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Cpg DNA Methylation Is a Key Epigenetic Modification in Vertebrates

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Cpg DNA Methylation Is a Key Epigenetic Modification in Vertebrates 1/22/2018 Epigenetic aging clocks for mammals CpG DNA methylation is a key epigenetic Steve Horvath University of California, Los Angeles modification in vertebrates • DNAm is known to be involved in – cell differentiation and development – regulation of gene expression – DNA structure – control of transposable elements, cryptic translation Opportunity for collaboration: • Increasing evidence that it can help • Looking for collaborators who have access to tissue/DNA samples explain why vertebrates age… from mammals of varying ages. • Will generate high quality DNA methylation data. Acknowledgement: Paul G. Allen Frontiers Group Human multi-tissue DNAm age estimator applies to the entire age span from cradle to grave Human multi-tissue DNAm age estimator • Step 1: Measure the DNA methylation levels of 353 CpGs. • Step 2: Form a weighted average • Step 3: Transform the average so it is in units of “years” Result: age estimate (a number) that is known as “epigenetic age” or “DNA methylation age” The human multi-tissue DNAm age estimator is the most accurate molecular biomarker of age to date. Hence the name “epigenetic clock”. Test set validation in multiple tissues Epigenetic age estimators in other mammals based on Reduced Representation Bisulfite Sequencing 1 1/22/2018 Several articles describe epigenetic clocks for mice. Gold standard anti-aging intervention slow aging. Technical and scientific challenges Overarching goal: Develop an epigenetic age estimator that applies • It is technically difficult to validate epigenetic age to all mammals (universal epigenetic clock) estimators based on Reduced Representation Bisulfite Sequencing due to Step 1: Develop a mammalian DNA methylation –non-overlapping sets of CpGs chip for CpGs in highly conserved DNA sequences –low sequencing depth Step 2: Develop an age estimator for each of 50 • Large number of species species. • How to compare age estimators across data sets Step 3: Develop a universal cross-species age and species? estimator Step 1: We are currently designing a mammalian Illumina DNA methylation chip that will profile 30k highly conserved CpGs The mammalian DNA methylation chip will cover ~30k highly conserved sites across mammals. Adriana Sperlea Species No. CpGs Species No. CpGs Species No. CpGs Species No. CpGs Aardvark 2.8E+04 Chinese tree shrew 3.4E+04 Guinea pig 2.5E+04 Pika 2.3E+04 Alpaca 3.5E+04 Cow 3.4E+04 Hedgehog 2.0E+04 Prairie vole 2.1E+04 Armadillo 2.7E+04 Crab-eating macaque 5.0E+04 Horse 3.5E+04 Rabbit 2.9E+04 Bactrian camel 3.2E+04 David's myotis bat 2.5E+04 Killer whale 3.4E+04 Rat 2.1E+04 Big brown bat 2.7E+04 Dog 3.7E+04 Lesser Egyptian jerboa 2.2E+04 Rhesus 4.7E+04 Black flying-fox 3.3E+04 Dolphin 3.2E+04 Manatee 2.7E+04 Sheep 3.3E+04 Brush-tailed rat 2.5E+04 Domestic goat 3.2E+04 Marmoset 4.1E+04 Shrew 2.3E+04 Bushbaby 3.4E+04 Elephant 2.7E+04 Megabat 3.0E+04 Squirrel 3.5E+04 Cape elephant shrew 2.4E+04 Ferret 3.7E+04 Microbat 2.6E+04 Squirrel monkey 4.2E+04 Human dog synteny map. Cape golden mole 2.5E+04 Gibbon 4.7E+04 Mouse 2.4E+04 Star-nosed mole 3.1E+04 Cat 3.7E+04 Golden hamster 2.1E+04 Naked mole-rat 2.6E+04 Tenrec 1.9E+04 Blocks in the dog genome are color Chimp 5.1E+04 Gorilla 5.0E+04 Orangutan 4.8E+04 Tibetan antelope 3.2E+04 Chinchilla 2.8E+04 Green monkey 5.0E+04 Pacific walrus 3.9E+04 Weddell seal 3.7E+04 coded according to their syntenic Chinese hamster 2.1E+04 Green monkey 4.9E+04 Pig 3.3E+04 White rhinoceros 3.7E+04 blocks in human chromosomes using the software Cynteny. 2 1/22/2018 Feasibility study: Epigenetic clock for mice based on only 1432 highly conserved CpGs Leave-one-out cross validation cor(Age, DNAmAge)r=0.74 Median error= 4.0 months The penalized regression model selected on average 202 CpGs Are 30k highly conserved CpGs enough for building an accurate age estimator? Michael Thompson, Richard Davis, Gary Churchill, M. Pellegrini Feasibility study: a new epigenetic clock for humans based on only 676 highly conserved CpGs New human epigenetic clock based on 404 highly conserved CpGs applies • The penalized regression model selected 404 CpGs. to the entire lifespan • High accuracy in test sets (r=0.88, error 5.8 years) B Training data cor=0.9, p<1e-200 C Test data cor=0.87, p<1e-200 19 42 4 3 19 9 9 3 939 323 9 9 99 10 28 30 1933 31 33 31310310139 13 28 3819 27319927 6 34192331279332327273931033227133271910133931313 39 3 24 233935312432731273327323381313926331932193938313838101013 14 3 2832324353302413233813263812835343273313263138273819327131823312919273311813381026332493831032931327927313311310338103133101193891339 10 335283124352333526342731242331231035313124319341912633272634338343110133893131838127192712733131833833243192931261319331010813313323108332331331013310313 16 33 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