Rocking the foundations of molecular genetics

In PNAS, Nelson et al. present intriguing evidence that challenges the fundamental tenets of genetics (1). It has long been assumed that the inherited contribution to phenotype is embedded in DNA sequence variations in, and interactions between, the genes endogenous to the organism, i.e., alleles derived from parents with some degree of de novo variation. This assumption underlies most genetic analysis, including the fleet of genome-wide association studies launched in recent years to identify genomic loci that influence complex human traits and diseases. Not surprisingly, in contrast to mutations in protein-coding sequences, which underlie high penetrance monogenic disorders, the vast majority of the identified loci map to non–protein-coding intergenic and intronic regions, which comprise the vast majority of the genome. These regions contain the regulatory information that controls gene expression and underlies most phenotypic variation (2).