title: Inter-individual variability contrasts with regional homogeneity in the human brain DNA methylome.
abstract: The possibility that alterations in DNA methylation are mechanistic drivers of development, aging and susceptibility to disease is widely acknowledged, but evidence remains patchy or inconclusive. Of particular interest in this regard is the brain, where it has been reported that DNA methylation impacts on neuronal activity, learning and memory, drug addiction and neurodegeneration. Until recently, however, little was known about the 'landscape' of the human brain methylome. Here we assay 1.9 million CpGs in each of 43 brain samples representing different individuals and brain regions. The cerebellum was a consistent outlier compared to all other regions, and showed over 16 000 differentially methylated regions (DMRs). Unexpectedly, the sequence characteristics of hypo- and hypermethylated domains in cerebellum were distinct. In contrast, very few DMRs distinguished regions of the cortex, limbic system and brain stem. Inter-individual DMRs were readily detectable in these regions. These results lead to the surprising conclusion that, with the exception of cerebellum, DNA methylation patterns are more homogeneous between different brain regions from the same individual, than they are for a single brain region between different individuals. This finding suggests that DNA sequence composition, not developmental status, is the principal determinant of the human brain DNA methylome.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK robert.illingworth@igmm.ed.ac.uk.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Illingworth
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gruenewald-Schneider
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK.
authors.forename: Dina
authors.initials: D
authors.lastname: De Sousa
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Webb
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK.
authors.forename: Cara
authors.initials: C
authors.lastname: Merusi
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK.
authors.forename: Alastair R W
authors.initials: AR
authors.lastname: Kerr
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Keith D
authors.initials: KD
authors.lastname: James
authors.affiliation: Neuropathology Unit, Division of Pathology, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Neuropathology Unit, Division of Pathology, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Walker
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Andrews
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Midlothian, EH9 3BF, UK a.bird@ed.ac.uk.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bird
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D018899:CpG Islands; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D006801:Humans
chemical_list: D004247:DNA