Genome-wide DNA methylation analysis of uniparental disomy cases reveals many novel imprinted loci in the human genome. R. S. Joshi, P. Garg, C. Borel, F. Cheung, A. Guilmatre, A. J. Sharp Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY.

   Genomic imprinting is a mechanism in which the expression of genes varies depending on whether they are maternally or paternally inherited. Imprinting occurs through an epigenetic mechanism involving differential DNA methylation and histone modifications on the two parental alleles, with most imprinted genes marked by CpG-rich differentially methylated regions (DMRs). Approximately 70 human imprinted genes have been identified to date, and imprinted loci have been associated both with rare syndromes, and with common diseases including diabetes and cancer. Previously we showed that DNA methylation profiling in cases of uniparental disomy (UPD) provides a unique system that allows the isolated study of DNA derived from a single parent (PMID: 20631049). We have assembled an unprecedented collection of DNA from 113 patients with UPD for 18 different chromosomes, allowing the efficient detection of DMRs associated with imprinted genes for 84% of the human genome. We performed DNA methylation profiling in our UPD cohort using Illumina Infinium 450K Methylation BeadArrays that yield quantitative data on ~482,000 CpGs at single-nucleotide resolution. Imprinted DMRs were defined by sites at which the maternal and paternal methylation levels for multiple probes diverged significantly from the biparental average. Using stringent thresholds, we were able to detect 19 out of 20 (95%) previously described DMRs, validating our methodology for the detection of imprinted loci. Using these same criteria we identified a total of 46 DMRs spanning all 16 chromosomes analysed, 27 of which were not previously described. This included novel DMRs on chromosomes 3, 5, 21 and 22 which have previously been considered to be devoid of imprinting, highlighting potential parent-of-origin effects in chromosomal aneuploidies such as Down syndrome. The quantitative nature of our data also allowed us to detect subtle but consistent reciprocal methylation differences between the two parental alleles that encompass hundreds of CpG sites extending across large (>1Mb) chromosomal regions at known imprinted regions such as 15q11-q13. We confirmed novel DMRs by bisulfite sequencing of informative trios to determine parent-of-origin methylation marks. Our data provide the first comprehensive genome-wide map of imprinted sites in the human genome, and provide novel insights into potential parent of origin effects in a variety of human disorders.

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