unenriched DNA using contrasting probe dye colors. This is a cost-effective way to sample nearly half of all CpG islands and promoter regions on a microarray with the then-available probe densities. A similar approach uses Affymetrix promoter-focused microarrays. In this case, methylation is determined by comparing bisulfite-treated with untreated DNA. Bisulfite converts unmethylated C residues to U residues, so a relatively robust hybridization signal in the bisulfite-treated sample indicates a preponderance of methylation. More recently, next-generation sequencing technologies supplanted microarray methods due to a reduction in costs and the higher resolution of detecting individually-methylated C residues. Whole-genome methyl-seq can be performed by comparing bisulfite-converted DNA with either an unconverted DNA sample or reference genome sequence as control. However, the reduced sequence complexity of DNA where all or most C residues have been converted to T can reduce the effective alignment with genome. Both to increase the alignment of converted sequence and to increase the sequencing depth for regions of interest, targeted bisulfite sequencing is available. For example, Agilent uses a large number of bead-immobilized hybridization probes to enrich CpG islands, promoters, and related sequence as part of its SureSelect™ Methyl-Seq Enrichment System. In summary, the microarray-based methods have the advantage
