Research Article: The evolution of CpG density and lifespan in conserved primate and mammalian promoters

Date Published: April 14, 2018

Publisher: Impact Journals

Author(s): Adam T. McLain, Christopher Faulk.


Gene promoters are evolutionarily conserved across holozoans and enriched in CpG sites, the target for DNA methylation. As animals age, the epigenetic pattern of DNA methylation degrades, with highly methylated CpG sites gradually becoming demethylated while CpG islands increase in methylation. Across vertebrates, aging is a trait that varies among species. We used this variation to determine whether promoter CpG density correlates with species’ maximum lifespan. Human promoter sequences were used to identify conserved regions in 131 mammals and a subset of 28 primate genomes. We identified approximately 1000 gene promoters (5% of the total), that significantly correlated CpG density with lifespan. The correlations were performed via the phylogenetic least squares method to account for trait similarity by common descent using phylogenetic branch lengths. Gene set enrichment analysis revealed no significantly enriched pathways or processes, consistent with the hypothesis that aging is not under positive selection. However, within both mammals and primates, 95% of the promoters showed a positive correlation between increasing CpG density and species lifespan, and two thirds were shared between the primate subset and mammalian datasets. Thus, these genes may require greater buffering capacity against age-related dysregulation of DNA methylation in longer-lived species.

Partial Text

Gene promoters are conserved across the animal radiation and as far back as non-fungi eukaryotes (i.e. holozoans) [1]. Promoters have many features, including TATA boxes, DNA binding sites, and most notably for our investigation, enrichment in CpG sites, which in high enough density are designated as CpG islands (CGIs) [2]. Much evolutionary focus has been on pairwise comparison of promoters between human and mouse, or human and chicken [3]. Yet, questions remain about the evolution of promoter features that can only be answered by comparison of multiple genomes of animals. Here we use the Eukaryotic Promoter Database ‘new’ (EPDnew) repository of verified human promoters to serve as a base for identifying promoters in other species [4]. In this study, we compare a genomic feature, CpG site density in promoters and a physiological trait, maximum lifespan, in several dozen species.

Increasing evidence has linked quantifiable phenotypic traits to DNA methylation status in regions around active genes. Over the long term, regions with low CpG density undergo mutation at a much more rapid rate than highly CpG-dense regions [21]. Base excision repair pathways have been shown to correlate with longer lived species and may influence the rate of deamination induced CpG mutations [22]. However, here we are most interested in the evolution and the gradation of underlying CpG density of promoter regions as a consequence of natural selection in the context of rapid mutation of CpG sites across species. We shed light on the question of how the evolution of CpG density correlates with a physiological trait. Our hypothesis is that greater CpG density in some genes gives more buffering capacity to absorb age-related changes in methylation without negatively affecting their expression.




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