Homology-dependent methylation in primate repetitive DNA

Abstract

In mammals, several studies have suggested that levels of methylation are higher in repetitive DNA than in nonrepetitive DNA, possibly reflecting a genome-wide defense mechanism against deleterious effects associated with transposable elements (TEs). To analyze the determinants of methylation patterns in primate repetitive DNA, we took advantage of the fact that the methylation rate in the germ line is reflected by the transition rate at CpG sites. We assessed the variability of CpG substitution rates in nonrepetitive DNA and in various TE and retropseudogene families. We show that, unlike other substitution rates, the rate of transition at CpG sites is significantly (37%) higher in repetitive DNA than in nonrepetitive DNA. Moreover, this rate of CpG transition varies according to the number of repeats, their length, and their level of divergence from the ancestral sequence (up to 2.7 times higher in long, lowly divergent TEs compared with unique sequences). This observation strongly suggests the existence of a homology-dependent methylation (HDM) mechanism in mammalian genomes. We propose that HDM is a direct consequence of interfering RNA-induced transcriptional gene silencing.RNA interference ͉ transposable element ͉ substitution rate ͉ CpG T ransposable element (TE) activity within genomes may have numerous deleterious consequences, such as their insertions into genes or regulatory elements, or genomic disorders resulting from ectopic recombination between homologous TE copies (1). Thus, specific mechanisms that limit such deleterious effects within genomes are expected to have arisen. Indeed, Selker et al.(2) discovered in Neurospora crassa a defense mechanism against TEs associated with DNA methylation [namely, RIP (Repeat Induced Point mutations)]. DNA methylation in the genome of N. crassa is exclusively confined to repeated sequences (3, 4) and causes their inactivation in no more than one generation (reviewed in ref. 3). Although this mechanism is not entirely understood, DNA methylation is triggered by the existence of two or more homologous DNA sequences longer than a few hundred base pairs (3). The immediate inactivation of methylated sequences in N. crassa is a result of massive C-to-T mutational events due to the deamination of methylated cytosines into thymines, which is likely to be induced by the methylase itself (5, 6). Another example indicating that DNA methylation controls the potential deleterious effects of TEs comes from plants: Only TEs exhibit high methylation levels, which prevents their expression (7,8). In mammals, several lines of experimental and theoretical evidence suggest the existence of a specific methylation pattern in TEs (9-14). For instance, TEs in Mus musculus retain their methylated state during early embryonic stages, whereas nonrepetitive DNA becomes nonmethylated (14). In the same species, Yates et al. (12) demonstrated that tandem B1 elements can induce strong de novo DNA methylation. In humans, Chesnokov and Schmid (11) discovered that Alu elements in the germ lin...

Association of interindividual differences in p14ARF promoter methylation with single nucleotide polymorphism in primary colorectal cancer

“…26 Furthermore, Meunier et al also recently reported that the methylation pattern in primate repetitive DNA is homology-dependent. 27 Therefore, it is likely that 2 nonhomologous alleles resulting from nucleotide polymorphism affect promoter methylation of the p14 ARF gene by causing heterozygous methylation within a repeat sequence.…”

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

“…Therefore, the substitution rate at CpG dinucleotides may be negatively correlated with GC content (defined as the percentage of G and C nucleotides). There are conflicting conclusions on this relationship [17][18][19].…”

“…We used a parsimony method [19][20][21][22][23] to identify sites that have been part of a CpG dinucleotide in the recent past (''CpG sites''). In addition, using the same method, we identified sites that have been part of a GpC dinucleotide (''GpC sites'', see the Methods section for details).…”

Epigenetic QTL Mapping inBrassica napus

“…This pattern of differential methylation was also detected between homologous ancestral blocks and may reflect a buffer of gene dosage resulting from formation of the amphidiploid (Paun et al 2010). In primate genomes, the degree of CpG methylation in homologous genomic regions varies between human, chimpanzee and baboon (Meunier et al 2005), suggesting the existence of a homology-dependent methylation (HDM) mechanism.…”