Asymmetrical evolution of promoter methylation of mammalian genes after duplication.

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Even though gene duplication is a key source of new genes and evolutionary innovation, it is unclear how duplicates survive the period immediately following gene duplication, in which both copies are functionally redundant. In the absence of epigenetic silencing, the abundance of the gene product would double after gene duplication, which would often have deleterious effects. However, recent duplicates exhibit low expression levels, which could be at least partially explained by high levels of promoter methylation. What evolutionary paths lead to duplicate hypermethylation, and does it affect both duplicates, or only one? Here, we compare levels of promoter methylation in 10 human and 16 mouse tissues, between singletons and duplicates and among human-mouse orthologs of different kinds (one-to-one, one-to-many, many-to-one, and many-to-many). Our results indicate that: (1) on average, duplicates are more methylated than singletons in mouse, but less methylated than singletons in human, (2) recently duplicated genes tend to exhibit high levels of promoter methylation, (3) genes that undergo duplication tend to be highly methylated before duplication, (4) after gene duplication, one of the copies (the daughter copy, i.e. the one that relocates to a new genomic context) tends to undergo an additional increase in promoter methylation, whereas the other (the parental copy, which remains in the original genomic location) tends to retain pre-duplication methylation levels, and (5) daughter copies tend to be lowly expressed. These observations support a model in which daughter copies are repressed via promoter hypermethylation and can thus survive the filter of purifying selection until both copies diverge functionally.