we recently used in situ hi c to create kilobase resolution 3d maps of mammalian genomes here we combine these maps with new hi c microscopy and genome editing experiments to study the physical structure of chromatin fibers domains and loops we find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer combining hi c data and novel mathematical theorems we show that contact domains are also not consistent with a fractal globule instead we use physical simulations to study two models of genome folding in one intermonomer attraction during polymer condensation leads to formation of an anisotropic tension globule in the other ccctc binding factor ctcf and cohesin act together to extrude unknotted loops during interphase both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops however the extrusion model explains a far wider array of observations such as why loops tend not to overlap and why the ctcf binding motifs at pairs of loop anchors lie in the convergent orientation finally we perform 13 genome editing experiments examining the effect of altering ctcf binding sites on chromatin folding the convergent rule correctly predicts the affected loops in every case moreover the extrusion model accurately predicts in silico the 3d maps resulting from each experiment using only the location of ctcf binding sites in the wt thus we show that it is possible to disrupt restore and move loops and domains using targeted mutations as small as a single base pair.