Comparative analysis of single-stranded and non-canonical DNA formation in human and other ape cells with telomere-to-telomere genomes
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Non-canonical (non-B) DNA secondary structures, e.g., G-quadruplexes and triplex DNA, are mutation hotspots and genome regulators contributing to disease and evolution. Yet they remain uncharacterized in complete genomes in vivo . Here we exploited the fact that many non-B DNA structures form single-stranded DNA (ssDNA). Using permanganate/S1 footprinting across 14 cell lines, we generated ssDNA profiles for human and six non-human ape telomere-to-telomere (T2T) genomes. Newly resolved satellite arrays—e.g., at ribosomal DNA and centromeres—displayed high ssDNA levels, implicating non-B DNA in satellite expansion and function. Hidden Markov Models applied to our ssDNA data revealed active genomic domains with specific functions—e.g., replication, transcription, or recombination—each enriched in particular non-B DNA types. Human-specific ssDNA domains correlated with nervous system genes, whereas cancer and embryonic cells showed increased ssDNA in transposable elements. Our ssDNA analysis across ape T2T genomes uncovered conserved and species-specific DNA structural dynamics central to genome regulation.
