DNA甲基化分析流程和软件集锦

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DNA甲基化分析流程示意图
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]

备注：
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 enrichment	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]

备注：
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。

各个软件后的参考文献请阅读论文原文查找。