Discovering genomic stripes at high resolution

Abstract

The 3.2 billion base pair human genome is 2 meters long laid end to end, yet fits into cells' nuclei around 5 microns in diameter on average. To accomplish this, the genome must fold into the nucleus without making knots. The folding structure of the genome is hierarchical and impacts key functionality of the cell. We currently have tools to assay genomic structure at coarse-grained resolution, but lack the tools to assay fine-grained structures, e.g. loops of DNA that form around genes. Here I present a first-in-class method to assay fine-grained structures, particularly genomic stripes, across entire human genomes at high resolution, demonstrating its functionality on 1200bp resolution, 400bp resolution, and even 200bp resolution, a scale intractable to analyze with current state-of-the-art algorithms. In addition to superior functionality and detection of stripes, my tool also contributes at least 2x runtime and 10x memory load improvements to the current state-of-the-art algorithm. Additionally, I present a biophysics-based statistical method to annotate the significance of each stripe structure, which draws on the fractal globule model of DNA packing within the nucleus. Preliminary analysis suggests that stripe regions are biologically relevant, potentially forming at key regions that interface with proteins in cells' nuclei to regulate genes. Gene regulation is a process fundamental for cell function, so these results are exciting, revealing the power of unbiased computational tools to reveal new biology.