Imperfect tandem repeats (TRs) of ≥400nt are associated with 365 human 5’-genic CpG islands (TR-CGIs). Most are clustered at chromosome ends, with a high density across chromosome 19. These genes are enriched in neurodevelopmental/behavioral disorders and show interindividual variation in methylation levels. A subset of TR-CGIs is highly methylated and remains so during reprogramming to primed iPSCs, but become unmethylated in naïve PSCs, as do imprinting control regions (ICRs). Transcript levels correlate with methylation for some TR-CGI genes. TR-CGIs occur as orthologs in primates, but the corresponding mouse promoter-CGIs are without TRs and unmethylated. Thus, non-imprinted TR-CGIs accompanied primate evolution, with unique ability to acquire methylation during embryonic development and resist reprogramming to a pluripotent stem cell state.

One-Sentence Summary

DNA unique to human and non-human primate genes can acquire lifelong CpG methylation mid-course to redirect fetal development.