resolution determination of three-dimensional genome architecture across a population of cells. In 3C, DNA is crosslinked, digested, and ligated; ligation products are then read using sequencing to determine pairs of DNA fragments which are close in space. Pairing SCNA data with HiC data allows us to examine the role of three-dimensional chromosomal architecture in the formation of somatic structural alterations.
By constructing a heatmap (or matrix) of Somatic Copy-Number Alterations (SCNAs) from (1), we demonstrate the influence of three-dimensional genome structure as determined by Hi-C (2) on the distribution of SCNAs. Towards this end, we developed a Maximum Likelihood framework and permutation procedures for statistically justified comparisons of heatmaps. These statistical techniques establish a connection between intra-chromosomal genomic alterations in cancer and the three-dimensional genomic architecture. Furthermore, the strength of this link is bolstered when we account for purifying selection. Our result provides evidence for a mutational mechanism of chromosomal alterations, and emphasizes the importance of spatial chromatin organization in addition to forces of natural selection for genome function. Finally, our work displays the potential of novel genomic technologies by connecting chromosomal alterations in cancer with three-dimensional genomic architecture at previously impossible megabase resolution.
1Harvard University Graduate Biophysics Program