Fig. 5.

Working model for polymorphic imprinting of the nc886 locus. All individuals we examined have the single paternally derived unmethylated allele at the nc886 DMR. In 75% of the human population, the nc886 DMR is monoallelically methylated on the maternally derived allele (Bottom), with the remaining 25% having no methylation on either allele (Top). Here, we demonstrate that the presence of an A or C polymorphism in the centromeric CTCF binding site is associated with local DNA methylation density in the nc886 DMR. We hypothesize that the presence of the A allele or increased DNA methylation density reduces CTCF binding, allowing DNA methylation to spread into the DMR. We reanalyzed data from Silver et al. (6) and Markunas et al. (54) and found that maternal age and season of conception contribute to the likelihood that a child will have imprinting at the nc886 DMR. Therefore, we propose that a combination of maternal factors shifts the balance between imprinted and not-imprinted status in children, with downstream phenotypic consequences such as BMI.