Associating Noncoding Variants with Disease Processes
As Dr. Stamatoyannopoulos and his colleagues pointed out in a 2012 paper in Science, the average individual is expected to harbor thousands of variants within noncoding genomic regions involved in gene regulation. But, they note, it is currently not possible to interpret reliably the functional consequences of genetic variation within any given transcription factor recognition sequence.
According to these authors, genome-wide association studies have identified many noncoding variants associated with common diseases and traits. In their own study, the investigators showed that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs).
Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. They further identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants, they noted, systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks.
The investigators also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait without prior knowledge of physiological mechanisms.
Their results, the authors concluded, suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
According to Dr. Stamatoyannopoulos, the research revealed that, with diseases, "It's not necessarily the gene but probably a network of genes that are working together." He added that regulatory DNA sequences, or "switches," may orchestrate entire networks. Such thoughts were affirmed by Eric Schadt, Ph.D., professor and chair of genetics and genomic sciences at Mount Sinai School of Medicine in New York. Dr. Schadt, who co-authored a perspective that accompanied the article, said, "They are affecting regions in the DNA that regulate whether genes should be expressed or not, and at what level. They are playing more of a regulatory role versus a protein-function role.”
The footnote to all of this is probably that knowing individual gene sequences that encode specific proteins is only the beginning of understanding the complexity of the human genome, but it may show how introns and other mechanisms control gene expression and ultimately shed light on many human diseases.