Analyzing whole genome bisulfite sequencing data from highly divergent genotypes

Nucleic Acids Research
Phillip WulfridgeKasper D Hansen

Abstract

In the study of DNA methylation, genetic variation between species, strains or individuals can result in CpG sites that are exclusive to a subset of samples, and insertions and deletions can rearrange the spatial distribution of CpGs. How to account for this variation in an analysis of the interplay between sequence variation and DNA methylation is not well understood, especially when the number of CpG differences between samples is large. Here, we use whole-genome bisulfite sequencing data on two highly divergent mouse strains to study this problem. We show that alignment to personal genomes is necessary for valid methylation quantification. We introduce a method for including strain-specific CpGs in differential analysis, and show that this increases power. We apply our method to a human normal-cancer dataset, and show this improves accuracy and power, illustrating the broad applicability of our approach. Our method uses smoothing to impute methylation levels at strain-specific sites, thereby allowing strain-specific CpGs to contribute to the analysis, while accounting for differences in the spatial occurrences of CpGs. Our results have implications for joint analysis of genetic variation and DNA methylation using bisulfite-c...Continue Reading

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Citations

Jan 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·O Y Olivia TseY M Dennis Lo
Mar 18, 2021·The Plant Journal : for Cell and Molecular Biology·Wei TongEnhua Xia
Aug 7, 2021·Biomolecules·Jongseong AhnDuhee Bang

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Datasets Mentioned

BETA
GSE52272
GSE19986
GSE87101

Methods Mentioned

BETA
deamination
methylation Sequencing
WGBS
genotyping

Software Mentioned

BWA
Bismark
Trim Galore !
Samtools
BS
meth
BSmooth
UNC Systems Genetics
bowtie2
BSMAP

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