SIMD Tutorial

1 Introduction

This package provides a inferential analysis method for detecting differentially expressed CpG sites in MeDIP-seq data. It uses statistical framework and EM algorithm, to identify differentially expressed CpG sites. The methods on this package are described in the article Methylation-level Inferences and Detection of Differential Methylation with Medip-seq Data by Yan Zhou, Jiadi Zhu, Mingtao Zhao, Baoxue Zhang, Chunfu Jiang and Xiyan Yang (2018, pending publication).

SIMD method is developed for jointly analyzing MeDIP-seq and MRE-seq data, which are derived from methylated DNA immunoprecipitation (MeDIP) experiments followed by sequencing (MeDIP-seq) and methyl-sensitive restriction enzymes experiments for unmethylated CpGs (MRE-seq). We have implemented the SIMD method via a set of R functions with the computational intensive parts written in C. We make a R package named SIMD, which is the abbreviation of Statistical Inferences with MeDIP-seq Data, and give a tutorial for the package. The method consist three steps.

Step 1: Data Pre-processing;

  • Calculate the CpG count.
  • Calculate the MRE CpG count.
  • Calculate MeDIP-seq tag count of each site of control and treatment samples.
  • Calculate MRE-seq tag count of each site of control and treatment samples.

Step 2: Calculating p-values of each CpG site by the EM algorithm;

Step 3: Select Significants.

We use a part of a real dataset to illustrate the usage of the SIMD package. The programs can run under the Linux system and windows 10 system. The R versions should larger than 3.5.0.

2 Preparations

Before installing SIMD package, the user must install three other R pack- ages, which can be done using the following commands:

install.packages("BiocManager")
BiocManager::install(c('edgeR', 'statmod','methylMnM'))

library(edgeR)
library(statmod)
library(methylMnM)

Next, to install the SIMD package into your R environment, start R and enter:

BiocManager::install("SIMD")

Then, the SIMD package is ready to load.

library(SIMD)

3 Data format

In order to reproduce the presented SIMD workflow, the package includes the example data sets, which is a part of a real data sets, including:

all_CpGsite_bin_chr18,
three_mre_cpg,
EM2_H1ESB1_MeDIP_sigleCpG,
EM2_H1ESB2_MeDIP_sigleCpG,
H1ESB1_MRE_sigleCpG,
and H1ESB2_MRE_sigleCpG, which is included in file example_data.RDdata in the data subdirectory of the SIMD package.

The files contain genomic regions from chromosome 18 only, as covered by short reads obtained from a MeDIP and MRE experiment of human H1ESB1 cells.

All output files are in a .bed format. The input file contain the following columns.

  • the first coulumn is of type character and contains the chromosome of the region (e.g. chr1)
  • the second column is of type numeric and contains the start position of the mapped read
  • the third column is of type numeric and contains the stop position of the mapped read
  • the fourth column is of type character and contains the strand information of the mapped read

For MRE-seq data, we need “+” and “-” strand information in mapping process, which is general located at the sixth column of the input file. Each row represents a mapped read. These information can be extracted from the output file(s) of common mapping tools.

4 Data Pre-processing

The SIMD program requires users to provide the genome-wide MeDIP-seq and MRE-seq reads and the reference genome. The pre-processing step involves calculation of MeDIP-seq and MRE-seq count and CpG and MRE-specific count in each CpG site. The mainly steps please refer the data pre-processing steps of R package MethylMnM.

In this manual, we use example data located in the data subdirectory of the SIMD package, and the example data is processed by MethylMnM package in advance. The path is:

datafile <- system.file("extdata", package="methylMnM")
filepath <- datafile[1]

The CpG count, MRE-CpG count, MeDIP-seq count and MRE-seq count of each site are stored at:

dirwrite <- paste(setwd(getwd()), "/", sep="")

Then we compute the number of actual short reads in each CpG site by the function of EMalgorithm(), which use EM algorithm to infer the actual reads by the observation fragments. The results are saved in file writefile and reportfile. We give an example as follows, the data is from data subdirectory of the SIMD package:

data(example_data)
allcpgfile <- EM_H1ESB1_MeDIP_sigleCpG
readshort <- paste(filepath, "/H1ESB1_MeDIP_18.extended.txt", sep="")
writefile <- paste(dirwrite, "EM2_H1ESB1_MeDIP_sigleCpG.bed", sep="")
reportfile <- paste(dirwrite, "EM2_H1ESB1_MeDIP_sigleCpG_report.bed", sep="")
EMalgorithm(cpgsitefile=readshort, allcpgfile=allcpgfile, category="1",
            writefile=writefile, reportfile=reportfile)
## [1] 1
##         V1     V2     V3           V4
## 1    chr18  10692  10694  2.699262074
## 2    chr18  10703  10705  3.464033797
## 3    chr18  10718  10720  5.013880075
## 4    chr18  10730  10732  4.575160390
## 5    chr18  10753  10755  4.367140836
## 6    chr18  10767  10769  3.949686891
## 7    chr18  10787  10789  3.006196402
## 8    chr18  10791  10793  2.721496577
## 9    chr18  10795  10797  2.703602326
## 10   chr18  10815  10817  2.514884741
## 11   chr18  10823  10825  2.335973283
## 12   chr18  10829  10831  2.380368655
## 13   chr18  10831  10833  2.380368655
## 14   chr18  10839  10841  2.226858406
## 15   chr18  10861  10863  1.500303502
## 16   chr18  10869  10871  1.248835637
## 17   chr18  10875  10877  1.136110056
## 18   chr18  10887  10889  0.831184543
## 19   chr18  10921  10923  0.232070026
## 20   chr18  10929  10931  0.232070026
## 21   chr18  10934  10936  0.232070026
## 22   chr18  10937  10939  0.232070026
## 23   chr18  10940  10942  0.179499689
## 24   chr18  10946  10948  0.131977440
## 25   chr18  10948  10950  0.090078076
## 26   chr18  10956  10958  0.090078076
## 27   chr18  10958  10960  0.090078076
## 28   chr18  10963  10965  0.090078076
## 29   chr18  10966  10968  0.056609652
## 30   chr18  10969  10971  0.056609652
## 31   chr18  10975  10977  0.028689994
## 32   chr18  10977  10979  0.028689994
## 33   chr18  10985  10987  0.028689994
## 34   chr18  10987  10989  0.028689994
## 35   chr18  10992  10994  0.028689994
## 36   chr18  10995  10997  0.028689994
## 37   chr18  10998  11000  0.028689994
## 38   chr18  11004  11006  0.007633588
## 39   chr18  11006  11008  0.007633588
## 40   chr18  11014  11016  0.007633588
## 41   chr18  11016  11018  0.007633588
## 42   chr18  11021  11023  0.000000000
## 43   chr18  11024  11026  0.000000000
## 44   chr18  11027  11029  0.000000000
## 45   chr18  11033  11035  0.000000000
## 46   chr18  11035  11037  0.000000000
## 47   chr18  11043  11045  0.000000000
## 48   chr18  11045  11047  0.000000000
## 49   chr18  11050  11052  0.000000000
## 50   chr18  11053  11055  0.000000000
## 51   chr18  11056  11058  0.000000000
## 52   chr18  11062  11064  0.000000000
## 53   chr18  11064  11066  0.000000000
## 54   chr18  11072  11074  0.000000000
## 55   chr18  11074  11076  0.000000000
## 56   chr18  11079  11081  0.000000000
## 57   chr18  11082  11084  0.000000000
## 58   chr18  11085  11087  0.000000000
## 59   chr18  11091  11093  0.000000000
## 60   chr18  11097  11099  0.000000000
## 61   chr18  11099  11101  0.000000000
## 62   chr18  11107  11109  0.000000000
## 63   chr18  11109  11111  0.000000000
## 64   chr18  11114  11116  0.000000000
## 65   chr18  11117  11119  0.000000000
## 66   chr18  11120  11122  0.000000000
## 67   chr18  11126  11128  0.012987013
## 68   chr18  11132  11134  0.052289815
## 69   chr18  11134  11136  0.052289815
## 70   chr18  11142  11144  0.215690742
## 71   chr18  11144  11146  0.215690742
## 72   chr18  11148  11150  0.215690742
## 73   chr18  11154  11156  0.215690742
## 74   chr18  11167  11169  0.752458799
## 75   chr18  11218  11220  1.778161361
## 76   chr18  11230  11232  2.067471968
## 77   chr18  11251  11253  2.381065646
## 78   chr18  11256  11258  2.381065646
## 79   chr18  11323  11325  1.586947232
## 80   chr18  11325  11327  1.586947232
## 81   chr18  11344  11346  1.304016697
## 82   chr18  11354  11356  1.304016697
## 83   chr18  11358  11360  1.080206567
## 84   chr18  11386  11388  1.357217972
## 85   chr18  11400  11402  1.498522320
## 86   chr18  11405  11407  1.498522320
## 87   chr18  11431  11433  1.934716599
## 88   chr18  11511  11513  1.633333333
## 89   chr18  11532  11534  1.250000000
## 90   chr18  11611  11613  1.254824561
## 91   chr18  11667  11669  0.583859649
## 92   chr18  11708  11710  0.583859649
## 93   chr18  11723  11725  1.006224256
## 94   chr18  11739  11741  0.753592677
## 95   chr18  11753  11755  0.427993898
## 96   chr18  11755  11757  0.306372276
## 97   chr18  11761  11763  0.306372276
## 98   chr18  11783  11785  0.306372276
## 99   chr18  11791  11793  0.306372276
## 100  chr18  11793  11795  0.306372276
## 101  chr18  11805  11807  0.165097821
## 102  chr18  11823  11825  0.165097821
## 103  chr18  11825  11827  0.165097821
## 104  chr18  11831  11833  0.240156060
## 105  chr18  11838  11840  0.330145314
## 106  chr18  11849  11851  0.643594231
## 107  chr18  11852  11854  0.643594231
## 108  chr18  11854  11856  0.643594231
## 109  chr18  11863  11865  0.544895607
## 110  chr18  11888  11890  0.498807414
## 111  chr18  11891  11893  0.498807414
## 112  chr18  11893  11895  0.498807414
## 113  chr18  11911  11913  0.465345380
## 114  chr18  11914  11916  0.465345380
## 115  chr18  11939  11941  1.006700023
## 116  chr18  11947  11949  1.006700023
## 117  chr18  11955  11957  1.006700023
## 118  chr18  11962  11964  1.006700023
## 119  chr18  11988  11990  1.328539266
## 120  chr18  11990  11992  1.328539266
## 121  chr18  11996  11998  1.297397153
## 122  chr18  12009  12011  1.260655285
## 123  chr18  12011  12013  1.096611451
## 124  chr18  12022  12024  0.938165718
## 125  chr18  12033  12035  1.079141471
## 126  chr18  12049  12051  1.069957085
## 127  chr18  12052  12054  1.069957085
## 128  chr18  12058  12060  1.069957085
## 129  chr18  12064  12066  1.232874600
## 130  chr18  12067  12069  0.960711886
## 131  chr18  12077  12079  1.014600378
## 132  chr18  12087  12089  0.894328774
## 133  chr18  12101  12103  0.894328774
## 134  chr18  12116  12118  0.799992328
## 135  chr18  12122  12124  0.690645692
## 136  chr18  12139  12141  0.499492449
## 137  chr18  12142  12144  0.499492449
## 138  chr18  12153  12155  0.332982687
## 139  chr18  12160  12162  0.667655848
## 140  chr18  12179  12181  0.635949061
## 141  chr18  12181  12183  0.635949061
## 142  chr18  12204  12206  0.714002799
## 143  chr18  12210  12212  0.768703286
## 144  chr18  12216  12218  0.768703286
## 145  chr18  12223  12225  0.520160207
## 146  chr18  12249  12251  1.649798014
## 147  chr18  12257  12259  1.569077544
## 148  chr18  12272  12274  1.841020424
## 149  chr18  12278  12280  2.145278803
## 150  chr18  12280  12282  2.145278803
## 151  chr18  12293  12295  2.684583553
## 152  chr18  12297  12299  2.881336107
## 153  chr18  12312  12314  2.708051515
## 154  chr18  12336  12338  3.231561757
## 155  chr18  12347  12349  3.557225147
## 156  chr18  12350  12352  3.843967217
## 157  chr18  12361  12363  4.021983139
## 158  chr18  12370  12372  4.738570382
## 159  chr18  12397  12399  4.053435423
## 160  chr18  12436  12438  4.464875891
## 161  chr18  12485  12487  4.155906381
## 162  chr18  12506  12508  4.485778804
## 163  chr18  12527  12529  5.386038747
## 164  chr18  12554  12556  4.969034214
## 165  chr18  12560  12562  4.603399740
## 166  chr18  12570  12572  4.417559580
## 167  chr18  12584  12586  5.875979779
## 168  chr18  12633  12635  6.706979747
## 169  chr18  12709  12711  4.963922243
## 170  chr18  12779  12781  1.448412698
## 171  chr18  12794  12796  0.535714286
## 172  chr18  12855  12857  0.581818182
## 173  chr18  12904  12906  2.254761905
## 174  chr18  12907  12909  2.726406926
## 175  chr18  12953  12955  6.237132651
## 176  chr18  12968  12970  5.809636434
## 177  chr18  13092  13094  3.305587818
## 178  chr18  13118  13120  2.056507937
## 179  chr18  13232  13234  3.563581795
## 180  chr18  13245  13247  3.370989202
## 181  chr18  13262  13264  7.480023511
## 182  chr18  13334  13336  5.346886973
## 183  chr18  13412  13414  4.600000000
## 184  chr18  13548  13550  0.000000000
## 185  chr18  13582  13584  0.000000000
## 186  chr18  13703  13705  0.000000000
## 187  chr18  13866  13868  7.000000000
## 188  chr18  13993  13995  7.500000000
## 189  chr18  14004  14006  7.500000000
## 190  chr18  14235  14237  0.000000000
## 191  chr18  14438  14440  0.000000000
## 192  chr18  14502  14504  0.000000000
## 193  chr18  14522  14524  0.000000000
## 194  chr18  14553  14555  0.000000000
## 195  chr18  14555  14557  0.000000000
## 196  chr18  14576  14578  0.000000000
## 197  chr18  14745  14747  0.000000000
## 198  chr18  14813  14815  0.000000000
## 199  chr18  14839  14841  0.000000000
## 200  chr18  14891  14893  0.000000000
## 201  chr18  15470  15472  0.000000000
## 202  chr18  16066  16068  0.000000000
## 203  chr18  16587  16589  0.000000000
## 204  chr18  17144  17146  0.000000000
## 205  chr18  17914  17916  0.000000000
## 206  chr18  17999  18001  0.000000000
## 207  chr18  18097  18099  0.000000000
## 208  chr18  18113  18115  0.000000000
## 209  chr18  18396  18398  0.000000000
## 210  chr18  18465  18467  0.000000000
## 211  chr18  18543  18545  0.000000000
## 212  chr18  19188  19190  0.000000000
## 213  chr18  19414  19416  0.000000000
## 214  chr18  19944  19946  0.000000000
## 215  chr18  20001  20003  0.000000000
## 216  chr18  20063  20065  0.000000000
## 217  chr18  20095  20097  0.000000000
## 218  chr18  20179  20181  0.000000000
## 219  chr18  20182  20184  0.000000000
## 220  chr18  20685  20687  1.000000000
## 221  chr18  20872  20874  0.000000000
## 222  chr18  21235  21237  0.000000000
## 223  chr18  21329  21331  0.000000000
## 224  chr18  21659  21661  0.000000000
## 225  chr18  21683  21685  0.000000000
## 226  chr18  21705  21707  0.000000000
## 227  chr18  21739  21741  0.000000000
## 228  chr18  21769  21771  0.000000000
## 229  chr18  21778  21780  0.000000000
## 230  chr18  21861  21863  0.000000000
## 231  chr18  21988  21990  0.000000000
## 232  chr18  22336  22338  0.000000000
## 233  chr18  22841  22843  0.000000000
## 234  chr18  23029  23031  0.000000000
## 235  chr18  23066  23068  0.000000000
## 236  chr18  23281  23283  0.000000000
## 237  chr18  23401  23403  0.000000000
## 238  chr18  23439  23441  0.000000000
## 239  chr18  23456  23458  0.000000000
## 240  chr18  23476  23478  0.000000000
## 241  chr18  23515  23517  0.000000000
## 242  chr18  23557  23559  0.000000000
## 243  chr18  23851  23853  0.000000000
## 244  chr18  23927  23929  0.000000000
## 245  chr18  24575  24577  0.000000000
## 246  chr18  25082  25084  0.000000000
## 247  chr18  25270  25272  0.000000000
## 248  chr18  25286  25288  0.000000000
## 249  chr18  25421  25423  0.000000000
## 250  chr18  25660  25662  0.000000000
## 251  chr18  25865  25867  0.000000000
## 252  chr18  25871  25873  0.000000000
## 253  chr18  26060  26062  0.000000000
## 254  chr18  26187  26189  0.000000000
## 255  chr18  26196  26198  0.000000000
## 256  chr18  26327  26329  0.000000000
## 257  chr18  26627  26629  0.200000000
## 258  chr18  26661  26663  0.733333333
## 259  chr18  26690  26692  0.733333333
## 260  chr18  26713  26715  0.166666667
## 261  chr18  26792  26794  0.166666667
## 262  chr18  26802  26804  0.000000000
## 263  chr18  26807  26809  0.000000000
## 264  chr18  26845  26847  0.000000000
## 265  chr18  26847  26849  0.000000000
## 266  chr18  26858  26860  0.000000000
## 267  chr18  26944  26946  0.000000000
## 268  chr18  26988  26990  0.000000000
## 269  chr18  27167  27169  0.000000000
## 270  chr18  27208  27210  0.000000000
## 271  chr18  27819  27821  0.344720497
## 272  chr18  27828  27830  0.344720497
## 273  chr18  27847  27849  0.919772257
## 274  chr18  27915  27917  1.343726708
## 275  chr18  27929  27931  1.343726708
## 276  chr18  27947  27949  0.902380952
## 277  chr18  27970  27972  0.327142857
## 278  chr18  27982  27984  0.327142857
## 279  chr18  27992  27994  0.146666667
## 280  chr18  28007  28009  0.000000000
## 281  chr18  28022  28024  0.000000000
## 282  chr18  28032  28034  0.000000000
## 283  chr18  28040  28042  0.000000000
## 284  chr18  28053  28055  0.000000000
## 285  chr18  28142  28144  0.000000000
## 286  chr18  28151  28153  0.000000000
## 287  chr18  28171  28173  0.000000000
## 288  chr18  28204  28206  0.000000000
## 289  chr18  28221  28223  0.000000000
## 290  chr18  28234  28236  0.000000000
## 291  chr18  28368  28370  0.000000000
## 292  chr18  28379  28381  0.000000000
## 293  chr18  28387  28389  0.000000000
## 294  chr18  28426  28428  0.000000000
## 295  chr18  28495  28497  0.000000000
## 296  chr18  28501  28503  0.000000000
## 297  chr18  28524  28526  0.000000000
## 298  chr18  28544  28546  0.000000000
## 299  chr18  28562  28564  0.000000000
## 300  chr18  28666  28668  0.000000000
## 301  chr18  28733  28735  0.000000000
## 302  chr18  28833  28835  0.000000000
## 303  chr18  28853  28855  0.000000000
## 304  chr18  28895  28897  0.000000000
## 305  chr18  28912  28914  0.000000000
## 306  chr18  29146  29148  0.000000000
## 307  chr18  29221  29223  0.000000000
## 308  chr18  29422  29424  0.000000000
## 309  chr18  29431  29433  0.000000000
## 310  chr18  29652  29654  0.000000000
## 311  chr18  29918  29920  0.000000000
## 312  chr18  29976  29978  0.000000000
## 313  chr18  30288  30290  0.000000000
## 314  chr18  30385  30387  0.000000000
## 315  chr18  30591  30593  0.000000000
## 316  chr18  30870  30872  0.000000000
## 317  chr18  30893  30895  0.000000000
## 318  chr18  30936  30938  0.000000000
## 319  chr18  31098  31100  0.000000000
## 320  chr18  31461  31463  0.000000000
## 321  chr18  31914  31916  0.000000000
## 322  chr18  31930  31932  0.000000000
## 323  chr18  32210  32212  0.000000000
## 324  chr18  32477  32479  0.000000000
## 325  chr18  32732  32734  0.000000000
## 326  chr18  32824  32826  0.000000000
## 327  chr18  33717  33719  0.000000000
## 328  chr18  34235  34237  0.000000000
## 329  chr18  34281  34283  0.000000000
## 330  chr18  34319  34321  0.000000000
## 331  chr18  34334  34336  0.000000000
## 332  chr18  34857  34859  0.000000000
## 333  chr18  34972  34974  0.000000000
## 334  chr18  34976  34978  0.000000000
## 335  chr18  35523  35525  0.000000000
## 336  chr18  35845  35847  0.000000000
## 337  chr18  35851  35853  0.000000000
## 338  chr18  35863  35865  0.000000000
## 339  chr18  35929  35931  0.000000000
## 340  chr18  35947  35949  0.000000000
## 341  chr18  35952  35954  0.000000000
## 342  chr18  35963  35965  0.000000000
## 343  chr18  35990  35992  0.000000000
## 344  chr18  35997  35999  0.000000000
## 345  chr18  36062  36064  0.206349206
## 346  chr18  36077  36079  0.206349206
## 347  chr18  36097  36099  0.206349206
## 348  chr18  36111  36113  0.732698413
## 349  chr18  36114  36116  0.732698413
## 350  chr18  36153  36155  0.732698413
## 351  chr18  36157  36159  0.382857143
## 352  chr18  36171  36173  0.160000000
## 353  chr18  36178  36180  0.160000000
## 354  chr18  36190  36192  0.160000000
## 355  chr18  36218  36220  0.160000000
## 356  chr18  36239  36241  0.160000000
## 357  chr18  36285  36287  0.000000000
## 358  chr18  36425  36427  0.000000000
## 359  chr18  36557  36559  0.000000000
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## 786  chr18  73245  73247  1.004264742
## 787  chr18  73248  73250  0.636566772
## 788  chr18  73255  73257  0.636566772
## 789  chr18  73257  73259  0.617473969
## 790  chr18  73261  73263  0.610051336
## 791  chr18  73263  73265  0.610051336
## 792  chr18  73267  73269  0.610051336
## 793  chr18  73272  73274  0.610051336
## 794  chr18  73281  73283  0.610051336
## 795  chr18  73286  73288  0.785639803
## 796  chr18  73288  73290  0.998238074
## 797  chr18  73314  73316  0.653672301
## 798  chr18  73319  73321  0.871230093
## 799  chr18  73337  73339  0.871230093
## 800  chr18  73351  73353  0.731475505
## 801  chr18  73370  73372  0.806980333
## 802  chr18  73374  73376  1.045898546
## 803  chr18  73376  73378  0.888983110
## 804  chr18  73408  73410  0.676107352
## 805  chr18  73445  73447  0.372026960
## 806  chr18  73465  73467  0.141276377
## 807  chr18  73490  73492  0.273474885
## 808  chr18  73493  73495  0.273474885
## 809  chr18  73496  73498  0.273474885
## 810  chr18  73500  73502  0.273474885
## 811  chr18  73505  73507  0.273474885
## 812  chr18  73511  73513  0.273474885
## 813  chr18  73516  73518  0.160330045
## 814  chr18  73518  73520  0.160330045
## 815  chr18  73520  73522  0.160330045
## 816  chr18  73522  73524  0.077035950
## 817  chr18  73525  73527  0.077035950
## 818  chr18  73532  73534  0.077035950
## 819  chr18  73547  73549  0.077035950
## 820  chr18  73551  73553  0.077035950
## 821  chr18  73559  73561  0.021276596
## 822  chr18  73561  73563  0.021276596
## 823  chr18  73591  73593  0.021276596
## 824  chr18  73611  73613  0.021276596
## 825  chr18  73652  73654  0.041666667
## 826  chr18  73663  73665  0.170289855
## 827  chr18  73668  73670  0.170289855
## 828  chr18  73705  73707  0.648272018
## 829  chr18  73738  73740  0.995525207
## 830  chr18  73740  73742  0.995525207
## 831  chr18  73763  73765  0.995525207
## 832  chr18  73826  73828  1.541470798
## 833  chr18  73838  73840  0.716435185
## 834  chr18  73897  73899  0.709821429
## 835  chr18  73914  73916  0.709821429
## 836  chr18  73920  73922  0.709821429
## 837  chr18  73922  73924  0.709821429
## 838  chr18  73943  73945  0.442857143
## 839  chr18  73951  73953  0.442857143
## 840  chr18  74091  74093  0.071428571
## 841  chr18  74111  74113  0.296703297
## 842  chr18  74169  74171  0.941232680
## 843  chr18  74221  74223  2.515578243
## 844  chr18  74260  74262  1.551814318
## 845  chr18  74262  74264  1.551814318
## 846  chr18  74324  74326  0.357142857
## 847  chr18  74344  74346  0.357142857
## 848  chr18  74346  74348  0.357142857
## 849  chr18  74389  74391  0.000000000
## 850  chr18  74471  74473  0.000000000
## 851  chr18  74487  74489  0.000000000
## 852  chr18  74497  74499  0.000000000
## 853  chr18  74499  74501  0.000000000
## 854  chr18  74503  74505  0.000000000
## 855  chr18  74582  74584  0.000000000
## 856  chr18  74608  74610  0.000000000
## 857  chr18  74724  74726  1.666666667
## 858  chr18  74726  74728  1.666666667
## 859  chr18  74784  74786  1.666666667
## 860  chr18  74859  74861  0.000000000
## 861  chr18  74911  74913  0.000000000
## 862  chr18  74918  74920  0.000000000
## 863  chr18  74941  74943  0.000000000
## 864  chr18  74949  74951  0.000000000
## 865  chr18  74965  74967  0.000000000
## 866  chr18  75091  75093  0.000000000
## 867  chr18  75099  75101  0.000000000
## 868  chr18  75172  75174  0.000000000
## 869  chr18  75212  75214  0.090909091
## 870  chr18  75224  75226  0.090909091
## 871  chr18  75257  75259  0.090909091
## 872  chr18  75284  75286  0.363636364
## 873  chr18  75314  75316  0.363636364
## 874  chr18  75347  75349  0.363636364
## 875  chr18  75355  75357  0.363636364
## 876  chr18  75401  75403  0.607092598
## 877  chr18  75411  75413  0.222910217
## 878  chr18  75418  75420  0.222910217
## 879  chr18  75435  75437  0.222910217
## 880  chr18  75441  75443  0.222910217
## 881  chr18  75443  75445  0.222910217
## 882  chr18  75474  75476  0.222910217
## 883  chr18  75504  75506  0.222910217
## 884  chr18  75522  75524  0.052631579
## 885  chr18  75534  75536  0.052631579
## 886  chr18  75576  75578  0.119298246
## 887  chr18  75580  75582  0.119298246
## 888  chr18  75583  75585  0.119298246
## 889  chr18  75591  75593  0.267182663
## 890  chr18  75594  75596  0.267182663
## 891  chr18  75602  75604  0.267182663
## 892  chr18  75610  75612  0.267182663
## 893  chr18  75619  75621  0.267182663
## 894  chr18  75650  75652  0.267182663
## 895  chr18  75656  75658  0.267182663
## 896  chr18  75662  75664  0.267182663
## 897  chr18  75691  75693  0.111455108
## 898  chr18  75713  75715  0.310039805
## 899  chr18  75717  75719  0.310039805
## 900  chr18  75733  75735  0.154061625
## 901  chr18  75751  75753  0.047619048
## 902  chr18  75758  75760  0.047619048
## 903  chr18  75760  75762  0.047619048
## 904  chr18  75763  75765  0.047619048
## 905  chr18  75765  75767  0.047619048
## 906  chr18  75769  75771  0.047619048
## 907  chr18  75774  75776  0.047619048
## 908  chr18  75776  75778  0.047619048
## 909  chr18  75788  75790  0.047619048
## 910  chr18  75821  75823  0.047619048
## 911  chr18  75824  75826  0.047619048
## 912  chr18  75839  75841  0.047619048
## 913  chr18  75844  75846  0.047619048
## 914  chr18  75863  75865  0.000000000
## 915  chr18  75867  75869  0.000000000
## 916  chr18  75884  75886  0.029411765
## 917  chr18  75892  75894  0.029411765
## 918  chr18  75901  75903  0.029411765
## 919  chr18  75929  75931  0.029411765
## 920  chr18  75951  75953  0.115966387
## 921  chr18  75954  75956  0.115966387
## 922  chr18  75957  75959  0.115966387
## 923  chr18  75960  75962  0.115966387
## 924  chr18  75964  75966  0.115966387
## 925  chr18  75969  75971  0.115966387
## 926  chr18  75976  75978  0.115966387
## 927  chr18  75980  75982  0.115966387
## 928  chr18  75982  75984  0.115966387
## 929  chr18  75984  75986  0.115966387
## 930  chr18  75986  75988  0.115966387
## 931  chr18  75988  75990  0.115966387
## 932  chr18  75996  75998  0.115966387
## 933  chr18  76011  76013  0.115966387
## 934  chr18  76015  76017  0.115966387
## 935  chr18  76023  76025  0.028571429
## 936  chr18  76025  76027  0.028571429
## 937  chr18  76055  76057  0.028571429
## 938  chr18  76074  76076  0.028571429
## 939  chr18  76091  76093  0.028571429
## 940  chr18  76107  76109  0.000000000
## 941  chr18  76125  76127  0.000000000
## 942  chr18  76168  76170  1.000000000
## 943  chr18  76201  76203  1.000000000
## 944  chr18  76224  76226  1.000000000
## 945  chr18  76228  76230  1.000000000
## 946  chr18  76246  76248  1.000000000
## 947  chr18  76259  76261  1.000000000
## 948  chr18  76298  76300  0.000000000
## 949  chr18  76300  76302  0.000000000
## 950  chr18  76344  76346  0.000000000
## 951  chr18  76354  76356  0.000000000
## 952  chr18  76361  76363  0.000000000
## 953  chr18  76416  76418  0.000000000
## 954  chr18  76524  76526  0.000000000
## 955  chr18  76589  76591  0.000000000
## 956  chr18  76651  76653  0.000000000
## 957  chr18  76813  76815  0.000000000
## 958  chr18  77123  77125  0.000000000
## 959  chr18  77266  77268  0.000000000
## 960  chr18  77485  77487  0.000000000
## 961  chr18  77853  77855  1.000000000
## 962  chr18  77908  77910  1.000000000
## 963  chr18  78001  78003  0.000000000
## 964  chr18  78065  78067  0.000000000
## 965  chr18  78082  78084  0.000000000
## 966  chr18  78102  78104  0.000000000
## 967  chr18  78122  78124  0.000000000
## 968  chr18  78147  78149  0.000000000
## 969  chr18  78202  78204  0.000000000
## 970  chr18  78247  78249  0.000000000
## 971  chr18  78345  78347  1.000000000
## 972  chr18  78359  78361  1.000000000
## 973  chr18  78408  78410  1.000000000
## 974  chr18  78531  78533  0.000000000
## 975  chr18  78740  78742  0.000000000
## 976  chr18  78760  78762  0.000000000
## 977  chr18  78768  78770  0.000000000
## 978  chr18  78785  78787  0.000000000
## 979  chr18  79224  79226  0.000000000
## 980  chr18  79294  79296  0.000000000
## 981  chr18  79364  79366  0.000000000
## 982  chr18  79434  79436  0.000000000
## 983  chr18  79502  79504  0.000000000
## 984  chr18  79536  79538  0.000000000
## 985  chr18  79604  79606  0.000000000
## 986  chr18  79627  79629  0.000000000
## 987  chr18  79908  79910  1.000000000
## 988  chr18  79969  79971  1.000000000
## 989  chr18  80077  80079  0.000000000
## 990  chr18  80166  80168  0.444444444
## 991  chr18  80193  80195  0.966666667
## 992  chr18  80247  80249  1.688888889
## 993  chr18  80333  80335  0.975000000
## 994  chr18  80371  80373  1.050000000
## 995  chr18  80394  80396  0.500000000
## 996  chr18  80448  80450  2.375000000
## 997  chr18  80596  80598  0.000000000
## 998  chr18  80650  80652  0.500000000
## 999  chr18  80709  80711  0.500000000
## 1000 chr18  80947  80949 19.000000000
## 1001 chr18  81276  81278  3.145454545
## 1002 chr18  81316  81318  1.787878788
## 1003 chr18  81350  81352  1.066666667
## 1004 chr18  81469  81471  0.000000000
## 1005 chr18  81501  81503  0.000000000
## 1006 chr18  81519  81521  0.000000000
## 1007 chr18  81635  81637  0.000000000
## 1008 chr18  81649  81651  0.000000000
## 1009 chr18  81805  81807  0.000000000
## 1010 chr18  81807  81809  0.000000000
## 1011 chr18  82026  82028  0.000000000
## 1012 chr18  82114  82116  0.000000000
## 1013 chr18  82157  82159  0.000000000
## 1014 chr18  82318  82320  0.619047619
## 1015 chr18  82358  82360  0.619047619
## 1016 chr18  82366  82368  0.619047619
## 1017 chr18  82412  82414  0.142857143
## 1018 chr18  82450  82452  0.000000000
## 1019 chr18  82483  82485  0.000000000
## 1020 chr18  82517  82519  0.000000000
## 1021 chr18  82578  82580  0.400000000
## 1022 chr18  82581  82583  0.400000000
## 1023 chr18  82589  82591  0.400000000
## 1024 chr18  82630  82632  0.400000000
## 1025 chr18  82652  82654  0.400000000
## 1026 chr18  82785  82787  0.000000000
## 1027 chr18  82880  82882  0.884057971
## 1028 chr18  82907  82909  1.260869565
## 1029 chr18  82909  82911  1.260869565
## 1030 chr18  82930  82932  1.260869565
## 1031 chr18  82975  82977  2.333333333
## 1032 chr18  83021  83023  3.000000000
## 1033 chr18  83141  83143  0.685714286
## 1034 chr18  83153  83155  1.528571429
## 1035 chr18  83214  83216  0.619047619
## 1036 chr18  83290  83292  0.166666667
## 1037 chr18  83396  83398  0.000000000
## 1038 chr18  83451  83453  0.000000000
## 1039 chr18  83502  83504  0.000000000
## 1040 chr18  83557  83559  0.000000000
## 1041 chr18  83608  83610  0.000000000
## 1042 chr18  83668  83670  0.000000000
## 1043 chr18  83722  83724  0.000000000
## 1044 chr18  83735  83737  1.000000000
## 1045 chr18  83754  83756  1.000000000
## 1046 chr18  83854  83856  1.000000000
## 1047 chr18  83868  83870  1.000000000
## 1048 chr18  83916  83918  0.000000000
## 1049 chr18  83926  83928  0.000000000
## 1050 chr18  84002  84004  0.000000000
## 1051 chr18  84022  84024  0.000000000
## 1052 chr18  84047  84049  0.000000000
## 1053 chr18  84071  84073  0.000000000
## 1054 chr18  84149  84151  1.000000000
## 1055 chr18  84181  84183  1.000000000
## 1056 chr18  84225  84227  1.000000000
## 1057 chr18  84429  84431  1.000000000
## 1058 chr18  84706  84708  2.039845261
## 1059 chr18  84721  84723  2.039845261
## 1060 chr18  84755  84757  1.773760438
## 1061 chr18  84770  84772  1.473838138
## 1062 chr18  84786  84788  1.473838138
## 1063 chr18  84805  84807  2.018067905
## 1064 chr18  84815  84817  1.623625372
## 1065 chr18  84882  84884  0.280256410
## 1066 chr18  84908  84910  0.354817814
## 1067 chr18  84922  84924  0.185263158
## 1068 chr18  84981  84983  0.498725074
## 1069 chr18  84987  84989  0.498725074
## 1070 chr18  85010  85012  1.063877084
## 1071 chr18  85036  85038  2.809312684
## 1072 chr18  85047  85049  3.433993952
## 1073 chr18  85094  85096  3.643517762
## 1074 chr18  85187  85189  4.629270186
## 1075 chr18  85228  85230  3.072463768
## 1076 chr18  85277  85279  1.086956522
## 1077 chr18  85503  85505  1.000000000
## 1078 chr18  85687  85689  0.000000000
## 1079 chr18  85695  85697  0.000000000
## 1080 chr18  85931  85933  0.000000000
## 1081 chr18  86110  86112  0.000000000
## 1082 chr18  86161  86163  0.000000000
## 1083 chr18  86222  86224  0.000000000
## 1084 chr18  86314  86316  0.000000000
## 1085 chr18  86413  86415  0.000000000
## 1086 chr18  86522  86524  0.000000000
## 1087 chr18  86583  86585  0.000000000
## 1088 chr18  86746  86748  1.500000000
## 1089 chr18  86850  86852  1.166666667
## 1090 chr18  86931  86933  0.333333333
## 1091 chr18  86957  86959  0.000000000
## 1092 chr18  86977  86979  0.000000000
## 1093 chr18  87012  87014  0.000000000
## 1094 chr18  87071  87073  0.000000000
## 1095 chr18  87150  87152  0.000000000
## 1096 chr18  87152  87154  0.000000000
## 1097 chr18  87311  87313  0.000000000
## 1098 chr18  87400  87402  0.000000000
## 1099 chr18  87614  87616  0.000000000
## 1100 chr18  87630  87632  0.000000000
## 1101 chr18  87652  87654  0.000000000
## 1102 chr18  87660  87662  0.000000000
## 1103 chr18  87690  87692  1.000000000
## 1104 chr18  87694  87696  1.000000000
## 1105 chr18  87740  87742  1.000000000
## 1106 chr18  87791  87793  1.000000000
## 1107 chr18  87811  87813  1.000000000
## 1108 chr18  87843  87845  0.000000000
## 1109 chr18  87880  87882  0.000000000
## 1110 chr18  88031  88033  0.000000000
## 1111 chr18  88067  88069  0.000000000
## 1112 chr18  88145  88147  0.000000000
## 1113 chr18  88216  88218  0.000000000
## 1114 chr18  88232  88234  0.000000000
## 1115 chr18  88306  88308  0.000000000
## 1116 chr18  88341  88343  0.000000000
## 1117 chr18  88354  88356  0.000000000
## 1118 chr18  88395  88397  0.000000000
## 1119 chr18  88401  88403  0.000000000
## 1120 chr18  88475  88477  0.666666667
## 1121 chr18  88497  88499  0.666666667
## 1122 chr18  88512  88514  0.666666667
## 1123 chr18  88647  88649  0.000000000
## 1124 chr18  88698  88700  0.000000000
## 1125 chr18  88821  88823  0.000000000
## 1126 chr18  88839  88841  0.000000000
## 1127 chr18  88981  88983  0.000000000
## 1128 chr18  89150  89152  0.666666667
## 1129 chr18  89165  89167  0.666666667
## 1130 chr18  89233  89235  0.666666667
## 1131 chr18  89343  89345  0.666666667
## 1132 chr18  89361  89363  0.666666667
## 1133 chr18  89372  89374  0.666666667
## 1134 chr18  89546  89548  0.000000000
## 1135 chr18  89602  89604  0.000000000
## 1136 chr18  89634  89636  0.000000000
## 1137 chr18  89696  89698  0.000000000
## 1138 chr18  89740  89742  0.000000000
## 1139 chr18  89756  89758  0.000000000
## 1140 chr18  89808  89810  0.000000000
## 1141 chr18  89832  89834  0.000000000
## 1142 chr18  89838  89840  0.000000000
## 1143 chr18  90062  90064  0.000000000
## 1144 chr18  90104  90106  0.000000000
## 1145 chr18  90174  90176  0.333333333
## 1146 chr18  90184  90186  0.333333333
## 1147 chr18  90241  90243  0.333333333
## 1148 chr18  90333  90335  0.200000000
## 1149 chr18  90336  90338  0.200000000
## 1150 chr18  90360  90362  0.200000000
## 1151 chr18  90413  90415  0.685714286
## 1152 chr18  90472  90474  0.507936508
## 1153 chr18  90534  90536  0.949404762
## 1154 chr18  90572  90574  1.165032680
## 1155 chr18  90596  90598  0.540441176
## 1156 chr18  90626  90628  0.540441176
## 1157 chr18  90662  90664  0.540441176
## 1158 chr18  90674  90676  0.235294118
## 1159 chr18  90696  90698  0.235294118
## 1160 chr18  90788  90790  0.000000000
## 1161 chr18  90800  90802  0.000000000
## 1162 chr18  90822  90824  0.250000000
## 1163 chr18  90840  90842  0.250000000
## 1164 chr18  90869  90871  1.141025641
## 1165 chr18  90897  90899  1.141025641
## 1166 chr18  90905  90907  1.141025641
## 1167 chr18  90999  91001  0.076923077
## 1168 chr18  91288  91290  0.500000000
## 1169 chr18  91360  91362  0.500000000
## 1170 chr18  91483  91485  0.000000000
## 1171 chr18  91799  91801  0.000000000
## 1172 chr18  92085  92087  0.000000000
## 1173 chr18  92125  92127  0.000000000
## 1174 chr18  92210  92212  0.000000000
## 1175 chr18  92228  92230  0.000000000
## 1176 chr18  92359  92361  0.000000000
## 1177 chr18  92412  92414  0.000000000
## 1178 chr18  92505  92507  0.000000000
## 1179 chr18  92551  92553  0.000000000
## 1180 chr18  92701  92703  0.000000000
## 1181 chr18  92928  92930  0.000000000
## 1182 chr18  92932  92934  0.000000000
## 1183 chr18  93005  93007  0.000000000
## 1184 chr18  93014  93016  0.000000000
## 1185 chr18  93157  93159  0.000000000
## 1186 chr18  93187  93189  0.000000000
## 1187 chr18  93195  93197  0.000000000
## 1188 chr18  93238  93240  0.000000000
## 1189 chr18  93362  93364  0.000000000
## 1190 chr18  93555  93557  0.000000000
## 1191 chr18  93578  93580  0.000000000
## 1192 chr18  93597  93599  0.076923077
## 1193 chr18  93607  93609  0.076923077
## 1194 chr18  93640  93642  0.076923077
## 1195 chr18  93651  93653  0.320512821
## 1196 chr18  93690  93692  0.320512821
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## 1225 chr18  95492  95494  0.659340659
## 1226 chr18  95516  95518  0.659340659
## 1227 chr18  95537  95539  0.659340659
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## 1230 chr18  95717  95719  0.143939394
## 1231 chr18  95724  95726  0.319357367
## 1232 chr18  95735  95737  0.319357367
## 1233 chr18  95744  95746  0.319357367
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## 1236 chr18  95790  95792  0.701753803
## 1237 chr18  95835  95837  1.584693643
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## 1239 chr18  95904  95906  1.296703510
## 1240 chr18  95914  95916  1.296703510
## 1241 chr18  95922  95924  1.296703510
## 1242 chr18  95928  95930  1.296703510
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## 1253 chr18  96301  96303  1.718688197
## 1254 chr18  96310  96312  1.377008056
## 1255 chr18  96316  96318  1.377008056
## 1256 chr18  96329  96331  0.636777017
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## 1260 chr18  96421  96423  0.180952381
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## 1262 chr18  96467  96469  0.066666667
## 1263 chr18  96469  96471  0.066666667
## 1264 chr18  96481  96483  0.066666667
## 1265 chr18  96488  96490  0.066666667
## 1266 chr18  96492  96494  0.355555556
## 1267 chr18  96497  96499  0.355555556
## 1268 chr18  96532  96534  0.355555556
## 1269 chr18  96564  96566  0.111111111
## 1270 chr18  96570  96572  0.111111111
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## 1321 chr18  97398  97400  0.148965517
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## 1323 chr18  97430  97432  0.148965517
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## 1325 chr18  97459  97461  0.972413793
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## 1328 chr18  97519  97521  0.360000000
## 1329 chr18  97574  97576  0.360000000
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## 1340 chr18  97865  97867  0.503289474
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## 1359 chr18 100002 100004  0.250000000
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## 1362 chr18 100183 100185  1.000000000
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## 1388 chr18 103792 103794  0.200000000
## 1389 chr18 103823 103825  0.200000000
## 1390 chr18 103853 103855  0.166666667
## 1391 chr18 103865 103867  0.166666667
## 1392 chr18 103869 103871  0.166666667
## 1393 chr18 103897 103899  0.166666667
## 1394 chr18 103945 103947  0.166666667
## 1395 chr18 103971 103973  0.166666667
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## 1403 chr18 105443 105445  0.431818182
## 1404 chr18 105475 105477  1.147727273
## 1405 chr18 105481 105483  1.147727273
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## 1411 chr18 106555 106557  0.000000000
## 1412 chr18 106748 106750  5.000000000
## 1413 chr18 106942 106944  2.000000000
## 1414 chr18 107235 107237  1.000000000
## 1415 chr18 107486 107488 12.179688350
## 1416 chr18 107507 107509 16.583251873
## 1417 chr18 107540 107542 14.795794279
## 1418 chr18 107589 107591  6.840553745
## 1419 chr18 107632 107634  3.600711754
## 1420 chr18 108155 108157 36.738372093
## 1421 chr18 108222 108224 72.261627907
## 1422 chr18 108540 108542 10.000000000
## 1423 chr18 108747 108749  4.229465450
## 1424 chr18 108775 108777  7.611212516
## 1425 chr18 108889 108891 29.159322034
## 1426 chr18 109082 109084  4.400000000
## 1427 chr18 109146 109148  1.600000000
## 1428 chr18 109283 109285 25.000000000
## 1429 chr18 109490 109492 12.392123288
## 1430 chr18 109510 109512  7.101027397
## 1431 chr18 109566 109568 11.052303861
## 1432 chr18 109643 109645  3.454545455
## 1433 chr18 109859 109861  7.000000000
## 1434 chr18 110008 110010 14.599303136
## 1435 chr18 110023 110025  5.382839721
## 1436 chr18 110033 110035  4.017857143
## 1437 chr18 110112 110114  0.000000000
## 1438 chr18 110172 110174  0.000000000
## 1439 chr18 110771 110773 18.222222222
## 1440 chr18 110839 110841  8.177777778
## 1441 chr18 110921 110923  7.600000000
## 1442 chr18 111061 111063  5.000000000
## 1443 chr18 111263 111265  0.000000000
## 1444 chr18 111398 111400 18.809523810
## 1445 chr18 111498 111500  0.190476190
## 1446 chr18 111675 111677  1.019379845
## 1447 chr18 111678 111680  1.019379845
## 1448 chr18 111713 111715  0.621943948
## 1449 chr18 111741 111743  0.216457961
## 1450 chr18 111755 111757  0.342664668
## 1451 chr18 111762 111764  0.342664668
## 1452 chr18 111769 111771  0.494997502
## 1453 chr18 111776 111778  0.494997502
## 1454 chr18 111778 111780  0.494997502
## 1455 chr18 111798 111800  0.494997502
## 1456 chr18 111825 111827  0.271489951
## 1457 chr18 111829 111831  0.126694387
## 1458 chr18 111836 111838  0.126694387
## 1459 chr18 111841 111843  0.126694387
## 1460 chr18 111853 111855  0.126694387
## 1461 chr18 111861 111863  0.126694387
## 1462 chr18 111871 111873  0.126694387
## 1463 chr18 111875 111877  0.245848926
## 1464 chr18 111879 111881  0.245848926
## 1465 chr18 111883 111885  0.245848926
## 1466 chr18 111886 111888  0.245848926
## 1467 chr18 111892 111894  0.245848926
## 1468 chr18 111894 111896  0.245848926
## 1469 chr18 111900 111902  0.143846154
## 1470 chr18 111911 111913  0.143846154
## 1471 chr18 111916 111918  0.143846154
## 1472 chr18 111919 111921  0.069230769
## 1473 chr18 111939 111941  0.069230769
## 1474 chr18 111944 111946  0.069230769
## 1475 chr18 111946 111948  0.069230769
## 1476 chr18 111952 111954  0.069230769
## 1477 chr18 111955 111957  0.019230769
## 1478 chr18 111960 111962  0.019230769
## 1479 chr18 111962 111964  0.019230769
## 1480 chr18 111967 111969  0.019230769
## 1481 chr18 111984 111986  0.019230769
## 1482 chr18 111993 111995  0.019230769
## 1483 chr18 111996 111998  0.019230769
## 1484 chr18 111998 112000  0.019230769
## 1485 chr18 112005 112007  0.019230769
## 1486 chr18 112043 112045  0.000000000
## 1487 chr18 112046 112048  0.000000000
## 1488 chr18 112048 112050  0.000000000
## 1489 chr18 112055 112057  0.000000000
## 1490 chr18 112061 112063  0.000000000
## 1491 chr18 112085 112087  0.000000000
## 1492 chr18 112093 112095  0.000000000
## 1493 chr18 112096 112098  0.000000000
## 1494 chr18 112106 112108  0.000000000
## 1495 chr18 112117 112119  0.000000000
## 1496 chr18 112133 112135  0.003773585
## 1497 chr18 112154 112156  0.458176101
## 1498 chr18 112162 112164  1.098560254
## 1499 chr18 112170 112172  1.853142488
## 1500 chr18 112172 112174  2.032811922
## 1501 chr18 112174 112176  2.438935974
## 1502 chr18 112178 112180  2.438935974
## 1503 chr18 112187 112189  2.950834502
## 1504 chr18 112211 112213  2.950834502
## 1505 chr18 112226 112228  2.950834502
## 1506 chr18 112256 112258  3.663112315
## 1507 chr18 112276 112278  4.604629639
## 1508 chr18 112309 112311  1.615448114
## 1509 chr18 112318 112320  0.681049719
## 1510 chr18 112330 112332  0.225133100
## 1511 chr18 112335 112337  0.156985093
## 1512 chr18 112343 112345  0.156985093
## 1513 chr18 112351 112353  0.156985093
## 1514 chr18 112372 112374  0.156985093
## 1515 chr18 112374 112376  0.156985093
## 1516 chr18 112389 112391  0.156985093
## 1517 chr18 112399 112401  0.091876751
## 1518 chr18 112408 112410  0.000000000
## 1519 chr18 112414 112416  0.000000000
## 1520 chr18 112425 112427  0.000000000
## 1521 chr18 112427 112429  0.000000000
## 1522 chr18 112453 112455  0.000000000
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## 1524 chr18 112485 112487  0.000000000
## 1525 chr18 112490 112492  0.000000000
## 1526 chr18 112500 112502  0.000000000
## 1527 chr18 112518 112520  0.000000000
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## 1529 chr18 112885 112887  0.000000000
## 1530 chr18 112891 112893  0.000000000
## 1531 chr18 112929 112931  0.000000000
## 1532 chr18 112992 112994  0.000000000
## 1533 chr18 113024 113026  0.000000000
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## 1541 chr18 114102 114104  1.000000000
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## 1557 chr18 116022 116024  0.000000000
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## 1559 chr18 116853 116855  0.000000000
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## 1566 chr18 117707 117709  0.000000000
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## 1584 chr18 119717 119719  0.250000000
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## 1586 chr18 119831 119833  0.900000000
## 1587 chr18 119886 119888  1.145454545
## 1588 chr18 119956 119958  0.363636364
## 1589 chr18 119966 119968  1.045454545
## 1590 chr18 119976 119978  1.045454545
## 1591 chr18 120215 120217  0.000000000
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## 1627 chr18 125241 125243  0.153846154
## 1628 chr18 125245 125247  0.153846154
## 1629 chr18 125247 125249  0.153846154
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## 1631 chr18 125335 125337  0.656177156
## 1632 chr18 125369 125371  0.656177156
## 1633 chr18 125379 125381  0.656177156
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## 1635 chr18 125391 125393  0.174242424
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## 1646 chr18 125791 125793  0.125000000
## 1647 chr18 125835 125837  0.125000000
## 1648 chr18 125843 125845  0.125000000
## 1649 chr18 125866 125868  0.000000000
## 1650 chr18 125924 125926  0.000000000
## 1651 chr18 126153 126155  0.000000000
## 1652 chr18 126199 126201  0.000000000
## 1653 chr18 126389 126391  0.000000000
## 1654 chr18 126531 126533  0.000000000
## 1655 chr18 126557 126559  0.000000000
## 1656 chr18 127486 127488  0.500000000
## 1657 chr18 127566 127568  0.500000000
## 1658 chr18 127740 127742  1.000000000
## 1659 chr18 127786 127788  0.000000000
## 1660 chr18 127804 127806  0.000000000
## 1661 chr18 127865 127867  0.000000000
## 1662 chr18 127991 127993  0.000000000
## 1663 chr18 128194 128196  0.000000000
## 1664 chr18 128434 128436  0.000000000
## 1665 chr18 128480 128482  0.000000000
## 1666 chr18 128845 128847  0.000000000
## 1667 chr18 128886 128888  0.000000000
## 1668 chr18 129015 129017  0.000000000
## 1669 chr18 129040 129042  0.000000000
## 1670 chr18 129175 129177  0.000000000
## 1671 chr18 129211 129213  0.000000000
## 1672 chr18 129429 129431  0.000000000
## 1673 chr18 129450 129452  0.000000000
## 1674 chr18 129659 129661  1.000000000
## 1675 chr18 129819 129821  0.500000000
## 1676 chr18 129832 129834  0.500000000
## 1677 chr18 130108 130110  0.000000000
## 1678 chr18 130228 130230  0.000000000
## 1679 chr18 130530 130532  0.000000000
## 1680 chr18 130645 130647  0.000000000
## 1681 chr18 130788 130790  0.000000000
## 1682 chr18 130920 130922  0.000000000
## 1683 chr18 130943 130945  0.000000000
## 1684 chr18 131138 131140  0.000000000
## 1685 chr18 131221 131223  1.000000000
## 1686 chr18 131264 131266  1.000000000
## 1687 chr18 131800 131802  0.000000000
## 1688 chr18 131925 131927  0.000000000
## 1689 chr18 131941 131943  0.000000000
## 1690 chr18 132001 132003  1.000000000
## 1691 chr18 132151 132153  0.000000000
## 1692 chr18 132331 132333  0.000000000
## 1693 chr18 132834 132836  0.725013291
## 1694 chr18 132842 132844  0.725013291
## 1695 chr18 132844 132846  0.725013291
## 1696 chr18 132854 132856  1.110015949
## 1697 chr18 132866 132868  1.110015949
## 1698 chr18 132887 132889  1.110015949
## 1699 chr18 132914 132916  0.282280702
## 1700 chr18 132945 132947  0.132631579
## 1701 chr18 132973 132975  0.580000000
## 1702 chr18 133009 133011  0.250000000
## 1703 chr18 133041 133043  0.250000000
## 1704 chr18 133263 133265  0.000000000
## 1705 chr18 133456 133458  0.000000000
## 1706 chr18 133869 133871  0.000000000
## 1707 chr18 133922 133924  1.000000000
## 1708 chr18 133975 133977  1.000000000
## 1709 chr18 134084 134086  0.000000000
## 1710 chr18 134296 134298  0.555555556
## 1711 chr18 134349 134351  1.844444444
## 1712 chr18 134355 134357  0.883333333
## 1713 chr18 134450 134452  1.150000000
## 1714 chr18 134472 134474  0.566666667
## 1715 chr18 134681 134683  0.000000000
## 1716 chr18 135212 135214  1.000000000
## 1717 chr18 135452 135454  0.000000000
## 1718 chr18 135516 135518  0.000000000
## 1719 chr18 135915 135917  0.000000000
## 1720 chr18 135973 135975  0.000000000
## 1721 chr18 136353 136355  0.000000000
## 1722 chr18 136458 136460  3.350000000
## 1723 chr18 136469 136471  3.350000000
## 1724 chr18 136601 136603  3.856776557
## 1725 chr18 136629 136631  0.778388278
## 1726 chr18 136670 136672  0.296703297
## 1727 chr18 136691 136693  0.296703297
## 1728 chr18 136704 136706  0.071428571
## 1729 chr18 136952 136954  0.869701941
## 1730 chr18 136956 136958  0.869701941
## 1731 chr18 136974 136976  0.869701941
## 1732 chr18 136997 136999  0.869701941
## 1733 chr18 137001 137003  0.495761553
## 1734 chr18 137031 137033  0.559431803
## 1735 chr18 137061 137063  0.953701279
## 1736 chr18 137071 137073  0.953701279
## 1737 chr18 137073 137075  0.682314706
## 1738 chr18 137094 137096  0.471633630
## 1739 chr18 137115 137117  1.269950444
## 1740 chr18 137132 137134  1.667466306
## 1741 chr18 137149 137151  2.213523281
## 1742 chr18 137155 137157  2.213523281
## 1743 chr18 137187 137189  1.040184672
## 1744 chr18 137344 137346  0.000000000
## 1745 chr18 137435 137437  0.000000000
## 1746 chr18 137500 137502  0.000000000
## 1747 chr18 137578 137580  0.000000000
## 1748 chr18 137694 137696  0.000000000
## 1749 chr18 137788 137790  0.000000000
## 1750 chr18 137828 137830  1.000000000
## 1751 chr18 137971 137973  0.333333333
## 1752 chr18 138036 138038  0.333333333
## 1753 chr18 138046 138048  0.333333333
## 1754 chr18 138213 138215  1.777777778
## 1755 chr18 138233 138235  3.222222222
## 1756 chr18 138364 138366  1.500000000
## 1757 chr18 138372 138374  1.500000000
## 1758 chr18 138780 138782  1.000000000
## 1759 chr18 138899 138901  0.000000000
## 1760 chr18 138913 138915  0.000000000
## 1761 chr18 138991 138993  0.000000000
## 1762 chr18 139301 139303  2.333333333
## 1763 chr18 139345 139347  2.333333333
## 1764 chr18 139387 139389  0.333333333
## 1765 chr18 139445 139447  0.000000000
## 1766 chr18 139678 139680  0.000000000
## 1767 chr18 139766 139768  0.000000000
## 1768 chr18 139835 139837  0.000000000
## 1769 chr18 139850 139852  1.000000000
## 1770 chr18 140054 140056  0.500000000
## 1771 chr18 140065 140067  0.500000000
## 1772 chr18 140250 140252  0.000000000
## 1773 chr18 140404 140406  0.000000000
## 1774 chr18 140433 140435  0.333333333
## 1775 chr18 140469 140471  0.333333333
## 1776 chr18 140549 140551  0.333333333
## 1777 chr18 140758 140760  0.250000000
## 1778 chr18 140865 140867  1.226470588
## 1779 chr18 140899 140901  0.619327731
## 1780 chr18 140905 140907  1.047992530
## 1781 chr18 141001 141003  3.071486928
## 1782 chr18 141009 141011  3.437500000
## 1783 chr18 141130 141132  0.347222222
## 1784 chr18 141405 141407  0.392857143
## 1785 chr18 141442 141444  0.839285714
## 1786 chr18 141446 141448  0.839285714
## 1787 chr18 141500 141502  0.309523810
## 1788 chr18 141519 141521  0.309523810
## 1789 chr18 141536 141538  0.309523810
## 1790 chr18 141612 141614  0.666666667
## 1791 chr18 141681 141683  2.333333333
## 1792 chr18 141770 141772  3.000000000
## 1793 chr18 141880 141882  0.500000000
## 1794 chr18 141935 141937  0.500000000
## 1795 chr18 142055 142057  0.000000000
## 1796 chr18 142221 142223  1.068965517
## 1797 chr18 142272 142274  0.143039591
## 1798 chr18 142281 142283  0.318007663
## 1799 chr18 142340 142342  0.842512771
## 1800 chr18 142344 142346  0.842512771
## 1801 chr18 142356 142358  1.283742598
## 1802 chr18 142366 142368  1.283742598
## 1803 chr18 142398 142400  0.569749216
## 1804 chr18 142432 142434  0.323863636
## 1805 chr18 142478 142480  0.323863636
## 1806 chr18 142585 142587  0.000000000
## 1807 chr18 142816 142818  0.000000000
## 1808 chr18 142876 142878  1.000000000
## 1809 chr18 143008 143010  0.000000000
## 1810 chr18 143209 143211  0.403846154
## 1811 chr18 143225 143227  0.625418060
## 1812 chr18 143251 143253  0.900820194
## 1813 chr18 143269 143271  0.619288663
## 1814 chr18 143297 143299  3.234537188
## 1815 chr18 143309 143311  3.234537188
## 1816 chr18 143349 143351  2.862450449
## 1817 chr18 143427 143429  1.425398535
## 1818 chr18 143437 143439  0.739739374
## 1819 chr18 143462 143464  0.483375959
## 1820 chr18 143525 143527  1.270588235
## 1821 chr18 143556 143558  0.975000000
## 1822 chr18 143564 143566  0.975000000
## 1823 chr18 143650 143652  1.250000000
## 1824 chr18 143802 143804  0.666666667
## 1825 chr18 143854 143856  0.666666667
## 1826 chr18 143874 143876  0.666666667
## 1827 chr18 144092 144094  1.300802139
## 1828 chr18 144120 144122  2.120248591
## 1829 chr18 144129 144131  2.120248591
## 1830 chr18 144139 144141  2.120248591
## 1831 chr18 144167 144169  0.589680590
## 1832 chr18 144176 144178  0.589680590
## 1833 chr18 144265 144267  1.605757576
## 1834 chr18 144275 144277  1.240000000
## 1835 chr18 144298 144300  1.240000000
## 1836 chr18 144319 144321  1.240000000
## 1837 chr18 144359 144361  0.833333333
## 1838 chr18 144418 144420  0.000000000
## 1839 chr18 144917 144919  0.000000000
## 1840 chr18 145108 145110  0.000000000
## 1841 chr18 145537 145539  0.000000000
## 1842 chr18 145546 145548  0.000000000
## 1843 chr18 145690 145692  0.000000000
## 1844 chr18 145793 145795  1.000000000
## 1845 chr18 145833 145835  1.000000000
## 1846 chr18 146361 146363  0.000000000
## 1847 chr18 146502 146504  0.500000000
## 1848 chr18 146564 146566  0.500000000
## 1849 chr18 146648 146650  0.313131313
## 1850 chr18 146718 146720  2.168350168
## 1851 chr18 146727 146729  2.168350168
## 1852 chr18 146736 146738  2.168350168
## 1853 chr18 146770 146772  1.181818182
## 1854 chr18 146885 146887  0.000000000
## 1855 chr18 146893 146895  0.000000000
## 1856 chr18 146901 146903  0.000000000
## 1857 chr18 146923 146925  0.000000000
## 1858 chr18 146925 146927  0.000000000
## 1859 chr18 146931 146933  0.000000000
## 1860 chr18 146948 146950  0.000000000
## 1861 chr18 146955 146957  0.000000000
## 1862 chr18 146963 146965  0.000000000
## 1863 chr18 146976 146978  0.000000000
## 1864 chr18 146987 146989  0.000000000
## 1865 chr18 147007 147009  0.000000000
## 1866 chr18 147011 147013  0.000000000
## 1867 chr18 147019 147021  0.000000000
## 1868 chr18 147023 147025  0.000000000
## 1869 chr18 147055 147057  1.000000000
## 1870 chr18 147066 147068  1.000000000
## 1871 chr18 147086 147088  1.000000000
## 1872 chr18 147100 147102  1.000000000
## 1873 chr18 147107 147109  1.000000000
## 1874 chr18 147111 147113  1.000000000
## 1875 chr18 147116 147118  1.000000000
## 1876 chr18 147144 147146  1.000000000
## 1877 chr18 147154 147156  1.000000000
## 1878 chr18 147160 147162  1.000000000
## 1879 chr18 147245 147247  0.000000000
## 1880 chr18 147355 147357  0.276190476
## 1881 chr18 147359 147361  0.276190476
## 1882 chr18 147361 147363  0.276190476
## 1883 chr18 147371 147373  0.276190476
## 1884 chr18 147415 147417  0.276190476
## 1885 chr18 147429 147431  0.276190476
## 1886 chr18 147449 147451  0.276190476
## 1887 chr18 147460 147462  0.066666667
## 1888 chr18 147502 147504  0.333333333
## 1889 chr18 147510 147512  0.333333333
## 1890 chr18 147534 147536  0.333333333
## 1891 chr18 147558 147560  0.333333333
## 1892 chr18 147566 147568  0.333333333
## 1893 chr18 147573 147575  0.333333333
## 1894 chr18 147596 147598  0.333333333
## 1895 chr18 147598 147600  0.333333333
## 1896 chr18 147627 147629  0.333333333
## 1897 chr18 147730 147732  0.000000000
## 1898 chr18 147768 147770  0.000000000
## 1899 chr18 147772 147774  0.000000000
## 1900 chr18 148033 148035  1.000000000
## 1901 chr18 148118 148120  1.000000000
## 1902 chr18 148465 148467  0.000000000
## 1903 chr18 148702 148704  0.500000000
## 1904 chr18 148719 148721  0.500000000
## 1905 chr18 148765 148767  0.142857143
## 1906 chr18 148773 148775  0.535714286
## 1907 chr18 148835 148837  0.535714286
## 1908 chr18 148862 148864  0.535714286
## 1909 chr18 148911 148913  0.125000000
## 1910 chr18 148920 148922  0.125000000
## 1911 chr18 149027 149029  0.000000000
## 1912 chr18 149193 149195  0.428571429
## 1913 chr18 149220 149222  0.428571429
## 1914 chr18 149255 149257  1.402597403
## 1915 chr18 149306 149308  2.837229437
## 1916 chr18 149381 149383  2.282284382
## 1917 chr18 149390 149392  2.282284382
## 1918 chr18 149408 149410  0.628205128
## 1919 chr18 149441 149443  1.128846154
## 1920 chr18 149451 149453  1.900320513
## 1921 chr18 149506 149508  0.514423077
## 1922 chr18 149589 149591  0.833333333
## 1923 chr18 149656 149658  0.333333333
## 1924 chr18 149751 149753  0.000000000
## 1925 chr18 149808 149810  1.000000000
## 1926 chr18 149966 149968  0.000000000
## 1927 chr18 150052 150054  0.000000000
## 1928 chr18 150105 150107  0.000000000
## 1929 chr18 150348 150350  0.000000000
## 1930 chr18 150384 150386  0.000000000
## 1931 chr18 150406 150408  0.000000000
## 1932 chr18 150412 150414  0.000000000
## 1933 chr18 150571 150573  0.000000000
## 1934 chr18 150604 150606  0.000000000
## 1935 chr18 150631 150633  0.000000000
## 1936 chr18 150662 150664  1.000000000
## 1937 chr18 150691 150693  1.000000000
## 1938 chr18 151049 151051  0.000000000
## 1939 chr18 151103 151105  0.000000000
## 1940 chr18 151114 151116  0.000000000
## 1941 chr18 151281 151283  2.200000000
## 1942 chr18 151318 151320  0.800000000
## 1943 chr18 151426 151428  0.000000000
## 1944 chr18 151454 151456  0.000000000
## 1945 chr18 152036 152038  3.000000000
## 1946 chr18 152398 152400  1.666666667
## 1947 chr18 152470 152472  0.333333333
## 1948 chr18 152720 152722  0.000000000
## 1949 chr18 152736 152738  0.000000000
## 1950 chr18 152744 152746  0.000000000
## 1951 chr18 152783 152785  0.000000000
## 1952 chr18 153065 153067  0.000000000
## 1953 chr18 153209 153211  1.000000000
## 1954 chr18 153295 153297  0.000000000
## 1955 chr18 153352 153354  0.000000000
## 1956 chr18 153482 153484  0.000000000
## 1957 chr18 153521 153523  0.140740741
## 1958 chr18 153545 153547  0.304861111
## 1959 chr18 153550 153552  0.304861111
## 1960 chr18 153582 153584  0.304861111
## 1961 chr18 153613 153615  0.580394525
## 1962 chr18 153636 153638  0.580394525
## 1963 chr18 153640 153642  0.580394525
## 1964 chr18 153645 153647  0.580394525
## 1965 chr18 153661 153663  0.324184783
## 1966 chr18 153683 153685  0.149456522
## 1967 chr18 153689 153691  0.149456522
## 1968 chr18 153791 153793  0.062500000
## 1969 chr18 153875 153877  1.247282609
## 1970 chr18 153887 153889  1.247282609
## 1971 chr18 153891 153893  1.247282609
## 1972 chr18 153951 153953  1.559782609
## 1973 chr18 153979 153981  0.635869565
## 1974 chr18 154304 154306  0.000000000
## 1975 chr18 154357 154359  1.300000000
## 1976 chr18 154365 154367  1.300000000
## 1977 chr18 154484 154486  0.981818182
## 1978 chr18 154522 154524  0.792344498
## 1979 chr18 154527 154529  0.792344498
## 1980 chr18 154536 154538  0.792344498
## 1981 chr18 154554 154556  0.792344498
## 1982 chr18 154616 154618  0.196172249
## 1983 chr18 154626 154628  0.052631579
## 1984 chr18 154670 154672  0.500000000
## 1985 chr18 154687 154689  0.500000000
## 1986 chr18 154882 154884  1.000000000
## 1987 chr18 155278 155280  0.444444444
## 1988 chr18 155287 155289  1.000000000
## 1989 chr18 155308 155310  2.000000000
## 1990 chr18 155413 155415  0.555555556
## 1991 chr18 155565 155567  0.000000000
## 1992 chr18 155576 155578  0.000000000
## 1993 chr18 155660 155662  0.000000000
## 1994 chr18 155676 155678  0.000000000
## 1995 chr18 155704 155706  0.000000000
## 1996 chr18 155797 155799  0.000000000
## 1997 chr18 155847 155849  0.000000000
## 1998 chr18 155868 155870  0.000000000
## 1999 chr18 155915 155917  0.000000000
## 2000 chr18 155969 155971  0.000000000

5 p-values of SIMD test

In order to detect different methylated CpG sites, we should calculate p-value of each site. The below codes are calculate p-value of each site with function EMtest(). The input files which include “datafile”, “cpgfile” and “mrecpgfile” are should have been generated by Step 1. The output file “writefile” will owneleven columns, that is, “chr”, “chrSt”,“chrEnd”, “Medip1”,“Medip2”, “MRE1”, “MRE2”, “cg”,“mrecg”,“pvalue”,“Ts”. We also output a reportfile which will include parameters “s1/s2”; “s3/s4”; “N1”; “N2”; “N3”; “N4”; “c1”; “c2” and “Spend time”.

data(example_data)
data1 <- EM2_H1ESB1_MeDIP_sigleCpG
data2 <- EM2_H1ESB2_MeDIP_sigleCpG
data3 <- H1ESB1_MRE_sigleCpG
data4 <- H1ESB2_MRE_sigleCpG
datafile <- cbind(data1,data2,data3,data4)
allcpg <- all_CpGsite_bin_chr18
mrecpg <- three_mre_cpg
dirwrite <-paste(setwd(getwd()), "/", sep="")

writefile <- paste(dirwrite, "pval_EM_H1ESB1_H1ESB21.bed", sep="")
reportfile <- paste(dirwrite, "report_pvalH1ESB1_H1ESB21.bed", sep="")

EMtest(datafile=datafile, chrstring=NULL, cpgfile=allcpg,mrecpgfile=mrecpg, 
       writefile=writefile, reportfile=reportfile,mreratio=3/7, psd=2, 
       mkadded=1, f=1)
## reading data ....
## adjustment weight f is :
## [1] 1
## Top line of dataset:
##      V1    V2    V3       V4 data2[, 4] data3[, 4] data4[, 4]
## 1 chr18 10692 10694 8.824992   7.185892          0          0
##      V1    V2    V3 V4
## 1 chr18 10692 10694  1
##      V1    V2    V3 V4
## 1 chr18 10692 10694  0
## Computing p-values for only MeDIP-seq windows: 1286
## Computing p-values for MeDIP-seq
##                     and MRE-seq windows: 714
## Exact compute p-values with product binomial distribution.
## Output to writefile.
## The End.

6 Select Significants

After getting p-values, we choose differentially expressed methylated CpG sites with p-values. The input file is the file which have been generated by Step 2. Then we assume the sites to be differentially expressed methylated CpGs when p-values less than pre-setting cutoffs, such as 10−3 or 10−5.