Presentation description

DNA methylation is an epigenetic mechanism for regulating gene transcription without changing the DNA sequence and plays important roles in development and cell differentiation. DNA methylation primarily occurs at CpG dinucleotides, which tend to be methylated. Conversely, areas with high CpG content, CpG islands, have characteristically low levels of methylation. The dynamics of methylation are well described in the context of development and across cell types, but it remains vastly under-studied especially when related to inheritance. The main goal of this analysis is to identify de novo methylation changes between generations, especially given the genome-wide demethylation and methylation that occurs during embryonic and germline development. To do so, we performed long-read genome sequencing on a large, four generation pedigree to capture both DNA sequence and DNA methylation levels across the genome. We first assessed methylation levels from 4 individuals (2 parents and their 2 children) at CpG islands on chromosome 21. We observe at least a 2-fold change in methylation at 3.4-4.0% of CpG sites on the paternal and 1.9-3.3% of CpG sites on the maternal haplotype. These preliminary results provide context for the expected amount of methylation variation between related individuals. Our next steps include expanding our analyses genome-wide and employing orthogonal validation for potential epimutations. This research will shed light on epigenetic inheritance in humans and create important references of variation, which is useful for understanding how changes in DNA methylation contribute to disease.