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.

Fig. 1.

Non-CpG substitution rate in nonrepetitive DNA and TEs. Substitution rate is the number of substitutions per non-CpG site since human–chimpanzee divergence. Confidence intervals at the 5% level are displayed. Complementary substitutions were pooled together. We used the notation XX̄ → YȲ to describe complementary substitutions (i.e., X̄ → Y + X̄ → Ȳ). For example, AT → GC = A → G + T → C.

Fig. 2.

CpG substitution rate in nonrepetitive DNA and TEs. Substitution rate is the number of substitutions per CpG site since human–chimpanzee divergence. (See legend of Fig. 1.)

Fig. 3.

CpG transition rate and size of TEs. GC → AT transition rate is the number of G → A + C → T transitions per CpG site since human–chimpanzee divergence. size, TE size. Confidence intervals at the 5% level are displayed.

Fig. 4.

CpG transition rate and divergence of TEs. div, TE divergence from its ancestral copy expressed as a percentage. (See legend of Fig. 3.)

Fig. 5.

CpG substitution rate as a function of size and divergence of TEs. Substitution rate is the number of substitutions per CpG site since human–chimpanzee divergence. size, TE size; div, TE divergence from its ancestral copy expressed as a percentage. (See legend of Fig. 1.)

Fig. 6.

Non-CpG and CpG transition rate in processed pseudogenes. Substitution rate is the number of substitutions per site in processed pseudogenes. “Tr CpG” denotes transition rate in CpG sites. Other rates are relative to non-CpG sites. rare, rare pseudogenes; numerous, numerous pseudogenes. Transversion rates were not presented because there were not enough substitutions for an accurate estimation. (See legend of Fig. 1.)