IDEAS home Printed from https://ideas.repec.org/a/bpj/sagmbi/v15y2016i1p55-67n5.html
   My bibliography  Save this article

HMM-Fisher: identifying differential methylation using a hidden Markov model and Fisher’s exact test

Author

Listed:
  • Sun Shuying

    (Department of Mathematics, Texas State University, San Marcos, TX 78666, USA)

  • Yu Xiaoqing

    (Department of Biostatistics, Yale University, New Haven, CT 06511, USA)

Abstract

DNA methylation is an epigenetic event that plays an important role in regulating gene expression. It is important to study DNA methylation, especially differential methylation patterns between two groups of samples (e.g. patients vs. normal individuals). With next generation sequencing technologies, it is now possible to identify differential methylation patterns by considering methylation at the single CG site level in an entire genome. However, it is challenging to analyze large and complex NGS data. In order to address this difficult question, we have developed a new statistical method using a hidden Markov model and Fisher’s exact test (HMM-Fisher) to identify differentially methylated cytosines and regions. We first use a hidden Markov chain to model the methylation signals to infer the methylation state as Not methylated (N), Partly methylated (P), and Fully methylated (F) for each individual sample. We then use Fisher’s exact test to identify differentially methylated CG sites. We show the HMM-Fisher method and compare it with commonly cited methods using both simulated data and real sequencing data. The results show that HMM-Fisher outperforms the current available methods to which we have compared. HMM-Fisher is efficient and robust in identifying heterogeneous DM regions.

Suggested Citation

  • Sun Shuying & Yu Xiaoqing, 2016. "HMM-Fisher: identifying differential methylation using a hidden Markov model and Fisher’s exact test," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 55-67, March.
  • Handle: RePEc:bpj:sagmbi:v:15:y:2016:i:1:p:55-67:n:5
    DOI: 10.1515/sagmb-2015-0076
    as

    Download full text from publisher

    File URL: https://doi.org/10.1515/sagmb-2015-0076
    Download Restriction: For access to full text, subscription to the journal or payment for the individual article is required.

    File URL: https://libkey.io/10.1515/sagmb-2015-0076?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    References listed on IDEAS

    as
    1. Ryan Lister & Mattia Pelizzola & Robert H. Dowen & R. David Hawkins & Gary Hon & Julian Tonti-Filippini & Joseph R. Nery & Leonard Lee & Zhen Ye & Que-Minh Ngo & Lee Edsall & Jessica Antosiewicz-Bourg, 2009. "Human DNA methylomes at base resolution show widespread epigenomic differences," Nature, Nature, vol. 462(7271), pages 315-322, November.
    2. Ryan Lister & Mattia Pelizzola & Yasuyuki S. Kida & R. David Hawkins & Joseph R. Nery & Gary Hon & Jessica Antosiewicz-Bourget & Ronan O’Malley & Rosa Castanon & Sarit Klugman & Michael Downes & Ruth , 2011. "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 68-73, March.
    3. Claude Becker & Jörg Hagmann & Jonas Müller & Daniel Koenig & Oliver Stegle & Karsten Borgwardt & Detlef Weigel, 2011. "Spontaneous epigenetic variation in the Arabidopsis thaliana methylome," Nature, Nature, vol. 480(7376), pages 245-249, December.
    4. Alexander Meissner & Tarjei S. Mikkelsen & Hongcang Gu & Marius Wernig & Jacob Hanna & Andrey Sivachenko & Xiaolan Zhang & Bradley E. Bernstein & Chad Nusbaum & David B. Jaffe & Andreas Gnirke & Rudol, 2008. "Genome-scale DNA methylation maps of pluripotent and differentiated cells," Nature, Nature, vol. 454(7205), pages 766-770, August.
    5. Ian R. Henderson & Steven E. Jacobsen, 2007. "Epigenetic inheritance in plants," Nature, Nature, vol. 447(7143), pages 418-424, May.
    6. Shawn J. Cokus & Suhua Feng & Xiaoyu Zhang & Zugen Chen & Barry Merriman & Christian D. Haudenschild & Sriharsa Pradhan & Stanley F. Nelson & Matteo Pellegrini & Steven E. Jacobsen, 2008. "Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning," Nature, Nature, vol. 452(7184), pages 215-219, March.
    7. Adam C. Bell & Gary Felsenfeld, 2000. "Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene," Nature, Nature, vol. 405(6785), pages 482-485, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yu Xiaoqing & Sun Shuying, 2016. "HMM-DM: identifying differentially methylated regions using a hidden Markov model," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 69-81, March.
    2. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Anyou Wang & Ying Du & Qianchuan He & Chunxiao Zhou, 2013. "A Quantitative System for Discriminating Induced Pluripotent Stem Cells, Embryonic Stem Cells and Somatic Cells," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    4. Yu Xiaoqing & Sun Shuying, 2016. "Comparing five statistical methods of differential methylation identification using bisulfite sequencing data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(2), pages 173-191, April.
    5. Jian Fang & Jianjun Jiang & Sarah M. Leichter & Jie Liu & Mahamaya Biswal & Nelli Khudaverdyan & Xuehua Zhong & Jikui Song, 2022. "Mechanistic basis for maintenance of CHG DNA methylation in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Yinwen Zhang & Hosung Jang & Rui Xiao & Ioanna Kakoulidou & Robert S. Piecyk & Frank Johannes & Robert J. Schmitz, 2021. "Heterochromatin is a quantitative trait associated with spontaneous epiallele formation," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    7. Olbricht Gayla R. & Craig Bruce A. & Doerge Rebecca W., 2012. "Incorporating Genomic Annotation into a Hidden Markov Model for DNA Methylation Tiling Array Data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(5), pages 1-37, November.
    8. Peng Ni & Neng Huang & Fan Nie & Jun Zhang & Zhi Zhang & Bo Wu & Lu Bai & Wende Liu & Chuan-Le Xiao & Feng Luo & Jianxin Wang, 2021. "Genome-wide detection of cytosine methylations in plant from Nanopore data using deep learning," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    9. Peter Sarkies & Jennifer Westoby & Rebecca Mary Kilner & Rahia Mashoodh, 2024. "Gene body methylation evolves during the sustained loss of parental care in the burying beetle," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    11. Xuelong Yao & Zongyang Lu & Zhanying Feng & Lei Gao & Xin Zhou & Min Li & Suijuan Zhong & Qian Wu & Zhenbo Liu & Haofeng Zhang & Zeyuan Liu & Lizhi Yi & Tao Zhou & Xudong Zhao & Jun Zhang & Yong Wang , 2022. "Comparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Rakesh Chettier & Lesa Nelson & James W Ogilvie & Hans M Albertsen & Kenneth Ward, 2015. "Haplotypes at LBX1 Have Distinct Inheritance Patterns with Opposite Effects in Adolescent Idiopathic Scoliosis," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-11, February.
    13. Xue Yue & Zhiyuan Xie & Moran Li & Kai Wang & Xiaojing Li & Xiaoqing Zhang & Jian Yan & Yimeng Yin, 2022. "Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Jinling Zhang & Xuebin Zhu & Yuhong Li & Lingyan Zhu & Shiming Li & Guoying Zheng & Qi Ren & Yonghong Xiao & Fumin Feng, 2016. "Correlation of CpG Island Methylation of the Cytochrome P450 2E1/2D6 Genes with Liver Injury Induced by Anti-Tuberculosis Drugs: A Nested Case-Control Study," IJERPH, MDPI, vol. 13(8), pages 1-9, August.
    15. Julia Minderjahn & Alexander Fischer & Konstantin Maier & Karina Mendes & Margit Nuetzel & Johanna Raithel & Hanna Stanewsky & Ute Ackermann & Robert Månsson & Claudia Gebhard & Michael Rehli, 2022. "Postmitotic differentiation of human monocytes requires cohesin-structured chromatin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Daniela Pacifico, 2018. "Upland Italian Potato Quality—A Perspective," Sustainability, MDPI, vol. 10(11), pages 1-11, October.
    17. Patricia Gerdes & Sue Mei Lim & Adam D. Ewing & Michael R. Larcombe & Dorothy Chan & Francisco J. Sanchez-Luque & Lucinda Walker & Alexander L. Carleton & Cini James & Anja S. Knaupp & Patricia E. Car, 2022. "Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    18. Sandhya Malla & Kanchan Kumari & Carlos A. García-Prieto & Jonatan Caroli & Anna Nordin & Trinh T. T. Phan & Devi Prasad Bhattarai & Carlos Martinez-Gamero & Eshagh Dorafshan & Stephanie Stransky & Da, 2024. "The scaffolding function of LSD1 controls DNA methylation in mouse ESCs," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    19. Xing Jian & Gary Felsenfeld, 2021. "Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    20. Jiyuan Hu & Tengfei Li & Zidi Xiu & Hong Zhang, 2015. "MAFsnp: A Multi-Sample Accurate and Flexible SNP Caller Using Next-Generation Sequencing Data," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-15, August.

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:bpj:sagmbi:v:15:y:2016:i:1:p:55-67:n:5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Peter Golla (email available below). General contact details of provider: https://www.degruyter.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.