Dong Zheng, Whitehead Joanne, Fu Maggie, MacIsaac Julia L, Rehkopf David H, Rosero-Bixby Luis, Kobor Michael S, Korthauer Keegan
Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Genome Science and Technology Graduate Program, University of British Columbia, 100-570 West 7th Avenue, Vancouver, BC V5Z 4S6, Canada.
Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
Cell Rep. 2025 Jun 24;44(6):115755. doi: 10.1016/j.celrep.2025.115755. Epub 2025 May 28.
The complete telomere-to-telomere human genome assembly (T2T-CHM13) and the draft human pangenome reference provide unique opportunities to refine DNA methylation (DNAm) studies. Here, we find that T2T-CHM13 calls 7.4% more CpGs genome wide compared to GRCh38 across four widely used short-read DNAm profiling methods and improves the evaluation of probe cross-reactivity and mismatch for Illumina DNAm arrays, yielding new and more reproducible sets of unambiguous probes. The pangenome reference further expands CpG calling by 4.5% in short-read sequencing data and identifies cross-population and population-specific unambiguous probes in DNAm arrays, owing to its improved representation of genetic diversity. These benefits facilitate the discovery of biologically relevant DNAm alterations in epigenome-wide association studies (EWASs). For instance, additional DNAm alterations enriched in cancer-related genes and pathways are identified in cancer EWASs. Together, this study highlights the practical applications of T2T-CHM13 and pangenome for genome biology and provides a basis for expansion of DNAm investigations.
完整的端粒到端粒人类基因组组装（T2T-CHM13）和人类泛基因组参考草图为完善DNA甲基化（DNAm）研究提供了独特的机会。在这里，我们发现，与GRCh38相比，在四种广泛使用的短读长DNAm分析方法中，T2T-CHM13在全基因组中识别出的CpG多7.4%，并改进了对Illumina DNAm阵列探针交叉反应性和错配的评估，产生了新的、更具可重复性的明确探针集。由于其对遗传多样性的更好表征，泛基因组参考在短读长测序数据中进一步将CpG识别率提高了4.5%，并在DNAm阵列中识别出跨群体和群体特异性的明确探针。这些优势有助于在全表观基因组关联研究（EWAS）中发现生物学上相关的DNAm改变。例如，在癌症EWAS中发现了更多富集于癌症相关基因和通路的DNAm改变。总之，本研究突出了T2T-CHM13和泛基因组在基因组生物学中的实际应用，并为扩展DNAm研究提供了基础。
