Human Molecular Genetics Advance Access published online on June 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi218
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1 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA; Present address: Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK
* To whom correspondence should be addressed. We investigated the CpG methylation of 19 specific members of Alu subfamilies in human DNA isolated from whole blood, using an assay based on methylation-sensitive restriction endonuclease digestion of genomic DNA and ‘hot-stop’ PCR. We found significant interindividual variability in the level of methylation for specific Alu elements among the members of 48, three-generation families. Surprisingly, some of the elements also displayed quantitative parent of origin methylation differences; i.e., the mean level of methylation differed significantly when the insertions were transmitted through paternal versus maternal meiosis. Bisulfite sequence analysis of individual elements at such loci suggests, further, that maternal and paternal elements differ in the propensity of particular CpG sites to become unmethylated. Some individuals who exhibited high levels of methylation at specific Alu elements came from families in which more than one member also exhibited abnormal patterns of methylation at the differentially methylated regions of the IGF2/H19 or IGF2R loci, suggesting that there may be heritable differences between individuals in the fidelity with which allelic DNA methylation differences are established or maintained. Quantitative parental origin differences in methylation were identified only for Alu elements that lie in sub-telomeric or sub-centromeric bands of human chromosomes, while those assayed at intermediate positions did not exhibit any significant differences. The centromere/telomere restricted location of the methylation differences and the fact that none of these differences occur in regions of chromosomes known to contain transcriptionally imprinted genes suggest that maternal/paternal epigenetic modifications may play additional roles in processes other than transcriptional control.
Received April 7, 2005
Revised May 30, 2005
Accepted June 14, 2005
Article
Interindividual variability and parent of origin DNA methylation differences at specific human Alu elements
2 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA
3 The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4
4 Eccles Institute of Human Genetics, and Department of Human Genetics, University of Utah, 15 N 2030 E, Salt Lake City, UT 84112, USA
5 Bucknell University, 701 Moore Avenue, Lewisburg, PA 17837, USA; Present address: Department of Molecular, Cellular and Developmental Biology, KBT 1044, Yale University, 219 Prospect Street, New Haven, CT 06511, USA
6 College of Science and Technology, Temple University, 1900 North 13th Street, Philadelphia, PA 19122, USA
7 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA; Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA
Carmen Sapienza, E-mail: esapienza{at}temple.edu
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