ABSTRACT Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered

through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips,

the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within

500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five—one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes—have

differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. Access through your institution Buy or subscribe This

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OF INTERGENERATIONAL EPIGENETIC INHERITANCE BY WHOLE GENOME DNA METHYLATION ANALYSIS IN TRIOS Article Open access 02 December 2023 ASSESSING THE CONTRIBUTION OF RARE VARIANTS TO COMPLEX

TRAIT HERITABILITY FROM WHOLE-GENOME SEQUENCE DATA Article 07 March 2022 PROFILING OF RUNS OF HOMOZYGOSITY FROM WHOLE-GENOME SEQUENCE DATA IN JAPANESE BIOBANK Article Open access 03 April

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agreement no. 218071 (CancerGene) to deCODE genetics. AUTHOR CONTRIBUTIONS A.K. and K.S. planned and directed the research. A.K. wrote the first draft of the paper and, together with K.S.,

V.S., G.M., G.T. and U.T., wrote most of the final version. A.K. and G.M. designed the method to determine parental origin. G.M., with assistance from P.I.O., implemented the algorithm.

D.F.G. wrote the code for association analysis taking parental origin into account and performed some initial analyses. P.S., S.B. and S.S. tabulated the established disease-associated

variants and the regions known to harbour imprinted genes. V.S. and G.T. contributed to the analysis of the diabetes data and, together with A.K. and U.T., planned the follow-up association

and functional studies. A.G., A.K. and M.L.F. imputed the untyped SNPs. S.N.S. and P.S. were responsible for the breast cancer and basal-cell carcinoma data. A.B.H., G.S. and R.B. provided

clinical data for T2D, O.Th.J., T.J. and H.S. provided clinical data for breast cancer, and J.H.O., B.S. and K.R.B. provided clinical data for basal-cell carcinoma. The DIAGRAM Consortium

provided the novel T2D-associated variants that are close to imprinted genes. Aslaug J., A.S., Adalbjorg J., K.Th.K. and S.A.G. performed the methylation and expression studies. A.C.F.-S.

assisted in the interpretation of the results from the association and functional studies. AUTHOR INFORMATION Author notes * Valgerdur Steinthorsdottir, Gisli Masson and Gudmar Thorleifsson:

These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland , Augustine Kong, Valgerdur Steinthorsdottir, Gisli Masson, 

Gudmar Thorleifsson, Patrick Sulem, Soren Besenbacher, Aslaug Jonasdottir, Asgeir Sigurdsson, Kari Th. Kristinsson, Adalbjorg Jonasdottir, Michael L. Frigge, Arnaldur Gylfason, Pall I.

Olason, Sigurjon A. Gudjonsson, Sverrir Sverrisson, Simon N. Stacey, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir & Kari Stefansson * Department of Dermatology,, Bardur Sigurgeirsson 

& Jon H. Olafsson * Department of Pathology,, Kristrun R. Benediktsdottir * Department of Oncology,, Helgi Sigurdsson & Oskar Th. Johannsson * Department of Surgery,, Thorvaldur

Jonsson * Department of Endocrinology and Metabolism, Landspitali-University Hospital, 101 Reykjavik, Iceland, Rafn Benediktsson, Astradur B. Hreidarsson & Gunnar Sigurdsson * Department

of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK Anne C. Ferguson-Smith * Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Unnur

Thorsteinsdottir & Kari Stefansson * Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Benjamin F. Voight, Soumya Raychaudhuri,

 Shaun Purcell, Steve A. McCarroll, Ayellet V. Segrè, Kristin Ardlie, Noël P. Burtt, Gabe Crawford, Amanda L. Elliott, Todd Green, Candace Guiducci, Richa Saxena, Mark J. Daly, Jose C.

Florez & David Altshuler * Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA., Benjamin F. Voight, Soumya

Raychaudhuri, Shaun Purcell, Todd Green, Richa Saxena, Mark J. Daly, Jose C. Florez & David Altshuler * Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.,

Benjamin F. Voight, Jose C. Florez, James B. Meigs & David Altshuler * Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109-2029, USA., Laura J. Scott, Ryan P.

Welch, Cristen J. Willer, Martha Ganser, Anne U. Jackson, Heather M. Stringham, Goncalo R. Abecasis & Michael Boehnke * deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland., Valgerdur

Steinthorsdottir, Gudmar Thorleifsson, Augustine Kong, G. Bragi Walters, Unnur Thorsteinsdottir & Kari Stefansson * CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur

Institute, F-59019 Lille, France., Christian Dina, Christine Proença, Stephane Cauchi & Philippe Froguel * INSERM, UMR915, CNRS, ERL3147, 44007 Nantes, France., Christian Dina * Wellcome

Trust Sanger Institute, Hinxton CB10 1HH, UK., Eleftheria Zeggini, Suzannah Bumpstead, Felicity Payne, Nicholas Smith & Inês Barroso * Wellcome Trust Centre for Human Genetics,

University of Oxford, Oxford OX3 7BN, UK., Eleftheria Zeggini, Teresa Ferreira, Katherine S. Elliott, Cecilia M. Lindgren, Inga Prokopenko, N. William Rayner, Neil R. Robertson, Andrew P.

Morris & Mark I. McCarthy. * Institute of Epidemiology, Helmholtz Zentrum Muenchen, 85764 Neuherberg, Germany., Cornelia Huth, Harald Grallert, Christian Gieger, Norman Klopp, Thomas

Meitinger, Ann-Kristin Petersen, Barbara Thorand, H.-Erich Wichmann & Thomas Illig * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377

Munich, Germany., Cornelia Huth, Harald Grallert & H.-Erich Wichmann * Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.,

Yurii S. Aulchenko, Najaf Amin, Jacqueline Witteman, Albert Hofman & Cornelia M. van Duijn * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3

7LJ, UK., Laura J. McCulloch, Amanda J. Bennett, Christopher J. Groves, Neelam Hassanali, Katharine R. Owen, Inga Prokopenko, N. William Rayner, Neil R. Robertson, Anna L. Gloyn & Mark

I. McCarthy. * Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada., Guanming Wu & Lincoln D. Stein * Division of Rheumatology,

Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA., Soumya Raychaudhuri * Stanley Center for Psychiatric Research, Broad

Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Shaun Purcell * Department of Molecular Biology, Harvard Medical School, Boston,

Massachusetts 02115, USA., Steve A. McCarroll, Ayellet V. Segrè, Amanda L. Elliott & David Altshuler * MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital,

Cambridge CB2 0QQ, UK., Claudia Langenberg, Simon Griffin & Nicholas J. Wareham * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA., Oliver

M. Hoffmann & Winston A. Hide * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA., Josée Dupuis * Departments of Nutrition and

Epidemiology, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA., Lu Qi, Peter Kraft, Qi Sun, David Hunter & Frank B. Hu * Department of Medicine,

Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts 02115, USA., Lu Qi, Marilyn Cornelis, Rob van Dam & Frank B. Hu *

Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands., Mandy van Hoek, Thijs van Herpt, Eric Sijbrands & Andre Uitterlinden * MRC Human Genetics

Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK., Pau Navarro * INSERM U780, F-94807 Villejuif, France., Beverley Balkau * University

Paris-Sud, F-91405 Orsay, France., Beverley Balkau * Landspitali University Hospital, 101 Reykjavik, Iceland., Rafn Benediktsson & Gunnar Sigurdsson * Icelandic Heart Association, 201

Kopavogur, Iceland., Rafn Benediktsson & Gunnar Sigurdsson * Division of Endocrinology, Diabetes and Metabolism, Ulm University, 89081 Ulm, Germany., Roza Blagieva & Bernhard O.

Boehm * The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA., Eric Boerwinkle * National Human Genome Research

Institute, National Institute of Health, Bethesda, Maryland 20892, USA., Lori L. Bonnycastle, Peter S. Chines, Michael R. Erdos, Mario A Morken, Narisu Narisu & Amy J. Swift * R&D

Centre, Skaraborg Institute, 541 30 Skövde, Sweden., Kristina Bengtsson Boström * Department of Internal Medicine, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, The Netherlands., Bert

Bravenboer * Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, F-91100 Corbeil-Essonnes, France., Guillaume Charpentier * Department of Biostatistics and Collaborative Studies

Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., David J. Couper * Diabetes Research Centre,, Alex S. F. Doney, Andrew D. Morris 

& Colin N. A. Palmer * Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK., Alex S. F. Doney, Andrew D. Morris & 

Colin N. A. Palmer * National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts 01702, USA., Caroline S. Fox * Division of Endocrinology, Diabetes, and

Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA., Caroline S. Fox * Centre for Population Health Sciences, University of Edinburgh,

Teviot Place, Edinburgh EH8 9AG, UK., Christopher S. Franklin, Igor Rudan, Harry Campbell & James F. Wilson * Hagedorn Research Institute, DK-2820 Gentofte, Denmark., Niels Grarup, 

Thomas Sparsø, Torben Hansen & Oluf Pedersen * CHU de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0801, INSERM U927, Université de Poitiers, UFR, Médecine Pharmacie, 86021 Poitiers

Cedex, France., Samy Hadjadj * Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf,

Germany., Christian Herder & Michael Roden * Folkhälsan Research Center, FIN-00014 Helsinki, Finland., Bo Isomaa & Tiinamaija Tuomi * Malmska Municipal Health Center and Hospital,

68601 Jakobstad, Finland., Bo Isomaa * DRWF Human Islet Isolation Facility and Oxford Islet Transplant Programme, University of Oxford, Old Road, Headington, Oxford OX3 7LJ, UK., Paul R. V.

Johnson * Research Centre for Prevention and Health, Glostrup University Hospital, DK-2600 Glostrup, Denmark., Torben Jørgensen * Department of Epidemiology, Department of Medicine, and

Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21287, USA., Wen H. L. Kao * Department of Medicine, University of Kuopio and

Kuopio University Hospital, FIN-70211 Kuopio, Finland., Johanna Kuusisto & Markku Laakso * Department of General Medical Practice, University of Aarhus, DK-8000 Aarhus, Denmark., Torsten

Lauritzen * Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21287, USA., Man Li * Department of Internal Medicine, Maxima MC, PO-Box 90052, 5600 PD Eindhoven, The

Netherlands., Alouisius Lieverse & Thijs van Herpt * Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, 205 02 Malmö,

Sweden., Valeriya Lyssenko, Peter Nilsson & Leif Groop * Department of Endocrinology, Diabetology, Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux

de Paris, 75877 Paris Cedex 18, France., Michel Marre * INSERM U695, Université Paris 7, 75870 Paris Cedex 18, France., Michel Marre * Department of Community Medicine and General Practice,

HUNT Research Center, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway., Kristian Midthjell, Carl Platou & Kristian Hveem * Genetics of Complex Traits, Institute

of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Magdalen Road, Exeter EX1 2LU, UK., John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Timothy M.

Frayling & Andrew T. Hattersley * Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Barrack Road, Exeter EX2 5DW, UK., John

R. B. Perry, Beverley M. Shields, Michael N. Weedon, Timothy M. Frayling & Andrew T. Hattersley * Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for

Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany., Wolfgang Rathmann & Klaus Strassburger * Department of Human Genetics, McGill University, Montreal

H3H 1P3, Canada., Ghislain Rocheleau & Rob Sladek * Department of Medicine, Faculty of Medicine, McGill University, Montreal H3A 1A4, Canada., Ghislain Rocheleau & Rob Sladek *

McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada., Ghislain Rocheleau & Rob Sladek * Department of Medicine/Metabolic Diseases, Heinrich Heine University

Düsseldorf, 40225 Düsseldorf, Germany., Michael Roden * Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital NHS Trust, Norwich NR1 7UY, UK., Michael J. Sampson

* Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA., Richa Saxena & David Altshuler * General Medicine Division, Massachusetts General Hospital, Boston,

Massachusetts, USA., Peter Shrader & James B. Meigs * Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA., Peter Shrader * Institut Interrégional pour la

Santé, F-37521 La Riche, France., Jean Tichet * Department of Medicine, Helsinki University Hospital, University of Helsinki, FIN-00290 Helsinki, Finland., Tiinamaija Tuomi & Leif Groop

* Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA., Richard N. Bergman * National Institutes of Health,

Bethesda, Maryland 20892, USA., Francis S. Collins * Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden., Ulf Gyllensten * University of

Southern Denmark, DK-5230 Odense, Denmark., Torben Hansen * Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK., Graham

A. Hitman * Department of Medicine, The Hospital of Levanger, N-7600 Levanger, Norway., Kristian Hveem * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina

27599-7264, USA., Karen L. Mohlke * Institute of Genetic Medicine, European Academy Bozen/Bolzano, Viale Druso 1, 39100 Bolzano, Italy., Peter P. Pramstaller * Croatian Centre for Global

Health, Faculty of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia., Igor Rudan * Institute for Clinical Medical Research, University Hospital “Sestre Milosrdnice”,

Vinogradska 29, 10000 Zagreb, Croatia., Igor Rudan * Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki FIN-00300, Finland., Jaakko Tuomilehto *

Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK., Mark Walker * Department of Preventive Medicine, Keck

Medical School, University of Southern California, Los Angeles, California 90089-9001, USA., Richard M. Watanabe * Division of Epidemiology and Community Health, University of Minnesota,

Minneapolis, Minnesota 55454, USA., James S. Pankow * Department of Biomedical Science, Panum, Faculty of Health Science, University of Copenhagen, 2200 Copenhagen, Denmark., Oluf Pedersen *

Faculty of Health Science, University of Aarhus, DK-8000 Aarhus, Denmark., Oluf Pedersen * Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland., Unnur Thorsteinsdottir & 

Kari Stefansson * Genomic Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK., Philippe Froguel * Diabetes Unit, Massachusetts General Hospital, Boston,

Massachusetts 02144, USA., David Altshuler * Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK., Mark I.

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inPubMed Google Scholar * Kari Stefansson View author publications You can also search for this author inPubMed Google Scholar CONSORTIA DIAGRAM CONSORTIUM * Benjamin F. Voight * , Laura J.

Scott * , Valgerdur Steinthorsdottir * , Christian Dina * , Eleftheria Zeggini * , Cornelia Huth * , Yurii S. Aulchenko * , Ryan P. Welch * , Gudmar Thorleifsson * , Laura J. McCulloch * , 

Teresa Ferreira * , Harald Grallert * , Najaf Amin * , Guanming Wu * , Cristen J. Willer * , Soumya Raychaudhuri * , Shaun Purcell * , Steve A. McCarroll * , Claudia Langenberg * , Oliver M.

Hoffmann * , Josée Dupuis * , Lu Qi * , Ayellet V. Segrè * , Mandy van Hoek * , Pau Navarro * , Kristin Ardlie * , Beverley Balkau * , Rafn Benediktsson * , Amanda J. Bennett * , Roza

Blagieva * , Eric Boerwinkle * , Lori L. Bonnycastle * , Kristina Bengtsson Boström * , Bert Bravenboer * , Suzannah Bumpstead * , Noël P. Burtt * , Guillaume Charpentier * , Peter S. Chines

* , Marilyn Cornelis * , David J. Couper * , Gabe Crawford * , Alex S. F. Doney * , Katherine S. Elliott * , Amanda L. Elliott * , Michael R. Erdos * , Caroline S. Fox * , Christopher S.

Franklin * , Martha Ganser * , Christian Gieger * , Niels Grarup * , Todd Green * , Simon Griffin * , Christopher J. Groves * , Candace Guiducci * , Samy Hadjadj * , Neelam Hassanali * , 

Christian Herder * , Bo Isomaa * , Anne U. Jackson * , Paul R. V. Johnson * , Torben Jørgensen * , Wen H. L. Kao * , Norman Klopp * , Augustine Kong * , Peter Kraft * , Johanna Kuusisto * , 

Torsten Lauritzen * , Man Li * , Alouisius Lieverse * , Cecilia M. Lindgren * , Valeriya Lyssenko * , Michel Marre * , Thomas Meitinger * , Kristian Midthjell * , Mario A Morken * , Narisu

Narisu * , Peter Nilsson * , Katharine R. Owen * , Felicity Payne * , John R. B. Perry * , Ann-Kristin Petersen * , Carl Platou * , Christine Proença * , Inga Prokopenko * , Wolfgang

Rathmann * , N. William Rayner * , Neil R. Robertson * , Ghislain Rocheleau * , Michael Roden * , Michael J. Sampson * , Richa Saxena * , Beverley M. Shields * , Peter Shrader * , Gunnar

Sigurdsson * , Nicholas Smith * , Thomas Sparsø * , Klaus Strassburger * , Heather M. Stringham * , Qi Sun * , Amy J. Swift * , Barbara Thorand * , Jean Tichet * , Tiinamaija Tuomi * , Rob

van Dam * , Thijs van Herpt * , G. Bragi Walters * , Michael N. Weedon * , Jacqueline Witteman * , Richard N. Bergman * , Stephane Cauchi * , Francis S. Collins * , Anna L. Gloyn * , Ulf

Gyllensten * , Torben Hansen * , Winston A. Hide * , Graham A. Hitman * , Albert Hofman * , David Hunter * , Kristian Hveem * , Markku Laakso * , Karen L. Mohlke * , Andrew D. Morris * , 

Colin N. A. Palmer * , Peter P. Pramstaller * , Igor Rudan * , Eric Sijbrands * , Lincoln D. Stein * , Jaakko Tuomilehto * , Andre Uitterlinden * , Mark Walker * , Nicholas J. Wareham * , 

Richard M. Watanabe * , Goncalo R. Abecasis * , Inês Barroso * , Bernhard O. Boehm * , Harry Campbell * , Mark J. Daly * , Jose C. Florez * , Timothy M. Frayling * , Leif Groop * , Andrew T.

Hattersley * , Frank B. Hu * , James B. Meigs * , Andrew P. Morris * , James S. Pankow * , Oluf Pedersen * , Rob Sladek * , Unnur Thorsteinsdottir * , H.-Erich Wichmann * , James F. Wilson

* , Thomas Illig * , Philippe Froguel * , Cornelia M. van Duijn * , Kari Stefansson * , David Altshuler * , Michael Boehnke *  & Mark I. McCarthy. CORRESPONDING AUTHORS Correspondence to

Augustine Kong, Augustine Kong, Kari Stefansson or Kari Stefansson. ETHICS DECLARATIONS COMPETING INTERESTS The authors from Decode Genetics Inc. own stocks and stock options in the

company. ADDITIONAL INFORMATION Lists of participants and affiliations appear at the end of the paper. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary

Notes, Supplementary Tables 1-9, Supplementary Figures 1-4 with Legends and Supplementary References. (PDF 355 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2

POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kong, A., Steinthorsdottir, V., Masson, G. _et al._ Parental origin of

sequence variants associated with complex diseases. _Nature_ 462, 868–874 (2009). https://doi.org/10.1038/nature08625 Download citation * Received: 14 August 2009 * Accepted: 29 October 2009

* Issue Date: 17 December 2009 * DOI: https://doi.org/10.1038/nature08625 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

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