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Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.

Bell, CG; Wilson, GA; Butcher, LM; Roos, C; Walter, L; Beck, S; (2012) Human-specific CpG "beacons" identify loci associated with human-specific traits and disease. Epigenetics , 7 (10) 1188 - 1199. 10.4161/epi.22127. Green open access

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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.

Type: Article
Title: Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.4161/epi.22127
Publisher version: http://dx.doi.org/10.4161/epi.22127
Language: English
Additional information: This work is made available under a Creative Commons license. PMCID: PMC3469460
Keywords: Animals, CpG Islands, DNA Methylation, Epigenesis, Genetic, Evolution, Molecular, Gene Expression Regulation, Genetic Variation, Humans, Primates, Promoter Regions, Genetic, Species Specificity
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/1377155
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