Human Molecular Genetics Advance Access originally published online on June 22, 2005
Human Molecular Genetics 2005 14(15):2135-2143; doi:10.1093/hmg/ddi218
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Interindividual variability and parent of origin DNA methylation differences at specific human Alu elements
1Fels Institute for Cancer Research and Molecular Biology, 2Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA, 3The Research Institute of McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada, 4Eccles Institute of Human Genetics and Department of Human Genetics, University of Utah, 15 N 2030 E, Salt Lake City, UT 84112, USA, 5Bucknell University, 701 Moore Avenue, Lewisburg, PA 17837, USA and 6College of Science and Technology, Temple University, 1900 North 13th Street, Philadelphia, PA 19122, USA
* To whom correspondence should be addressed. Tel: +1 2157077373; Fax: +1 2157071454; Email: sapienza{at}temple.edu
Received April 7, 2005; Revised May 30, 2005; Accepted June 14, 2005
We investigated the CpG methylation of 19 specific members of Alu sub-families in human DNA isolated from whole blood, using an assay based on methylation-sensitive restriction endonuclease digestion of genomic DNA and ‘hot-stop’ polymerase chain reaction. 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, whereas 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.
Present address: Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK.
Present address: Department of Molecular, Cellular and Developmental Biology, KBT 1044, Yale University, 219 Prospect Street, New Haven, CT 06511, USA.
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