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

Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
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.
1559-2294
1188-1199
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Wilson, Gareth A.
6af36a85-7d05-4989-9ab3-d8adac4d5eb8
Butcher, Lee M.
7744895f-2b21-42e3-80fe-17272f22c75e
Roos, Christian
d270f68b-2c11-41f3-b10b-a2fe6d4d8ddc
Walter, Lutz
edc3e97f-af3d-4f90-9f45-fd4be013ccb9
Beck, Stephan
50f0c07a-19a8-4bca-adbc-af41a3800412
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Wilson, Gareth A.
6af36a85-7d05-4989-9ab3-d8adac4d5eb8
Butcher, Lee M.
7744895f-2b21-42e3-80fe-17272f22c75e
Roos, Christian
d270f68b-2c11-41f3-b10b-a2fe6d4d8ddc
Walter, Lutz
edc3e97f-af3d-4f90-9f45-fd4be013ccb9
Beck, Stephan
50f0c07a-19a8-4bca-adbc-af41a3800412

Bell, Christopher G., Wilson, Gareth A., Butcher, Lee M., Roos, Christian, Walter, Lutz and Beck, Stephan (2012) Human-specific CpG "beacons" identify loci associated with human-specific traits and disease. Epigenetics, 7 (10), 1188-1199. (doi:10.4161/epi.22127). (PMID:22968434)

Record type: Article

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.

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Accepted/In Press date: 9 August 2012
e-pub ahead of print date: 11 September 2012
Published date: October 2012
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400985
URI: https://eprints.soton.ac.uk/id/eprint/400985
ISSN: 1559-2294
PURE UUID: cc61bf07-5afd-420f-8098-24a5773f6544
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 13:28
Last modified: 29 Aug 2019 00:31

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