Hostname: page-component-586b7cd67f-t7czq Total loading time: 0 Render date: 2024-11-23T03:50:46.678Z Has data issue: false hasContentIssue false
  • English
  • Français

Preliminary indications that the Attachment and Biobehavioral Catch-up Intervention alters DNA methylation in maltreated children

Published online by Cambridge University Press:  19 December 2019

Julie R. Hoye Open the ORCID record for Julie R. Hoye [Opens in a new window] ,
David Cheishvili ,
Heather A. Yarger Open the ORCID record for Heather A. Yarger [Opens in a new window] ,
Tania L. Roth ,
Moshe Szyf  and
Mary Dozier
Julie R. Hoye*
Affiliation:
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
David Cheishvili
Affiliation:
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, CAN
Heather A. Yarger
Affiliation:
Department of Psychology, University of Maryland, College Park, MD, USA
Tania L. Roth
Affiliation:
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA
Moshe Szyf
Affiliation:
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, CAN
Mary Dozier*
Affiliation:
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA
*
Author for Correspondence: Julie Hoye or Mary Dozier, 108 Wolf Hall, 105 The Green, Newark, DE19716. E-mail: [email protected] or [email protected]
Author for Correspondence: Julie Hoye or Mary Dozier, 108 Wolf Hall, 105 The Green, Newark, DE19716. E-mail: [email protected] or [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Maltreatment during development is associated with epigenetic changes to the genome. Enhancing caregiving may mitigate these effects. Attachment and Biobehavioral Catch-Up (ABC) is an intervention that has been shown to improve parent–child relationships and a variety of biological and behavioral outcomes among children that are involved in Child Protective Services. This preliminary study, using a small sample size, explored whether children who received ABC exhibit different methylation patterns than those who received a control intervention. The participants included 23 children aged 6–21 months who were randomized to receive ABC (n = 12) or a control intervention (n = 11). While the children displayed similar methylation patterns preintervention, DNA methylation varied between the ABC and control groups at 14,828 sites postintervention. Functional pathway analyses indicated that these differences were associated with gene pathways that are involved in cell signaling, metabolism, and neuronal development. This study is one of the first to explore parenting intervention effects on children's DNA methylation at the whole genome level in infancy. These preliminary findings provide a basis for hypothesis generation in further research with larger-scale studies regarding the malleability of epigenetic states that are associated with maltreatment.

Keywords

DNA methylationepigeneticsinterventionmaltreatmentparenting
Type
Regular Articles
Information
Development and Psychopathology , Volume 32 , Special Issue 4: Conceptualizing and Interrogating Autism Spectrum Disorder from a Developmental Psychopathology Framework , October 2020 , pp. 1486 - 1494
Check for updates
Copyright
Copyright © Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., … Sherlock, G. (2000). Gene Ontology: Tool for the unification of biology. Nature Genetics, 25, 25–29. doi: 10.1038/75556CrossRefGoogle ScholarPubMed
Baker-Andresen, D., Ratnu, V. S., & Bredy, T. W. (2013). Dynamic DNA methylation: A prime candidate for genomic metaplasticity and behavioral adaptation. Trends in Neuroscience, 36, 3–13. doi: 10.1016/j.tins.2012.09.003CrossRefGoogle ScholarPubMed
Bakermans-Kranenburg, M. J., Van Ijzendoorn, M. H., & Juffer, F. (2003). Less is more: Meta-analyses of sensitivity and attachment interventions in early childhood. Psychological Bulletin, 129, 195–215. doi:10.1037/0033-2909.129.2.195CrossRefGoogle ScholarPubMed
Bernard, K., Dozier, M., Bick, J., & Gordon, M. K. (2015). Intervening to enhance cortisol regulation among children at risk for neglect: Results of a randomized clinical trial. Development Psychopathology, 27, 829–841. doi:10.1017/S095457941400073XCrossRefGoogle ScholarPubMed
Bernard, K., Dozier, M., Bick, J., Lewis-Morrarty, E., Lindhiem, O., & Carlson, E. (2012). Enhancing attachment organization among maltreated children: Results of a randomized clinical trial. Child Development, 83, 623–636. doi:10.1111/j.1467-8624.2011.01712.xCrossRefGoogle ScholarPubMed
Bernard, K., Hostinar, C. E., & Dozier, M. (2015). Intervention effects on diurnal cortisol rhythms of Child Protective Services–referred infants in early childhood: Preschool follow-up results of a randomized clinical trial. JAMA Pediatrics, 169, 112–119. doi:10.1001/jamapediatrics.2014.2369CrossRefGoogle ScholarPubMed
Bick, J., & Dozier, M. (2013). The effectiveness of an attachment-based intervention in promoting foster mothers’ sensitivity toward foster infants. Infant Mental Health Journal, 34, 95–103. doi:10.1002/imhj.21373CrossRefGoogle ScholarPubMed
Bick, J., Naumova, O., Hunter, S., Barbot, B., Lee, M., Luthar, S. S., … & Grigorenko, E. L. (2012). Childhood adversity and DNA methylation of genes involved in the hypothalamus–pituitary–adrenal axis and immune system: Whole-genome and candidate-gene associations. Development and Psychopathology, 24, 1417–1425. doi: 10.1017/S0954579412000806CrossRefGoogle ScholarPubMed
Bick, J., Palmwood, E., Zajac, L., Simons, R., & Dozier, M. (2019). Early parenting intervention and adverse family environments affect neural function in middle childhood. Biological Psychiatry, 85, 326–335. doi: 10.1016/j.biopsych.2018.09.020.CrossRefGoogle ScholarPubMed
Brenet, F., Moh, M., Funk, P., Feierstein, E., Viale, A. J., Socci, N. D., & Scandura, J. M. (2011). DNA methylation of the first exon is tightly linked to transcriptional silencing. PloS One, 6, e14524. doi:10.1371/journal.pone.0014524CrossRefGoogle ScholarPubMed
Brody, G. H., Yu, T., Chen, E., Beach, S. R.H., & Miller, G. E. (2016). Family-centered prevention ameliorates the longitudinal association between risky family processes and epigenetic aging. Journal of Child Psychology and Psychiatry, 57, 566–574. doi:10.1111/jcpp.12495CrossRefGoogle ScholarPubMed
Caron, E. B., Bernard, K., & Dozier, M. K. (2016). In Vivo feedback predicts parent behavior change in the Attachment and Biobehavioral Catch-up Intervention. Journal of Clinical Child and Adolescent Psychology, 47, S35–S46. doi:10.1080/15374416.2016.1141359CrossRefGoogle ScholarPubMed
Caron, E., Weston-Lee, P., Haggerty, D., & Dozier, M. (2016). Community implementation outcomes of attachment and biobehavioral catch-up. Child Abuse & Neglect, 53, 128–137. doi:10.1016/j.chiabu.2015.11.010CrossRefGoogle ScholarPubMed
Cedar, H., & Bergman, Y. (2009). Linking DNA methylation and histone modification: Patterns and paradigms. Nature Review Genetics, 10, 295–304. doi:10.1038/nrg2540CrossRefGoogle ScholarPubMed
Champagne, F. A., Weaver, I. C., Diorio, J., Dymov, S., Szyf, M., & Meaney, M. J. (2006). Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology, 147, 2909–2915. doi:10.1210/en.2005-1119CrossRefGoogle ScholarPubMed
Cicchetti, D., Hetzel, S., Rogosch, F. A., Handley, E. D., & Toth, S. L. (2016). An investigation of child maltreatment and epigenetic mechanisms of mental and physical health risk. Developmental Psychopathology, 28, 1305–1317. doi:10.1017/S0954579416000869CrossRefGoogle ScholarPubMed
Cicchetti, D., & Toth, S. L. (2005). Child maltreatment. Annual Review of Clinical Psychology, 1, 409–438. doi: 10.1146/annurev.clinpsy.1.102803.144029CrossRefGoogle ScholarPubMed
Dalton, V. S., Kolshus, E., & McLoughlin, D. M. (2014) Epigenetics and depression: Return of the repressed. Journal of Affective Disorders, 155, 1–12. doi:10.1016/j.jad.2013.10.028CrossRefGoogle ScholarPubMed
Doherty, T. S., Blaze, J., Keller, S. M., & Roth, T. L. (2017). Phenotypic outcomes in adolescence and adulthood in the scarcity-adversity model of low nesting resources outside the home cage. Developmental Psychobiology, 59, 703–714. doi:10.1002/dev.21547CrossRefGoogle ScholarPubMed
Doherty, T. S., Forster, A., & Roth, T. L. (2016). Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. Behavioural Brain Research, 298, 55–61. doi:10.1016/j.bbr.2015.05.028CrossRefGoogle Scholar
Farh, K. K., Marson, A., Zhu, J., Kleinewietfeld, M., Housley, W. J., Beik, S., … Bernstein, B. E. (2015). Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature, 518, 337–343. doi:10.1038/nature13835CrossRefGoogle ScholarPubMed
Garg, E., Chen, L., Nguyen, T. T.T., Pokhivsneva, I., Chen, L. M., Unternaehrer, E., … Mavan Study Team (2018). The early care environment and DNA methylome variation in childhood. Developmental Psychopathology, 30, 891–903. doi:10.1017/S0954579418000627.CrossRefGoogle ScholarPubMed
Handy, D. E., Castro, R., & Loscalzo, J. (2011). Epigenetic modifications: Basic mechanisms and role in cardiovascular disease. Circulation, 123, 2145–2156. doi:10.1161/CIRCULATIONAHA.110.956839CrossRefGoogle ScholarPubMed
Jones, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Review Genetics, 13, 484–492. doi:10.1038/nrg3230CrossRefGoogle ScholarPubMed
Khulan, B., Manning, J. R., Dunbar, D. R., Seckl, J. R., Raikkonen, K., Eriksson, J. G., & Drake, A. J. (2014). Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state. Translational Psychiatry, 4, e448. doi:10.1038/tp.2014.94CrossRefGoogle ScholarPubMed
Lewis-Morrarty, E., Dozier, M., Bernard, K., Terracciano, S. M., & Moore, S. V. (2012). Cognitive flexibility and theory of mind outcomes among foster children: Preschool follow-up results of a randomized clinical trial. Journal of Adolescent Health, 51, S17–22. doi:10.1016/j.jadohealth.2012.05.005CrossRefGoogle ScholarPubMed
Lind, T., Bernard, K., Ross, E., & Dozier, M. (2014). Intervention effects on negative affect of CPS-referred children: Results of a randomized clinical trial. Child Abuse & Neglect, 38, 1459–1467. doi:10.1016/j.chiabu.2014.04.004CrossRefGoogle ScholarPubMed
Lubin, F. D., Roth, T. L., & Sweatt, J. D. (2008). Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. Journal of Neuroscience, 28, 10576–10586. doi:10.1523/jneurosci.1786-08.2008CrossRefGoogle ScholarPubMed
Maunakea, A. K., Chepelev, I., Cui, K., & Zhao, K. (2013). Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Research, 23, 1256–1269. doi:10.1038/cr.2013.110CrossRefGoogle ScholarPubMed
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., … Meaney, M. J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348. doi:10.1038/nn.2270CrossRefGoogle ScholarPubMed
Melchior, M., Moffitt, T. E., Milne, B. J., Poulton, R., & Caspi, A. (2007). Why do children from socioeconomically disadvantaged families suffer from poor health when they reach adulthood? A life-course study. American Journal of Epidemiology, 166, 966–974. doi:10.1093/aje/kwm155CrossRefGoogle ScholarPubMed
Mi, H., Huang, X., Muruganujan, A., Tang, H., Mills, C., Kang, D., & Thomas, P. D. (2017). PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Research, 45, D183–189. doi:10.1093/nar/gkw1138CrossRefGoogle ScholarPubMed
Mi, H., Muruganujan, A., Casagrande, J. T., & Thomas, P. D. Large-scale gene function analysis with the PANTHER classification system. Nature Protocols, 8, 1551–1566. doi:10.1038/nprot.2013.092CrossRefGoogle Scholar
Miller, G. E., Chen, E., & Parker, K. J. (2011). Psychological stress in childhood and susceptibility to the chronic diseases of aging: Moving toward a model of behavioral and biological mechanisms. Psychological Bulletin, 137, 959–997. doi:10.1037/a0024768CrossRefGoogle Scholar
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 23–38. doi:10.1038/npp.2012.112CrossRefGoogle ScholarPubMed
Morris, T. J., Butcher, L. M., Feber, A., Teschendorff, A. E., Chakravarthy, A. R., Wojdacz, T. K., & Beck, S. (2013). ChAMP: 450k chip analysis methylation pipeline. Bioinformatics, 30, 428–430. doi:10.1093/bioinformatics/btt684CrossRefGoogle ScholarPubMed
Murgatroyd, C., & Spengler, D. (2011). Epigenetic programming of the HPA axis: early life decides. Stress, 14, 581–589. doi: 10.3109/10253890.2011.602146CrossRefGoogle ScholarPubMed
Naumova, O. Y., Lee, M., Koposov, R., Szyf, M., Dozier, M., & Grigorenko, E. L. (2012) Differential patterns of whole-genome DNA methylation in institutionalized children and children raised by their biological parents. Developmental Psychopathology, 24, 143–155. 1 doi:10.1017/S0954579411000605CrossRefGoogle ScholarPubMed
O'Donnell, K. J., Chen, L., MacIsaac, J. L., McEwen, L. M., Nguyen, T., Beckmann, K., … Meaney, M. J. (2018). DNA methylome variation in a perinatal nurse-visitation program that reduces child maltreatment: A 27 year follow-up. Translational Psychiatry, 8(15), 1–9. doi:10.1038/s41398-017-0063-9Google Scholar
Olds, D. L., Eckenrode, J., Henderson, C. R., Kitzman, H., Powers, J., Cole, R., … & Luckey, D. (1997). Long-term effects of home visitation on maternal life course and child abuse and neglect: Fifteen-year follow-up of a randomized trial. JAMA, 278, 637–643. doi:10.1001/jama.1997.03550080047038CrossRefGoogle ScholarPubMed
Olds, D., Henderson, C. R. Jr, Cole, R., Eckenrode, J., Kitzman, H., Luckey, D., … & Powers, J. (1998). Long-term effects of nurse home visitation on children's criminal and antisocial behavior: 15-year follow-up of a randomized controlled trial. JAMA, 280, 1238–1244. doi:10.1001/jama.280.14.1238CrossRefGoogle ScholarPubMed
Olds, D. L., Kitzman, H., Cole, R., Robinson, J., Sidora, K., Luckey, D. W., … & Holmberg, J. (2004). Effects of nurse home-visiting on maternal life course and child development: Age 6 follow-up results of a randomized trial. Pediatrics, 114, 1550–1559. doi:10.1542/peds.2004-0962CrossRefGoogle ScholarPubMed
Perroud, N., Salzmann, A., Prada, P., Nicastro, R., Hoeppli, M. E., Furrer, S., … Malafosse, A. (2013). Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene. Translational Psychiatry, 3, e207. doi:10.1038/tp.2012.140CrossRefGoogle ScholarPubMed
Prados, J., Stenz, L., Courtet, P., Prada, P., Nicastro, R., Adouan, W., … Perroud, N. (2015). Borderline personality disorder and childhood maltreatment: A genome-wide methylation analysis. Genes Brain Behavior, 14, 177–188. doi:10.1111/gbb.12197CrossRefGoogle ScholarPubMed
Ramey, C. T., McGinness, G. D., Cross, L., Collier, A. M., & Barrie-Blackley, S. (1982). The Abecedarian approach to social competence: Cognitive and linguistic intervention for disadvantaged preschoolers. In Borman, K. (Ed.), The social life of children in a changing society (145–174). Hillsdale, NJ: Erlbaum.Google Scholar
R Core Team. (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.Google Scholar
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research, 43, e47. doi:10.1093/nar/gkv007CrossRefGoogle ScholarPubMed
Roberts, S., Lester, K. J., Hudson, J. L., Rapee, R. M., Creswell, C., Cooper, P. J., … Eley, T. C. (2014). Serotonin transporter methylation and response to cognitive behaviour therapy in children with anxiety disorders. Translational Psychiatry, 4, e444. doi:10.1038/tp.2014.83CrossRefGoogle ScholarPubMed
Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009). Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry, 65, 760–769. doi:10.1016/j.biopsych.2008.11.028CrossRefGoogle ScholarPubMed
Sameroff, A. J., & Fiese, B. H. (2000). Transactional regulation: The developmental ecology of early intervention. Handbook of early childhood intervention, 2, 135–159.CrossRefGoogle Scholar
Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., … Binder, E. B. (2015). DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168, 36–44. doi:10.1002/ajmg.b.32278CrossRefGoogle Scholar
Stamoulis, C., Vanderwert, R. E., Zeanah, C. H., Fox, N. A., & Nelson, C. A. (2015). Early psychosocial neglect adversely impacts developmental trajectories of brain oscillations and their interactions. Journal of Cognitive Neuroscience, 27(12), 2512–2528. doi:10.1162/jocn_a_00877CrossRefGoogle ScholarPubMed
Tabachnick, A. R., Raby, K. L., Goldstein, A., Zajac, L., & Dozier, M. (2019). Effects of an attachment-based intervention in infancy on children's autonomic regulation during middle childhood. Biological Psychology, 143, 22–31. doi:10.1016/j.biopsycho.2019.01CrossRefGoogle ScholarPubMed
Teschendorff, A. E., Marabita, F., Lechner, M., Bartlett, T., Tegner, J., Gomez-Cabrero, D., & Beck, S. (2012). A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics, 29, 189–196. doi:10.1093/bioinformatics/bts680CrossRefGoogle ScholarPubMed
Thompson, T. M., Sharfi, D., Lee, M., Yrigollen, C. M., Naumova, O. Y., & Grigorenko, E. L. (2013). Comparison of whole-genome DNA methylation patterns in whole blood, saliva, and lymphoblastoid cell lines. Behavior Genetics, 43, 168–176. doi:10.1007/s10519-012-9579-1CrossRefGoogle ScholarPubMed
Toperoff, G., Aran, D., Kark, J. D., Rosenberg, M., Dubnikov, T., Nissan, B., … Hellman, A. (2011). Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Human Molecular Genetics, 21, 371–383. doi:10.1093/hmg/ddr472CrossRefGoogle ScholarPubMed
Toth, S. L., Gravener-Davis, J. A., Guild, D. J., & Cicchetti, D. (2013). Relational interventions for child maltreatment: Past, present, and future perspectives. Development Psychopathology, 25, 1601–1617. doi:10.1017/S0954579413000795CrossRefGoogle ScholarPubMed
Tottenham, N., Hare, T. A., Quinn, B. T., McCarry, T. W., Nurse, M., Gilhooly, T., … & Thomas, K. M. (2010). Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Developmental Science, 13, 46–61. doi:10.1111/j.1467-7867.2009.00852.xCrossRefGoogle ScholarPubMed
Unternaehrer, E., Meyer, A. H., Burkhardt, S. C., Dempster, E., Staehli, S., Theill, N., … Meinlschmidt, G. (2015). Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women. Stress, 18, 451–461. doi:10.3109/10253890.2015.1038992CrossRefGoogle ScholarPubMed
Vanderwert, R. E., Marshall, P. J., Nelson III, C. A., Zeanah, C. H., & Fox, N. A. (2010). Timing of intervention affects brain electrical activity in children exposed to severe psychosocial neglect. PLoS One, 5, e11415. doi: 10.1371/journal.pone.0011415CrossRefGoogle ScholarPubMed
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., … Meaney, M. J. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854. doi:10.1038/nn1276CrossRefGoogle ScholarPubMed
Weinfield, N. S., Sroufe, L. A., Egeland, B., & Carlson, E. (2008). Individual differences in infant-caregiver attachment: Conceptual and empirical aspects of security. In Cassidy, J., & Shaver, P. R. (Eds.) Handbook of attachment: Theory, research, and clinical applications (2nd ed., pp. 78–101). NY: Guilford Press.Google Scholar
Yang, B. Z., Zhang, H., Ge, W., Weder, N., Douglas-Palumberi, H., Perepletchikova, F., … Kaufman, J. (2013). Child abuse and epigenetic mechanisms of disease risk. American Journal of Preventive Medicine, 44, 101–107. doi:10.1016/j.amepre.2012.10.012CrossRefGoogle ScholarPubMed
Yarger, H. A., Bernard, K., Caron, E. B., Wallin, A., & Dozier, M. (2019). Enhancing parenting quality for young children adopted internationally: Results of a randomized controlled trial. Journal of Clinical Child & Adolescent Psychology, 16, 1–13. doi:10.1080/15374416.2018.1547972Google Scholar
Yarger, H. A., Hoye, J. R., & Dozier, M. (2016). Trajectories of change in Attachment and Biobehavioral Catch-Up among high-risk mothers: A randomized clinical trial. Infant Mental Health Journal, 37, 525–536. doi:10.1002/imhj.21585CrossRefGoogle ScholarPubMed
Yehuda, R., Flory, J. D., Bierer, L. M., Henn-Haase, C., Lehrner, A., Desarnaud, F., … Meaney, M. J. (2015). Lower methylation of glucocorticoid receptor gene promoter 1 F in peripheral blood of veterans with posttraumatic stress disorder. Biological Psychiatry, 77, 356–364. doi:10.1016/j.biopsych.2014.02.006CrossRefGoogle ScholarPubMed
Ziller, M. J., Gu, H., Müller, F., Donaghey, J., Tsai, L. T., Kohlbacher, O., … Meissner, A. (2013). Charting a dynamic DNA methylation landscape of the human genome. Nature, 500, 477–481. doi:10.1038/nature12433CrossRefGoogle ScholarPubMed
Supplementary material: File

Hoye et al. supplementary material

Table S1

Download Hoye et al. supplementary material(File)
File 17.7 KB