All forms of genetic variation originate from new mutations, making it crucial to understand their rates and mechanisms. Here, we use long-read sequencing from Pacific Biosciences (PacBio) to investigate de novo mutations that accumulated in 12 inbred mouse lines derived from three commonly used inbred strains (C3H, C57BL/6, and FVB) maintained for 8 to 15 generations in a mutation accumulation (MA) experiment. We built chromosome-level genome assemblies based on the MA line founders’ genomes and then employed a combination of read and assembly-based methods to call the complete spectrum of new mutations. On average, there are about 45 mutations per haploid genome per generation, about half of which (54%) are insertions and deletions shorter than 50 bp (indels). The remainder are single-nucleotide mutations (SNMs; 44%) and large structural mutations (SMs; 2%). We found that the degree of DNA repetitiveness is positively correlated with SNM and indel rates and that a substantial fraction of SMs can be explained by homology-dependent mechanisms associated with repeat sequences. Most (90%) indels can be attributed to microsatellite contractions and expansions, and there is a marked bias toward 4 bp indels. Among the different types of SMs, tandem repeat mutations have the highest mutation rate, followed by insertions of transposable elements (TEs). We uncover a rich landscape of active TEs, notable differences in their spectrum among MA lines and strains, and a high rate of gene retroposition. Our study offers novel insights into mammalian genome evolution and highlights the importance of repetitive elements in shaping genomic diversity.

中文翻译：

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通过长读长测序推断的小鼠新突变的发生率和谱


所有形式的遗传变异都源于新的突变，因此了解它们的速率和机制至关重要。在这里，我们使用 Pacific Biosciences （PacBio） 的长读长测序来研究在 12 个近交系小鼠品系中积累的从头突变，这些突变来源于三种常用的近交系菌株（C3H、C57BL/6 和 FVB），在突变积累 （MA） 实验中维持 8 至 15 代。我们基于 MA 系创始人的基因组构建了染色体水平的基因组组装，然后采用基于读取和组装的方法相结合来调用新突变的完整谱图。平均而言，每代每个单倍体基因组大约有 45 个突变，其中约一半 （54%） 是短于 50 bp 的插入和缺失（插入缺失）。其余为单核苷酸突变 （SNM;44%） 和大结构突变 （SM;2%）。我们发现 DNA 重复程度与 SNM 和 indel 率呈正相关，并且很大一部分 SMs 可以用与重复序列相关的同源依赖性机制来解释。大多数 （90%） 插入缺失可归因于微卫星收缩和扩张，并且明显偏向 4 bp 插入缺失。在不同类型的 SMs 中，串联重复突变的突变率最高，其次是转座因子 （TE） 的插入。我们揭示了丰富的活性 TE 景观，MA 品系和菌株之间谱的显着差异，以及高基因逆转录率。我们的研究为哺乳动物基因组进化提供了新的见解，并强调了重复元件在塑造基因组多样性中的重要性。