CCB Colloquium: Katherine S. Pollard

Topic: A population genetic view of human chromatin organization

Abstract: Genetic variation affects cellular and organismal biology through modifying genes and regulatory elements. But the degree to which it influences or is influenced by chromatin structure is less well understood. I will discuss several projects that bring together large-scale human genome sequencing, chromatin capture (Hi-C), and functional genomics (ChIP-seq) data to explore the interplay of genome evolution and chromatin organization. We show that topological domain (TAD) boundaries are under strong negative selection across primates and in healthy people¬–but not in patients with autism, developmental delay, and cancer–suggesting a broad role for “enhancer hijacking” in human disease. Secondly, we explore concordance between genetic architecture (linkage disequilibrium (LD)) and chromatin organization in 22 cell types and find no correlation between LD maps and chromatin interaction maps at any distance scale above the 5 kilobase resolution of the Hi-C data. Finally, we demonstrate that many transcription factors bind genome sites containing specific local DNA structures that do not match out current concept of sequence motifs, which opens the door to an expanded view of how mutations can alter regulatory elements. Together these studies illustrate how biophysics and genetics can be brought together through computational modeling to shed new light on genome function.