Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray

被引:1072
作者
Chen, Yi-an [1 ,2 ]
Lemire, Mathieu [3 ]
Choufani, Sanaa [1 ]
Butcher, Darci T. [1 ]
Grafodatskaya, Daria [1 ]
Zanke, Brent W. [3 ,4 ]
Gallinger, Steven [5 ]
Hudson, Thomas J. [3 ,6 ]
Weksberg, Rosanna [1 ,2 ,7 ,8 ]
机构
[1] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada
[2] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada
[3] Ontario Inst Canc Res, Toronto, ON, Canada
[4] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada
[5] Univ Hlth Network, Toronto Gen Hosp, Dept Surg, Toronto, ON, Canada
[6] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[7] Univ Toronto, Dept Med Genet, Toronto, ON, Canada
[8] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada
关键词
DNA methylation; CpGs; oligonucleotide probe; Illumina microarray; SNPs; polymorphic CpG; cross-reactive probe; DNA METHYLATION; SUBSET-QUANTILE; NORMALIZATION;
D O I
10.4161/epi.23470
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
DNA methylation, an important type of epigenetic modification in humans, participates in crucial cellular processes, such as embryonic development, X-inactivation, genomic imprinting and chromosome stability. Several platforms have been developed to study genome-wide DNA methylation. Many investigators in the field have chosen the Illumina Infinium HumanMethylation microarray for its ability to reliably assess DNA methylation following sodium bisulfite conversion. Here, we analyzed methylation profiles of 489 adult males and 357 adult females generated by the Infinium HumanMethylation450 microarray. Among the autosomal CpG sites that displayed significant methylation differences between the two sexes, we observed a significant enrichment of cross-reactive probes co-hybridizing to the sex chromosomes with more than 94% sequence identity. This could lead investigators to mistakenly infer the existence of significant autosomal sex-associated methylation. Using sequence identity cutoffs derived from the sex methylation analysis, we concluded that 6% of the array probes can potentially generate spurious signals because of co-hybridization to alternate genomic sequences highly homologous to the intended targets. Additionally, we discovered probes targeting polymorphic CpGs that overlapped SNPs. The methylation levels detected by these probes are simply the reflection of underlying genetic polymorphisms but could be misinterpreted as true signals. The existence of probes that are cross-reactive or of target polymorphic CpGs in the Illumina HumanMethylation microarrays can confound data obtained from such microarrays. Therefore, investigators should exercise caution when significant biological associations are found using these array platforms. A list of all cross-reactive probes and polymorphic CpGs identified by us are annotated in this paper.
引用
收藏
页码:203 / 209
页数:7
相关论文
共 16 条
[1]   Parental ages and levels of DNA methylation in the newborn are correlated [J].
Adkins, Ronald M. ;
Thomas, Fridtjof ;
Tylavsky, Frances A. ;
Krushkal, Julia .
BMC MEDICAL GENETICS, 2011, 12
[2]   Racial Differences in Gene-Specific DNA Methylation Levels are Present at Birth [J].
Adkins, Ronald M. ;
Krushkal, Julia ;
Tylavsky, Frances A. ;
Thomas, Fridtjof .
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, 2011, 91 (08) :728-736
[3]   A map of human genome variation from population-scale sequencing [J].
Altshuler, David ;
Durbin, Richard M. ;
Abecasis, Goncalo R. ;
Bentley, David R. ;
Chakravarti, Aravinda ;
Clark, Andrew G. ;
Collins, Francis S. ;
De la Vega, Francisco M. ;
Donnelly, Peter ;
Egholm, Michael ;
Flicek, Paul ;
Gabriel, Stacey B. ;
Gibbs, Richard A. ;
Knoppers, Bartha M. ;
Lander, Eric S. ;
Lehrach, Hans ;
Mardis, Elaine R. ;
McVean, Gil A. ;
Nickerson, DebbieA. ;
Peltonen, Leena ;
Schafer, Alan J. ;
Sherry, Stephen T. ;
Wang, Jun ;
Wilson, Richard K. ;
Gibbs, Richard A. ;
Deiros, David ;
Metzker, Mike ;
Muzny, Donna ;
Reid, Jeff ;
Wheeler, David ;
Wang, Jun ;
Li, Jingxiang ;
Jian, Min ;
Li, Guoqing ;
Li, Ruiqiang ;
Liang, Huiqing ;
Tian, Geng ;
Wang, Bo ;
Wang, Jian ;
Wang, Wei ;
Yang, Huanming ;
Zhang, Xiuqing ;
Zheng, Huisong ;
Lander, Eric S. ;
Altshuler, David L. ;
Ambrogio, Lauren ;
Bloom, Toby ;
Cibulskis, Kristian ;
Fennell, Tim J. ;
Gabriel, Stacey B. .
NATURE, 2010, 467 (7319) :1061-1073
[4]   Genome-wide DNA methylation profiling using Infinium® assay [J].
Bibikova, Marina ;
Le, Jennie ;
Barnes, Bret ;
Saedinia-Melnyk, Shadi ;
Zhou, Lixin ;
Shen, Richard ;
Gunderson, Kevin L. .
EPIGENOMICS, 2009, 1 (01) :177-200
[5]   Associations with early-life socio-economic position in adult DNA methylation [J].
Borghol, Nada ;
Suderman, Matthew ;
McArdle, Wendy ;
Racine, Ariane ;
Hallett, Michael ;
Pembrey, Marcus ;
Hertzman, Clyde ;
Power, Chris ;
Szyf, Moshe .
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2012, 41 (01) :62-74
[6]   Sequence overlap between autosomal and sex-linked probes on the Illumina HumanMethylation27 microarray [J].
Chen, Yi-an ;
Choufani, Sanaa ;
Ferreira, Jose Carlos ;
Grafodatskaya, Daria ;
Butcher, Darci T. ;
Weksberg, Rosanna .
GENOMICS, 2011, 97 (04) :214-222
[7]  
Dedeurwaerder S, 2011, EPIGENOMICS-UK, V3, P771, DOI [10.2217/epi.11.105, 10.2217/EPI.11.105]
[8]   Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals [J].
Jaenisch, R ;
Bird, A .
NATURE GENETICS, 2003, 33 (Suppl 3) :245-254
[9]   Cancer epigenetics comes of age [J].
Jones, PA ;
Laird, PW .
NATURE GENETICS, 1999, 21 (02) :163-167
[10]  
Kent WJ, 2002, GENOME RES, V12, P656, DOI [10.1101/gr.229202, 10.1101/gr.229202. Article published online before March 2002]