title: Information recovery from low coverage whole-genome bisulfite sequencing.
abstract: The cost of whole-genome bisulfite sequencing (WGBS) remains a bottleneck for many studies and it is therefore imperative to extract as much information as possible from a given dataset. This is particularly important because even at the recommend 30X coverage for reference methylomes, up to 50% of high-resolution features such as differentially methylated positions (DMPs) cannot be called with current methods as determined by saturation analysis. To address this limitation, we have developed a tool that dynamically segments WGBS methylomes into blocks of comethylation (COMETs) from which lost information can be recovered in the form of differentially methylated COMETs (DMCs). Using this tool, we demonstrate recovery of ∼30% of the lost DMP information content as DMCs even at very low (5X) coverage. This constitutes twice the amount that can be recovered using an existing method based on differentially methylated regions (DMRs). In addition, we explored the relationship between COMETs and haplotypes in lymphoblastoid cell lines of African and European origin. Using best fit analysis, we show COMETs to be correlated in a population-specific manner, suggesting that this type of dynamic segmentation may be useful for integrated (epi)genome-wide association studies in the future.
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Libertini
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Torre I, 08028 Barcelona, Spain.
authors.forename: Simon C
authors.identifier: 0000-0002-9550-0897
authors.initials: SC
authors.lastname: Heath
authors.affiliation: Division of Surgery and Interventional Science, University College London, London W1W 7EJ, UK.
authors.forename: Rifat A
authors.initials: RA
authors.lastname: Hamoudi
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Torre I, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.affiliation: Illumina Inc., San Diego, California 92121, USA.
authors.forename: Agata
authors.identifier: 0000-0002-2642-8756
authors.initials: A
authors.lastname: Czyz
authors.affiliation: Illumina Inc., San Diego, California 92121, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Ruotti
authors.affiliation: Department of Molecular Biology, Radboud University Nijmegen, Nijmegen 6525 GA, Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.|British Heart Foundation Centre of Excellence, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Torre I, 08028 Barcelona, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015203:Reproducibility of Results; D013447:Sulfites / Q000737:chemistry; D000073336:Whole Genome Sequencing / Q000379:methods*
chemical_list: D013447:Sulfites; C042345:hydrogen sulfite