Janine M. LaSalle, Ph.D., Isaac N. Pessah, Ph.D.
University of California-Davis
R01ES021707, R01ES014901, P01ES011269
NIEHS grantees discovered how independent genetic and environmental factors can affect a larger set of genes important to brain development and autism spectrum disorders (ASD). The findings showed how some genes linked to ASD might be altered because of a specific genetic mutation combined with exposure to polychlorinated biphenyl (PCB) 95, a widespread environmental contaminant and neurotoxicant.
The researchers studied the combined effects of PCB 95 and chromosomal duplications, which are genetic mutations that can arise from errors in DNA replication and repair. Duplication of genetic material in chromosome 15, or Dup15q, has been previously associated with ASD. By studying brain samples with and without this chromosomal duplication, the researchers identified thousands of variations that affected genes. Many of the variations are related to differences in DNA methylation, the process by which molecules are added to regions of DNA to control whether a gene is expressed.
The researchers exposed cells with Dup15q and normal cells to PCB 95 to discern whether the genetic or the environmental factor was linked to variations in ASD-associated genes. They found that 65 percent of genes with reduced DNA methylation in the samples exposed to PCB 95 were also affected by Dup15q. They also found that the cells with a combination of Dup15q and PCB 95 exposure had unique genetic variations that were not seen when the two factors were studied separately.
The findings provide new evidence that environmental factors can influence the function of genes linked to ASD by altering DNA methylation. The work also points to ASD-related genes that may be possible drug targets or potential markers for predicting autism earlier.
Citation: Dunaway KW, Islam MS, Coulson RL, Lopez SJ, Vogel Ciernia A, Chu RG, Yasui DH, Pessah IN, Lott P, Mordaunt C, Meguro-Horike M, Horike SI, Korf I, LaSalle JM. 2016. Cumulative impact of polychlorinated biphenyl and large chromosomal duplications on DNA methylation, chromatin, and expression of autism candidate genes. Cell Rep 17(11):3035−3048.