Long-read sequencing reveals diverse patterns of epigenetic inheritance in mice

Abstract

DNA methylation is a heritable epigenetic mark that encodes information about gene function and regulation independent of DNA sequence. Despite the established roles of methylation quantitative trait loci (meQTLs) and genomic imprinting in the intergenerational transmission of DNA methylation patterns between parents and offspring, comparatively little is known about the nature of this transmission and its relationship to DNA sequence. To investigate this intergenerational epigenetic inheritance, we developed a computational pipeline for the analysis of phased DNA methylation data from nanopore long-read sequencing of genetically diverse mouse crosses, designed to minimize the introduction of reference and technical biases while maximizing the amount of information available for analysis. We applied this pipeline to inbred samples and F1 crosses of two such strains and identified a diverse set of epigenetic inheritance patterns, including an abundance of cis- and trans-acting meQTLs, widespread sex-specific DNA methylation, novel imprinted genes including one located on the X chromosome, and several forms of non-Mendelian transmission of DNA methylation patterns. Subsequent targeted nanopore sequencing by adaptive sampling of F2 mice from the same mouse strains, enabled the differentiation of inheritance patterns mediated by cis- and trans-acting genetic determinants, as well as those transmitted through genetically independent mechanisms. The abundance and diversity of the identified patterns of intergenerational epigenetic inheritance underscores the critical importance of their consideration in the study of heredity, and our work provides both the experimental and computational methods necessary to do so.

Biography

Adam Davidovich is a biomedical engineering PhD candidate in the Feinberg Laboratory at Johns Hopkins University. His research focuses on the relationship between epigenetics and common, complex disease. Adam, is predominantly interested in understanding how DNA methylation can function as a mediator of both genetic and environmental contributions to phenotypic heritability and disease, with a particular focus on developing targeted approaches to reverse disease phenotypes using epigenetic modification.