Since Jacob and Monod's characterization of the role of DNA elements in gene 
control, it has been recognized that the linear organization of genome structure 
is important for the regulation of gene transcription and hence the 
manifestation of phenotypes. Similarly, it has long been hypothesized that the 
spatial organization (in three dimensions evolving through time), as part of the 
epigenome, makes a significant contribution to the genotype-phenotype 
transition. Proximity ligation assays commonly known as chromosome conformation 
capture (3C) and 3C based methodologies (e.g., GCC, HiC and ChIA-Pet) are 
increasingly being incorporated into empirical studies to investigate the role 
that three-dimensional genome structure plays in the regulation of phenotype. 
The apparent simplicity of these methodologies-crosslink chromatin, digest, 
dilute, ligate, detect interactions-belies the complexity of the data and the 
considerations that should be taken into account to ensure the generation and 
accurate interpretation of reliable data. Here we discuss the probabilistic 
nature of these methodologies and how this contributes to their endogenous 
limitations.