Chittoor Sai Swaroop, Giunta Simona
Laboratory of Genome Evolution, Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, 00185 Rome, Italy.
Laboratory of Genome Evolution, Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, 00185 Rome, Italy.
Am J Hum Genet. 2024 Dec 5;111(12):2707-2719. doi: 10.1016/j.ajhg.2024.10.016. Epub 2024 Nov 18.
Secondary structures are non-canonical arrangements of nucleic acids due to intra-strand interactions, including base pairing, stacking, or other higher-order features that deviate from the standard double-helical conformation. While these structures are extensively studied in RNA, they can also form when DNA becomes single stranded, creating topological roadblocks that can impact essential DNA-based processes such as replication, transcription, and repair, ultimately affecting genome stability. The availability of a complete linear sequence of human genomes, including repetitive loci, enables the prediction of DNA secondary structures comparing across various regions. Here, we evaluate the intrinsic properties of linear single-stranded DNA sequences derived from sampling specialized human loci such as centromeres, pericentromeres, ribosomal DNA (rDNA), and coding regions from the CHM13 genome. Our comparative analysis of predicted secondary structures across human chromosomes revealed the heightened presence, complexity, and instability of secondary structures within the centromere, which gradually decreased toward the pericentromere onto chromosomes' arms, on average lowest in coding regions. Notably, centromeric repeats exhibited the highest level of topological complexity within both the active and divergent domains, even when compared to other repetitive tandem satellites, such as rDNA in acrocentric chromosomes. Our findings provide evidence of the intrinsic self-hybridizing properties of centromere repeats, which are capable of generating complex topological structures that may functionally correlate with chromosome missegregation, especially when centromeric chromatin is disrupted. Processes such as long non-coding RNA transcription, recombination, and other mechanisms that dechromatinize and unwind stretches of linear DNA in these regions create in vivo opportunities for the DNA acrobatics hereby predicted.
二级结构是由于链内相互作用而形成的核酸非标准排列，包括碱基配对、堆积或其他偏离标准双螺旋构象的高阶特征。虽然这些结构在RNA中得到了广泛研究，但当DNA变为单链时也会形成，从而产生拓扑障碍，影响诸如复制、转录和修复等基于DNA的关键过程，最终影响基因组稳定性。人类基因组完整线性序列的可用性，包括重复位点，使得能够预测不同区域的DNA二级结构。在这里，我们评估了从人类特定位点（如着丝粒、着丝粒周围区域、核糖体DNA（rDNA）和CHM13基因组的编码区域）采样得到的线性单链DNA序列的内在特性。我们对人类染色体上预测的二级结构进行的比较分析表明，着丝粒内二级结构的存在、复杂性和不稳定性增加，从着丝粒周围区域到染色体臂逐渐降低，平均在编码区域最低。值得注意的是，着丝粒重复序列在活性和发散结构域内均表现出最高水平的拓扑复杂性，即使与其他重复串联卫星序列（如近端着丝粒染色体中的rDNA）相比也是如此。我们的研究结果提供了着丝粒重复序列内在自杂交特性的证据，这些特性能够产生复杂的拓扑结构，可能在功能上与染色体错分离相关，特别是当着丝粒染色质被破坏时。诸如长链非编码RNA转录、重组以及其他使这些区域的线性DNA去染色质化和解旋的机制，为本文预测的DNA杂技表演创造了体内机会。
