Epigenetic Information from Ancient DNA Provides New Insights into Human Evolution

nucleotides. The human genome contains more than 28 million CpG sites; 7% of them are clustered within CpG islands and approximately 45% exist within repetitive elements [Rollins et al., 2006]. DNA methylation is not only sequence dependent; it is highly dynamic during development and susceptible to environmental factors. At least for a small number of well-characterized loci, such as imprinting control regions or certain gene promoters [Horsthemke, 2006; Galetzka et al., 2012], it is possible to infer phenotypic information from DNA methylation patterns, which cannot be inferred from the DNA sequence alone [Vidaki et al., 2013]. In this light, the study of methylation profiles in ancient DNA can provide an additional layer of information for paleoanthropologists to draw conclusions about human evolution. However, DNA methylation decays over years, which has rendered epigenetic analysis of prehistoric specimens an unrealistic ambition until very recently. In a milestone paper, Gokhman et al. [2014] reconstructed DNA methylation profiles of the Neanderthal and the Denisovan, both extinct human antecessors, using sophisticated bioinformatic analyses of next-generation sequencing data. During tens of thousands of years, methylated and unmethylated cytosines in ancient DNA were degraded into thymines and uracils, respectively. Enrichment of the analyzed DNA sequences with thymines allowed the authors to estimate DNA methylation proxies Phenotypic differences can be attributed to variation in both the DNA sequence and gene regulation. The latter is influenced by stochastic, environmental, and genetic factors. Epigenetic processes that are biochemical modifications of DNA and chromatin play a major role in gene regulation during development, differentiation, and disease processes [Feinberg, 2007; Jirtle and Skinner, 2007]. A mammalian body is composed of >200 different cell types following unique developmental trajectories during ontogenesis from fertilization to death of the organism. Because all these trajectories are blueprinted by the same DNA sequence in each somatic cell, one can imagine the impact of transcriptional control on phenotypic development and diversity [Smith and Meissner, 2013]. This is true for variation not only within but also between species, notably between human and nonhuman primates [Hernando-Herraez et al., 2013]. The striking phenotypic differences between chimpanzees and present-day humans cannot be fully explained by an approximately 5% DNA sequence divergence (counting indels) [Chimpanzee Sequencing and Analysis Consortium, 2005], in particular considering that mice and rats exhibit relatively small phenotypic differences and yet are much more diverged in their sequence. The most thoroughly studied type of epigenetic modification is DNA methylation, which mainly occurs at position 5 of the pyrimidine ring in the context of CG diPublished online: September 24, 2014