Epigenetic drift in aging twins

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1 Epigenetic drift in aging twins Qihua Tan, MD, PhD Kaare Christensen, MD, PhD Lene Christiansen, PhD Epidemiology, Biostatistics and Biodemography, Institute of Public Health Unit of Human Genetics, Institute of Clinical Research University of Southern Denmark

" Dan and Scott Shillum are identical twins, genetic clones produced from the accidental division of a single fertilised egg into two embryos in their mother's womb some 40 years ago.

2 "I'm a couple of inches taller, and I've got a bigger frame" says Scott. "You mean fatter" laughs Dan. "We started to drift apart physically in our teens" Scott continues, rising to the challenge, "I played rugby because I was bigger, faster, stronger. Dan was more football." Dan and Scott Shillum are identical twins, genetic clones produced from the accidental division of a single fertilised egg into two embryos in their mother's womb some 40 years ago. Which is quite surprising when you meet them because - apart from sounding the same, and finishing each others sentences like an old married couple - Dan and Scott don't look that similar at all. Brothers certainly, but not necessarily twins, and definitely not identical.

3 Mapping chromosomal regions with differential DNA methylation in MZ twins by using comparative genomic hybridization for methylated DNA. Competitive hybridization onto normal metaphase chromosomes of the AIMS products generated from 3- and 50-year-old twin pairs. Examples of the hybridization of chromosomes 1, 3, 12, and 17 are displayed. The 50- year-old twin pair shows abundant changes in the pattern of DNA methylation observed by the presence of green and red signals that indicate hypermethylation and hypomethylation events, whereas the 3-year-old twins have a very similar distribution of DNA methylation indicated by the presence of the yellow color obtained by equal amounts of the green and red dyes. Significant DNA methylation changes are indicated as thick red and green blocks in the ideograms. Fraga et al. 2005, PNAS, 102:

4 The longitudinal analysis of epigenetic changes in a population cohort of monozygotic (MZ) twins is a strategy that can be particularly informative for understanding epigenetic variation and its links to disease. MZ twins share their DNA sequence, parents, birth date and sex, and are likely to have experienced a very similar prenatal environment. The figure highlights tissue-specific epigenetic marks (green) being established during gestation, which are stably maintained through life in both twins. Some stochastic epigenetic drift (orange) occurs during development, resulting in some epigenetic discordance between the two twins, but this is not necessarily related to the phenotype of interest. Non-shared environmental risk factors (lightning symbol) can induce exposure-specific alterations (red), which may be present across cell types but induce pathogenic changes only in tissues in which the disease-associated gene (blue bar) is expressed. The longitudinal sampling from these twins would highlight high phenotypic and epigenetic concordance at time A, with some stochastic epigenetic drift. After exposure (time B), the twins might become discordant for disease and show epigenetic differences at the diseaseassociated locus. Further sampling at time C might identify changes caused by the disease itself or perhaps a tissuespecific effect of medication. Mill & Heijmans, Nature Reviews Genetics 14, (2013)

5 Intra-class correlation coefficient (ICC) Measuring reliability of repeated measurements Different from Pearson s correlation coefficient

6 Longitudinal twin design: Genetics of the Epigenetic drift in aging twins 20 MZ pairs 23 DZ pairs

8 Intra-pair difference in CpG methylation in 10 ten years

9 MZ twin pairs Birth weight discordant Blood samples at adult ages 150 pairs of MZ twins aged 30-74

10 Intra-pair correlation coefficient (ICC) on whole genome DNA methylation

11 Intra-pair difference in CpG methylation: young vs old twins

12 Age patterns of epigenetic drift: EWAS

13 EWAS on aging twins Longitudinal data Linear Mixed Effects model using a kinship matrix Ymeth age 0 1 2sex 3agesex u e Var( u) 2 g K 2 Var( e) I e K=0.5 for MZ twin pairs, K=0.25 for DZ

14 Manhattan Plot for EWAS on aging: autosomal chromosomes

15 Summary of aging associated DNA methylation P<5e-05 A total of 21 CpGs 13 hypo-, 8 hyper-methylated P<1e-05 A total of 3 CpGs 2 hypo-, 1 hyper-methylated

16 Manhattan Plot for EWAS on sex-specific effect of aging: autosomal chromosomes

17 Volcano plot for X-linked CpGs

18 Same CpGs displaying different age-dependent methylation patterns in males and females

19 The top significant X-linked CpG site displays demethylation with aging in almost all male twins

20 EWAS on young and old twins Cross-sectional data Linear Mixed Effects model using a kinship matrix Ymeth age 0 1 2sex 3agesex u e Var( u) 2 g K 2 Var( e) I e K=0.5 for all MZ twin pairs

21 Manhattan Plot for EWAS on age: cross-sectional autosomal chromosomes

24 Summary of age associated DNA methylation P<5e-05: 610 hypo-, 478 hyper-methylated P<1e-05: 322 hypo-, 222 hyper-methylated P<1e-06: 128 hypo-, 86 hyper-methylated P<1e-07: 56 hypo-, 40 hyper-methylated P<1e-08: 28 hypo-, 17 hyper-methylated

25 Manhattan Plot for EWAS on age-sex interaction autosomal chromosomes

26 Volcano plot for X-linked CpGs

27 Longitudinal to Cross-sectional Cross-sectional 30-36

28 Summary: 1. There is a slightly increasing epigenetic dissimilarity with aging within twin pairs. 2. The age-dependent patterns of top CpGs are dominated by hypomethylation in both longitudinal and cross-sectional data. 3. Aging can be acompanied by progressive hypomethylation on the X-chromosome in males.

29 Biological questions Is aging associated with loose of genomic stability? Dominant pattern of hypomethylation in the aging genome. Can age-associated hypomethylation of X- chromosome in males as compared with females explain the female advantage in aging?

Research Article Power Estimation for Gene-Longevity Association Analysis Using Concordant Twins

Genetics Research International, Article ID 154204, 8 pages http://dx.doi.org/10.1155/2014/154204 Research Article Power Estimation for Gene-Longevity Association Analysis Using Concordant Twins Qihua