In Science this week, a team of University of Washington researchers report that a large number of disease-associated gene variants are localized near regulatory DNA, providing new insights into the genetic basis for a variety of disorders. Through an analysis of human cell and tissue samples, the investigators found that non-coding variants linked to diseases are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites — most of which are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. They identified distinct gene targets for hundreds of the DHSs, and found that "disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks."
Elsewhere in Science, a pair of Massachusetts Institute of Technology researchers looked at regions of the human genome not shared with other mammals and discovered that a "broad range of transcribed and regulatory non-conserved elements show decreased human diversity, suggesting lineage-specific purifying selection." Meantime, conserved elements lacking activity showed increased human diversity, indicating that some recently became non-functional. These findings suggest that continued turnover in regulatory regions, with at least an additional four percent of the human genome subject to lineage-specific constraint.
Finally, researchers from the University of California, San Diego, report on the discovery of mutations in a single gene that appear to cause a rare form of epilepsy-associated autism. Specifically, inactivating mutations in the gene BCKDK were found in consanguineous families with autism, epilepsy, and intellectual disability. The condition is partially treatable in mice fed diets high in branched chain amino acids, which are reduced by BCKDK mutations, and the investigators found that similar dietary supplementation could normalize branched chain amino acid levels in humans. "Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome."