The evolution of CpG density and lifespan in conserved primate and mammalian promoters.

Adam T Mclain,Christopher Faulk

doi:10.18632/aging.101413

Abstract

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.

Highlights

Gene promoters are conserved across the animal radiation and as far back as non-fungi eukaryotes (i.e.holozoans) [1]
While the total number of promoters identified varied greatly across mammalian genomes across millions of years (MYA), from 24,686 in Pan troglodytes to 3 in Odocoileus virginianus, GC content remained consistent across species from 43.7% in Daubentonia madagascariensis to 60.0% in
We broke our dataset into two groups, mammals and primates, since we expect that the collection of genes that have evolved to affect lifespan is likely cladespecific

Summary

Introduction

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]. Questions remain about the evolution of promoter features that can www.aging‐us.com. Methylation of the cytosine in CpG dinucleotides results in the formation of 5-methylcytosine, a covalent modification that can impact gene expression. CpGs are of particular interest for understanding gene function and the impact of epigenetic influences Resource developed for comparative biology studies, containing life history traits of over 4000 species [16].

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Conclusion