Are complex traits underpinned by polygenic molecular traits? A reflection on the complexity of gene expression

Variation in complex traits is controlled by multiple genes. The prevailing assumption is that such polygenic complex traits are underpinned by variation in elementary molecular traits, such as gene expression, which themselves have a simple genetic basis. Here, we review recent advances that reveal the captivating complexity of gene regulation: the cell type, time point, and magnitude of gene expression are not merely dependent on a couple of regulators; rather, they result from a probabilistic process shaped by cis- and trans-regulatory elements collaboratively integrating internal and external cues with the tightly regulated dynamics of DNA. In addition, the finding that genetic variants linked to complex diseases in humans often do not co-localize with quantitative trait loci modulating gene expression, along with the role of nonfunctional transcription factor (TF) binding sites, suggests that some of the genetic effects influencing gene expression variation may be indirect. If the number of genomic positions responsible for TF binding, TF binding site search time, DNA conformation and accessibility as well as regulation of all trans-acting factors is indeed vast, is it plausible that the complexity of elementary molecular traits approaches the complexity of higher-level organismal traits? Although it is hard to know the answer to this question, we motivate it by reviewing the complexity of the molecular machinery further.