Workflow of high-throughput DNA methylation analysis. The workflow shows the basic process of high-throughput DNA methylation analysis by existing bioinformatics tools. The bioinformatics tools are shown in the ellipses and the corresponding functions in the neighboring boxs.


表1:基于二代测序检测DNA甲基化的方法(NGS-based technologies for detecting DNA methylation)

Pretreatment method Genome coverage NGS-based analysis Application Ref
Endonuclease digestion Moderate Methl-seq Assay a range of genomic elements; allowing a broader survey of regions than classic methylation studies limited to CpG islands and promoters [16]
HELP-seq Measurement of repetitive sequences, copy-number variability, allele-specific and smaller fragments (<50bp) ;Sensitivity of detection of hypomethylated loci [12,75]
MSCC Identification of the unmethylated region of a genome by pinpointing unmethylated CpGs at single base-pair resolution [13,14]
Affinity enrichment Moderate MeDIP-seq Generation of unbiased, cost-effective, and full-genome methylation levels without the limitations of restriction sites or CpG islands; [1,76]
MIRA-seq Analyze recovered or double-stranded methylated DNA on a genome-wide scale; Applicable to various clinical and diagnostic situations. [19]
MDB-seq Applied to any biological settings to identify differentially methylated regions at the genomic scale [18]
MethylCap-seq Detection of differentially methylated regions with high genome coverage; Detect DMRs in clinical samples [20,77]
Bisulfite conversion High BS-seq Sensitively measure cytosine methylation on a genome-wide scale within specific sequence contexts [48,78]
RRBS Analyze a limited number of gene promoters and regulatory sequence elements in a large number of samples; Analyzing and comparing genomic methylation patterns [11,28]
BSPP Focus sequencing on the most informative genomic regions ;exon capturing and SNP genotyping; Detecting methylation in large genomes [29]
BC-seq Detect site-specific switches in methylation; Determine DNA methylation frequencies in CGIs sampled from a variety of genomic settings including promoters, exons, introns, and intergenic loci [30]


表2:短Reads比对算法(Alignment tools for short reads.)

Resources URL Ref
MAQ http://maq.sourceforge.net/ [33]
SOAPaligner/soap2 http://soap.genomics.org.cn/index.html [36]
Bowtie http://bowtie-bio.sourceforge.net/index.shtml [32]
BLAT http://genome.ucsc.edu/cgi-bin/hgBlat [79]
BWA http://maq.sourceforge.net/ [80]
BFAST http://bfast.sourceforge.net [81]
SHRiMP http://compbio.cs.toronto.edu/shrimp. [82]



  • SOAP, Short Oligonucleotide Analysis Package;
  • MAQ, Mapping and Assembly with Quality;
  • BLAT, BLAST-like alignment tool;
  • BWA, Burrows-Wheeler Alignment;
  • BFAST, BLAT-like Fast Accurate Search Tool;
  • SHRiMP, The Short-Read Mapping Package.


表3:检测峰值算法( Peak detection algorithms)

Algorithm Description Availability Ref
MACS Model-based analysis of ChIP-Seq http://liulab.dfci.harvard.edu/MACS/ [41]
ChIPseeqer in-depth analysis of ChIP-seq datasets http://physiology.med.cornell.edu/faculty/elemento/lab/CS_files/ChIPseeqer-2.0.tar.gz [83]
HPeak A HMM-based algorithm for defining read enriched regions www.sph.umich.edu/csg/qin/HPeak [84]
CASSys ChIP-seq data Analysis Software System http://localness.zbh.uni-hamburg.de/~ProjektChipSeq/cgi-bin/login.rb [85]
PeakSeq A general scoring approach for ChIP-seq data analysis. http://info.gersteinlab.org/PeakSeq [86]
Sole-Search Integrated peak-calling and analysis software http://chipseq.genomecenter.ucdavis.edu/cgi-bin/chipseq.cgi [87]
SISSRS Precise identification of binding sites from short reads generated from ChIP-Seq experiment http://sissrs.rajajothi.com/ [88]
BayesPeak Bayesian analysis of ChIP-seq data http://bioconductor.org/packages/release/bioc/html/BayesPeak.html [42]
PeakRanger A cloud-enabled peak caller for ChIP-seq data http://www.modencode.org/software/ranger/ [89]
FindPeaks 3.1 A tool for identifying areas of
http://www.bcgsc.ca/platform/bioinfo/software/findpeaks [40]
Sole-Search An integrated analysis program for peak detection and functional annotation using ChIP-seq data http://chipseq.genomecenter.ucdavis.edu/cgi-bin/chipseq.cgi [87]
PeakAnalyzer Genome-wide annotation of chromatin binding and modification loci http://www.bioinformatics.org/peakanalyzer/wiki/ [90]
chromaSig A Probabilistic Approach to Finding Common Chromatin Signatures http://bioinformatics-renlab.ucsd.edu/rentrac/wiki/ChromaSig [43]
Fish the ChIPs A pipeline for automated genomic
annotation of ChIP-Seq data
http://bio.ifom-ieo-campus.it/ftc/ [91]


 表4:分析亚硫酸盐测序测序数据的计算工具(Analysis of bisulfite sequencing data with computational tools)

Resources Purpose URL Ref
RRBSMAP A fast, accurate and user-friendly alignment tool for reduced representation bisulfite sequencing http://rrbsmap.computational-epigenetics.org/ [92]
BSMAP Ahole genome bisulfite sequence mapping http://code.google.com/p/bsmap/ [48]
BS Seeker Precise mapping for bisulfite sequencing http://pellegrini.mcdb.ucla.edu/BS_Seeker/BS_Seeker.html [46]
Bismark Map and determine the Methylation state of BS-Seq read http://www.bioinformatics.bbsrc.ac.uk/projects/bismark/ [47]
SOCS-B An alignment algorithm for bisulfite sequencing using the Applied Biosystems SOLiD System http://solidsoftwaretools.com/gf/project/socs/ [93]
BRAT Bisulfite-treated reads analysis tool http://compbio.cs.ucr.edu/brat/ [94]
BISMA Analysis of bisulfite Sequencing data from both unique and repetitive sequences http://biochem.jacobs-university.de/BDPC/BISMA/ [95]
BiQAnalyzerHT Locus-specific analysis of DNA methylation by high-throughput bisulfite sequencing http://biq-analyzer-ht.bioinf.mpi-inf.mpg.de/ [49]
CpGviewer Sequence analysis and editing for bisulphite genomic sequencing projects http://xserve1.leeds.ac.uk/~iancarr/cpgviewer [50]
CpG PatternFinder Windows-based program for bisulphite DNA - [52]
CyMATE Bisulphite-based analysis of plant genomic DNA http://www.gmi.oeaw.ac.at/CyMATE [51]
GenomeStudio Software Analyzing data generated from Illumina assays - -
MethMarker Design, optimize and validate DNA methylation biomarkers for a given DMR http://methmarker.mpi-inf.mpg.de/ [96]
BDPC Bisulfite sequencing Data methylation analysis. http://biochem.jacobs-university.de/BDPC [97]
MethylCoder Software pipeline for bisulte-treated sequences https://github.com/brentp/methylcode [98]
QUMA Quantification tool for methylation analysis http://quma.cdb.riken.jp/ [53]



  • CyMATE ,Cytosine Methylation Analysis Tool for Everyone;
  • BSMAP, Bisulphite Sequence Mapping Program;
  • BISMA, Bisulfite Sequencing DNA Methylation Analysis;
  • BRAT,bisulte-treated reads analysis tool;
  • DMR, differentially methylated DNA region;
  • QUMA, Quantification Tool For Methylation Analysis.


表5:其他生物信息学软件(Bioinformatics tools)

Tools Purpose UTR Ref
MethDB Database for DNA methylation data http://www.methdb.de [54]
MethyCancer Database Database of cancer DNA methylation data http://methycancer.psych.ac.cn/ [57]
PubMeth Database of DNA methylation literature http://www.pubmeth.org/ [99]
NGSmethDB Database for DNA methylation data at single-base resolution http://bioinfo2.ugr.es/NGSmethDB/gbrowse/ [55]
DBCAT Database of CpG islands and analytical tools for identifying comprehensive methylation profiles in cancer cells http://dbcat.cgm.ntu.edu.tw/ [100]
MethylomeDB Database of DNA methylation profiles of the brain http://epigenomics.columbia.edu/methylomedb/index.html [56]
DiseaseMeth Human disease methylation database http://bioinfo.hrbmu.edu.cn/diseasemeth [58]
CpG IE Identification of CpG islands http://bioinfo.hku.hk/cpgieintro.html [63]
CpG IS Identification of CpG islands http://cpgislands.usc.edu/ [64]
CG clusters Identification of CpG islands http://greallylab.aecom.yu.edu/cgClusters/ [68]
CpGcluster Identification of CpG islands http://bioinfo2.ugr.es/CpGcluster [67]
CpGIF Identification of CpG islands http://www.usd.edu/~sye/cpgisland/CpGIF.htm [101]
CpG_MI Identification of CpG islands http://bioinfo.hrbmu.edu.cn/cpgmi [66]
CpGProD Identification of CpG islands http://pbil.univ-lyon1.fr/software/cpgprod.html [65]
EpiGRAPH Genome scale statistical analysis http://epigraph.mpi-inf.mpg.de/WebGRAPH [71]
Galaxy General purpose analysis http://main.g2.bx.psu.edu/ [102]
QDMR Identification of differentially methylated regions http://bioinfo.hrbmu.edu.cn/qdmr. [103]
Batman MeDIP DNA methylation analysis tool http://td-blade.gurdon.cam.ac.uk/software/batman [23]
CisGenome Browser A flexible tool for genomic data visualization http://biogibbs.stanford.edu/~jiangh/browser/ [70]
MethVisual Visualization and exploratory statistical analysis of DNA methylation profiles from bisulfite sequencing http://methvisual.molgen.mpg.de/ [104]
MethTools A toolbox to visualize and analyze DNA methylation data http://genome.imb-jena.de/methtools/ [105]


以上内容摘选自:Su J, Huang D, Yan H, Liu H, Zhang Y (2012) Advances in Bioinformatics Tools for High-Throughput Sequencing Data of DNA Methylation. Hereditary Genet 1:107. doi: 10.4172/2161-1041.1000107。


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