Combinatorial identification of DNA methylation patterns over age in the human brain

Behrooz Torabi Moghadam, Michal Dabrowski, Bozena Kaminska, Manfred G. Grabherr, Jan Komorowski

DNA methylation plays a key role in developmental processes, which is reflected in changing methylation patterns at specific CpG sites over the lifetime of an individual. The underlying mechanisms are complex and possibly affect multiple genes or entire pathways. We applied a multivariate approach to identify combinations of CpG sites that undergo modifications when transitioning between developmental stages. Monte Carlo feature selection produced a list of ranked and statistically significant CpG sites, while rule-based models allowed for identifying particular methylation changes in these sites. Our rule-based classifier reports combinations of CpG sites, together with changes in their methylation status in the form of easy-to-read IF-THEN rules, which allows for identification of the genes associated with the underlying sites. We utilized machine learning and statistical methods to discretize decision class (age) values to get a general pattern of methylation changes over the lifespan. The CpG sites present in the significant rules were annotated to genes involved in brain formation, general development, as well as genes linked to cancer and Alzheimer's disease.