Genome-wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non-human primates

BMC Evolutionary Biology (Impact Factor: 3.41). 08/2012; 12(1):144. DOI: 10.1186/1471-2148-12-144
Source: PubMed

ABSTRACT Background
The highly improved cognitive function is the most significant change in human evolutionary history. Recently, several large-scale studies reported the evolutionary roles of DNA methylation; however, the role of DNA methylation on brain evolution is largely unknown.

To test if DNA methylation has contributed to the evolution of human brain, with the use of MeDIP-Chip and SEQUENOM MassARRAY, we conducted a genome-wide analysis to identify differentially methylated regions (DMRs) in the brain between humans and rhesus macaques. We first identified a total of 150 candidate DMRs by the MeDIP-Chip method, among which 4 DMRs were confirmed by the MassARRAY analysis. All 4 DMRs are within or close to the CpG islands, and a MIR3 repeat element was identified in one DMR, but no repeat sequence was observed in the other 3 DMRs. For the 4 DMR genes, their proteins tend to be conserved and two genes have neural related functions. Bisulfite sequencing and phylogenetic comparison among human, chimpanzee, rhesus macaque and rat suggested several regions of lineage specific DNA methylation, including a human specific hypomethylated region in the promoter of K6IRS2 gene.

Our study provides a new angle of studying human brain evolution and understanding the evolutionary role of DNA methylation in the central nervous system. The results suggest that the patterns of DNA methylation in the brain are in general similar between humans and non-human primates, and only a few DMRs were identified.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic mechanisms traditionally have been studied in the domains of development and disease, but they may also play important roles in ecological and evolutionary processes. In this article, we revisit historical as well as recent studies that indicate significant impacts of epigenetic processes on evolution. Our main focus is DNA methylation, which is a prevalent chemical modification of genomic DNA. First, it has been long known that DNA methylation acts as a major mutational facilitator in animal genomes and influences nucleotide compositions of genomes. More recently, genome-wide analyses have demonstrated that the current levels of DNA methylation can be predicted from the evolutionary signatures of DNA methylation, indicating that these two processes are intimately correlated. Indeed, the recent explosive growth in the knowledge of genomic DNA methylation in wide-ranging taxa has revealed that patterns of DNA methylation are surprisingly conserved across deep phylogenies. Interestingly, comparative analyses of humans and closely related primate species show that genomic regions that do show evolutionary divergence of DNA methylation are enriched for developmental and tissue specializations. A key question is how epigenetic patterns transmit between generations and impact evolutionary dynamics. On the one hand, some studies report direct transmissions of epigenetic features to the next generation. On the other hand, it is becoming clear that genomic sequence variants exist that encode and presumably regulate distinctive epigenetic patterns. For instance, numerous single-nucleotide polymorphisms that affect DNA-methylation patterns have been discovered in human populations. These studies begin to unveil a dynamic interplay between genomic and epigenomic factors across long and short evolutionary timescales.
    Integrative and Comparative Biology 05/2014; DOI:10.1093/icb/icu040 · 2.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Covalent modifications of nucleotides, such as methylation or hydroxymethylation of cytosine, regulate gene expression. Early environmental risk factors play a role in mental disorders in adulthood. This may be in part mediated by epigenetic DNA modifications. Methods for comprehensive analysis of DNA methylation and hydroxymethylation include DNA modification methods such as bisulfite sequencing, or collection of methylated, hydroxymethylated, or unmethylated DNA by specific binding proteins, antibodies, or restriction enzymes, followed by sequencing or microarray analysis. Results from these experiments should be interpreted with caution because each method gives different result. Cytosine hydroxymethylation has different effects on gene expression than cytosine methylation; methylation of CpG islands is associated with lower gene expression, whereas hydroxymethylation in intragenic regions is associated with higher gene expression. The role of hydroxymethylcytosine is of particular interest in mental disorders because the modification is enriched in the brain and synapse related genes, and it exhibits dynamic regulation during development. Many DNA methylation patterns are conserved across species, but there are also human specific signatures. Comprehensive analysis of DNA methylation shows characteristic changes associated with tissues, brain regions, cell types, and developmental states. Thus, differences in DNA methylation status between tissues, brain regions, cell types, and developmental stages should be considered when the role of DNA methylation in mental disorders is studied. Several disease-associated changes in methylation have been reported: hypermethylation of SOX10 in schizophrenia, hypomethylation of HCG9 (HLA complex group 9) in bipolar disorder, hypermethylation of PRIMA1, hypermethylation of SLC6A4 (serotonin transporter) in bipolar disorder, and hypomethylation of ST6GALNAC1 in bipolar disorder. These findings need to be replicated in different patient populations to be generalized. Further studies including animal experiments are necessary to understand the roles of DNA methylation in mental disorders.
    Neuropharmacology 01/2014; DOI:10.1016/j.neuropharm.2013.12.019 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.
    Epigenetics: official journal of the DNA Methylation Society 01/2014; 9(4). DOI:10.4161/epi.27689 · 5.11 Impact Factor

Full-text (3 Sources)

Available from
Jul 22, 2014