基于简单真核模型盘基网柄菌研究富含A/T串联重复序列的突变机制

DNA突变对生物个体及物种演化都有重要影响。突变发生涉及DNA损伤与修复的许多分子通路，仍有许多重要问题有待解决。富含A/T的短串联重复序列在真核基因组中广泛存在并参与重要生物学过程。这类序列是突变的高发区域，其突变发生的相关机制缺乏完整认识。DNA突变发生频率很低且涉及许多分子通路，在复杂生物模型开展研究具有局限性。由于简单真核模型盘基网柄菌的基因组具有大量富含A/T串联重复序列，且它的许多DNA修复基因与哺乳类同源，我们拟将利用该模型研究富含A/T串联重复序列的突变发生机制。本项目将结合细胞及分子生物学、高通量组学、生物信息学等手段来研究盘基网柄菌中富含A/T串联重复序列的突变规律，揭示其突变发生的关键分子通路，并与人类相关数据作比较，加深对人类基因组该类序列突变机制的认识。本项目将为哺乳类尤其人类的相关研究提供重要参考，也将拓展盘基网柄菌模型在突变及DNA损伤与修复研究中的应用。

DNA mutations play important roles in organisms and species evolution. DNA mutagenesis involves various DNA damage and repair pathways, many details of which remain to be elucidated. A/T-rich short tandem repeats are abundant in eukaryotic genomes and participate in important biological processes. These sequences are mutation hotspots, but the understanding of underlying mutagenic mechanisms remain incomplete. As DNA mutations occur in very low frequency and are associated with many molecular pathways, investigation in complex organisms has limitations. Because the simple eukaryotic model Dictyostelium discoideum is enriched for A/T-rich short tandem repeats in its genome, and many of its DNA repair genes have homologues in mammals, we propose to use this model to investigate mutational mechanisms of A/T-rich tandem repeats. We will combine cellular and molecular biology, high-throughput omics and bioinformatics to study the mutational patterns of A/T-rich tandem repeats in D. discoideum, and identify the key molecular pathways associated with the mutagenesis. Furthermore, we will do comparative analysis between D. discoideum and human, aiming to gain better understanding for A/T-rich tandem repeats in the human genome. The proposed work can provide important insights for future studies in mammals (especially human) and extend the application of D. discoideum in research areas of mutations, DNA damage and repair.