title: Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
abstract: Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed "CpG beacons") as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10(-3)) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10(-3)). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK. christopher.bell@ucl.ac.uk
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Wilson
authors.forename: Lee M
authors.initials: LM
authors.lastname: Butcher
authors.forename: Christian
authors.initials: C
authors.lastname: Roos
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D011323:Primates / Q000235:genetics; D011401:Promoter Regions, Genetic; D013045:Species Specificity