Trends in DNA methylation with age replicate across diverse human populations

Abstract

30Aging is associated with widespread changes in genome-wide patterns of DNA methylation. 31Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with 32 chronological age have been previously identified. However, the majority of these studies have 33 focused primarily on cosmopolitan populations living in the developed world; it is not known if 34 age-related patterns of DNA methylation at these loci are similar across a broad range of human 35 genetic and ecological diversity. We investigated genome-wide methylation patterns using 36 saliva and whole blood derived DNA from two traditionally hunting and gathering African 37 populations: the Baka of the western Central African rainforest and the ≠Khomani San of the 38 South African Kalahari Desert. We identify hundreds of CpG sites whose methylation levels are 39 significantly associated with age, thousands that are significant in a meta-analysis, and replicate 40 trends previously reported in populations of non-African descent. We confirm that an age-41 associated site in the gene ELOVL2 shows a remarkably congruent relationship with aging in 42 humans, despite extensive genetic and environmental variation across populations. We also 43 demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect 44 methylation trends at some known age-associated CpG sites. Our study explores the 45 relationship between CpG methylation and chronological age in populations of African hunter-46 gatherers, who rely on different diets across diverse ecologies. While many age-related CpG Introduction 51Aging is a degenerative process that is associated with changes in many molecular, cellular and 52 physiological factors. Identifying biomarkers associated with these changes is of great interest 53 to researchers for generating accurate predictions of both chronological and biological age in 54 humans for health care and forensic applications. Recent epigenomic studies have shown that 55 patterns of DNA methylation change substantially with chronological age: genome-wide 56 methylation levels decrease with increasing age, while particular genomic regions, such as CpG 57 islands, become more methylated with increasing age 1-5 . An epigenome-wide study examining 58 over 475,000 CpG sites found significant age-associated changes in DNA methylation at almost 59 one-third of sites 2 , demonstrating the extensive and stereotypic effect of aging on the human 60 epigenome. Many previously proposed molecular biomarkers for aging, including leukocyte 61 telomere length 6 , aspartic acid racemization 7 and expression levels of certain genes 8-10 , can be 62 challenging to apply for age estimation, due to lack of precision, instability over time, or difficulty 63 in measuring the quantity of interest 11 . In contrast, DNA methylation values measured from 64 relatively few (from three to up to a few hundred) age-associated CpG sites (a-CpGs) have 65 been shown to yield highly precise and accurate estimates of chronological age [12][13...

Human Immunology through the Lens of Evolutionary Genetics

“…Human populations are known to display considerable genetic diversity, but their degree of epigenetic diversity has been poorly studied to date. A few studies have provided an initial assessment of the contribution of genetic factors and gene-by-environment (G 3 E) interactions to the variation of DNA methylation at population level (Carja et al, 2017;Fagny et al, 2015;Fraser et al, 2012;Galanter et al, 2017;Gopalan et al, 2017;Heyn et al, 2013;Moen et al, 2013). In African populations, the differences in DNA methylation levels associated with differences in lifestyle (farming versus hunting and gathering) have been shown to relate mostly to developmental processes and to display strong associations with nearby genetic variants (meQTLs), which are themselves enriched in selection signals (Fagny et al, 2015).…”

Epigenome-wide change and variation in DNA methylation from birth to late adolescence

“…Considerable DNAm differences have been found between populations [76][77][78] , but research on age-associated DNAm differences is scarce. One study 79 reported evidence for overlap in age-associated CpGs in two African populations with studies on European-ancestry populations, but more research is needed to map the generalizability of longitudinal DNAm changes among different populations.…”

Age-related Differences in Monocyte DNA Methylation and Immune Function in Healthy Kenyan Adults and Children

“…Using a threshold for absolute beta value difference of 0.15, we identified 14,259 differentially methylated CpG sites, with 11,535 sites hyper-methylated in adults vs. children and 2,724 hypo-methylated in adults vs. children (P < 0.01, FDR-adjusted P < 0.05) ( Figure 1B; Additional file 2). (10,13,29) as well as whole blood (20,21,33) (Table 1; Additional file 2). For example, we found hyper-methylation in adults vs. children at the site cg22454769 in the FHL2 locus, and similar findings of hyper-methylation with older age have been reported in whole blood samples (20,21) as well as in studies of isolated monocytes by Tserel et al (29) and Saare et al (10).…”

“…Additionally, it is important to take into account the influence that genetic factors and geneenvironment interactions have on the aging epigenome, yet the majority of studies on age-related methylation markers have been performed in populations with European ancestry, and few have been performed in African populations (32,33). Here, we aimed to analyze DNA methylation profiles and innate immune phenotypes and functions of purified monocytes from healthy individuals living in western Kenya, comparing children aged 1-9 years to adults aged [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] years. Participants for this study were enrolled in a larger observational cohort study of naturally acquired immunity to malaria (34,35).…”