POPARCH: The role of POPulation scale genetic variation in chromosome 3D ARChitecture

The linear one-dimensional (1D) DNA fiber inside each Eukaryotic cell nucleus folds into a precise three-dimensional (3D) structure, whose structural preservation is vital for correct cell homeostasis and gene-regulatory mechanisms. Previous studies showed that if 3D structure is altered, aberrant phenotypes and diseases can arise. However, little is known on how 1D variation can affect 3D genome variation. Although recently developed technologies allow researchers to generate data to characterize the 3D structural patterns, as of yet no studies have systematically examined how this affects inter-individual 3D variation. I hypothesize a substantial fraction of 3D genome structural variation is controlled through 1D variation, affecting gene expression, and lastly phenotypes. I will test this by quantifying 1D and 3D genomic variation from 100 individuals selected from a chicken cohort my host raised under extremely well-controlled environmental conditions, making it the largest study of its kind up to today, and the first to use an in vivo animal model. Then, computationally I will develop an analytical framework and produce a catalog of DNA sequence variants that condition 3D genome structure. Upon executing my research, I expect to provide a new explanation on how non-coding DNA variants can exert their effect, thus offer new testable hypotheses to researchers interested in genotype-phenotype transitions. This is a proof-of-concept project and, should I be correct, will open a door to expansion in other species, including humans, with a large potential use in medical genomics, thus facilitating pharmacological interventions by disentangling causal intermediate processes. By combining my 3D genomics expertise with the host’s population-statistical genomics knowledge, on his unparalleled cohort of chickens, I will develop unique expertise to place me as the pioneer of a completely new, multidisciplinary field.