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DNA Methylation Networks Underlying Mammalian Traits

View ORCID ProfileA. Haghani, A.T. Lu, C.Z. Li, T.R. Robeck, K. Belov, C.E. Breeze, R.T. Brooke, S. Clarke, C.G. Faulkes, Z. Fei, S.H. Ferguson, C.J. Finno, V.N. Gladyshev, V. Gorbunova, R.G. Goya, A.N. Hogan, C.J. Hogg, T.A. Hore, H. Kiaris, P. Kordowitzki, G. Banks, W.R. Koski, K. Mozhui, A. Naderi, E.A. Ostrander, K.M. Parsons, J. Plassais, J. Robbins, K.E. Sears, A. Seluanov, K.J. Steinman, B. Szladovits, M.J. Thompson, D. Villar, N. Wang, View ORCID ProfileG.S. Wilkinson, B.G. Young, J. Zhang, View ORCID ProfileJ.A. Zoller, J. Ernst, X.W. Yang, K. Raj, View ORCID ProfileS. Horvath
doi: https://doi.org/10.1101/2021.03.16.435708
A. Haghani
1Dept. of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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  • ORCID record for A. Haghani
A.T. Lu
1Dept. of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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C.Z. Li
2Dept. of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
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T.R. Robeck
3Zoological Operations, SeaWorld Parks and Entertainment, Orlando, Florida, USA
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K. Belov
4School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
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C.E. Breeze
5Altius Institute for Biomedical Sciences, Seattle, WA, USA
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R.T. Brooke
6Epigenetic Clock Development Foundation, Los Angeles, CA, USA
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S. Clarke
7AgResearch, Invermay Agricultural Centre, Mosgiel, Otago, New Zealand
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C.G. Faulkes
8School of Biological and Chemical Sciences, Queen Mary University of London, London, UK
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Z. Fei
2Dept. of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
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S.H. Ferguson
9Fisheries and Oceans Canada, University Crescent, Winnipeg, Canada
32Dept. of Biological Sciences, University of Manitoba, Winnipeg, Canada
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C.J. Finno
10Dept. of Population Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA, USA
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V.N. Gladyshev
11Division of Genetics, Dept. of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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V. Gorbunova
12Depts. of Biology and Medicine, University of Rochester, Rochester, NY, USA
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R.G. Goya
13Biochemistry Research Institute of La Plata, Histology and Pathology, School of Medicine, University of La Plata, La Plata, Argentina
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A.N. Hogan
14Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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C.J. Hogg
4School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
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T.A. Hore
15Dept. of Anatomy, University of Otago, Dunedin, New Zealand
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H. Kiaris
16Dept. of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, SC, USA
33Peromyscus Genetic Stock Center, University of South Carolina, SC, USA
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P. Kordowitzki
17Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Poland
34Institute for Veterinary Medicine, Nicolaus Copernicus University, Torun, Poland
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G. Banks
18Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire, UK
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W.R. Koski
19LGL Limited, King City, ON, Canada
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K. Mozhui
20Dept. of Preventive Medicine, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
35Dept. of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
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A. Naderi
16Dept. of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, SC, USA
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E.A. Ostrander
14Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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K.M. Parsons
21Conservation Biology Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, Washington, USA
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J. Plassais
14Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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J. Robbins
22Center for Coastal Studies, Provincetown, MA, USA
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K.E. Sears
23Dept. of Ecology and Evolutionary Biology, UCLA, Los Angeles, CA, USA
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A. Seluanov
12Depts. of Biology and Medicine, University of Rochester, Rochester, NY, USA
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K.J. Steinman
24Species Preservation Laboratory, SeaWorld San Diego, California, USA
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B. Szladovits
25Dept. of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, UK
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M.J. Thompson
26Dept. Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
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D. Villar
27Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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N. Wang
28Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of Calif ornia Los Angeles, Los Angeles, CA, USA
36Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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G.S. Wilkinson
29Dept. of Biology, University of Maryland, College Park, USA
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B.G. Young
9Fisheries and Oceans Canada, University Crescent, Winnipeg, Canada
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J. Zhang
1Dept. of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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J.A. Zoller
2Dept. of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
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J. Ernst
30Dept. of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, USA
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X.W. Yang
28Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of Calif ornia Los Angeles, Los Angeles, CA, USA
36Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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K. Raj
31Radiation Effects Dept., Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, UK
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S. Horvath
1Dept. of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
2Dept. of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
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  • For correspondence: shorvath@mednet.ucla.edu
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Summary

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.

Competing Interest Statement

SH is a founder of the non-profit Epigenetic Clock Development Foundation which plans to license several patents from his employer UC Regents. These patents list SH and JE as inventors. The other authors declare no conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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DNA Methylation Networks Underlying Mammalian Traits
A. Haghani, A.T. Lu, C.Z. Li, T.R. Robeck, K. Belov, C.E. Breeze, R.T. Brooke, S. Clarke, C.G. Faulkes, Z. Fei, S.H. Ferguson, C.J. Finno, V.N. Gladyshev, V. Gorbunova, R.G. Goya, A.N. Hogan, C.J. Hogg, T.A. Hore, H. Kiaris, P. Kordowitzki, G. Banks, W.R. Koski, K. Mozhui, A. Naderi, E.A. Ostrander, K.M. Parsons, J. Plassais, J. Robbins, K.E. Sears, A. Seluanov, K.J. Steinman, B. Szladovits, M.J. Thompson, D. Villar, N. Wang, G.S. Wilkinson, B.G. Young, J. Zhang, J.A. Zoller, J. Ernst, X.W. Yang, K. Raj, S. Horvath
bioRxiv 2021.03.16.435708; doi: https://doi.org/10.1101/2021.03.16.435708
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DNA Methylation Networks Underlying Mammalian Traits
A. Haghani, A.T. Lu, C.Z. Li, T.R. Robeck, K. Belov, C.E. Breeze, R.T. Brooke, S. Clarke, C.G. Faulkes, Z. Fei, S.H. Ferguson, C.J. Finno, V.N. Gladyshev, V. Gorbunova, R.G. Goya, A.N. Hogan, C.J. Hogg, T.A. Hore, H. Kiaris, P. Kordowitzki, G. Banks, W.R. Koski, K. Mozhui, A. Naderi, E.A. Ostrander, K.M. Parsons, J. Plassais, J. Robbins, K.E. Sears, A. Seluanov, K.J. Steinman, B. Szladovits, M.J. Thompson, D. Villar, N. Wang, G.S. Wilkinson, B.G. Young, J. Zhang, J.A. Zoller, J. Ernst, X.W. Yang, K. Raj, S. Horvath
bioRxiv 2021.03.16.435708; doi: https://doi.org/10.1101/2021.03.16.435708

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