Rocking the foundations of molecular genetics.

I n 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–proteincoding 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). However, the perplexing and much debated surprise has been that most genomewide association studies have superficially failed to locate more than a small percentage of the inherited component of complex traits. This may be a result of a number of possibilities that are not mutually exclusive (3, 4), including systematic underestimation of the fraction of the heritability and epistatic interactions measured by common SNPs used to monitor haplotype blocks, a larger than expected contribution of rare recent variants that lie under the SNP typing radar, and intergenerational epigenetic inheritance (5), which is not polled by DNA sequence. However, the latter has not thus far been paid much attention or given much credence as a major factor.