Key Points SHM targeting for a DNA 5-mer motif can differ by position. Direction of differential targeting conserved across subjects and alleles. Differential targeting correlates with mutability of wider neighborhood of motifs. Somatic hypermutation (SHM) generates much of the Ab diversity necessary for affinity maturation and effective humoral immunity. The activation-induced cytidine deaminase–induced DNA lesions and error-prone repair that underlie SHM are known to exhibit intrinsic biases when targeting the Ig sequences. Computational models for SHM targeting often model the targeting probability of a nucleotide in a motif-based fashion, assuming that the same DNA motif is equally likely to be targeted regardless of its position along the Ig sequence. The validity of this assumption, however, has not been rigorously studied in vivo. In this study, by analyzing a large collection of 956,157 human Ig sequences while controlling for the confounding influence of selection, we show that the likelihood of a DNA 5-mer motif being targeted by SHM is not the same at different positions in the same Ig sequence. We found position-dependent differential SHM targeting for about three quarters of the 38 and 269 unique motifs from more than half of the 292 and 1912 motif–allele pairs analyzed using productive and nonproductive Ig sequences, respectively. The direction of the differential SHM targeting was largely conserved across individuals with no allele-specific effect within an IgH variable gene family, but was not consistent with general decay of SHM targeting with increasing distance from the transcription start site. However, SHM targeting did correlate positively with the mutability of the wider sequence neighborhood surrounding the motif. These findings provide insights and future directions for computational efforts toward modeling SHM.

中文翻译：

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体细胞超变的位置相关差异靶向

关键点 SHM 靶向 DNA 5 聚体基序可能因位置而异。在受试者和等位基因之间保守的差异靶向方向。差异靶向与更广泛的主题邻域的可变性相关。体细胞超突变 (SHM) 产生亲和力成熟和有效体液免疫所需的大部分抗体多样性。已知作为 SHM 基础的活化诱导的胞苷脱氨酶诱导的 DNA 损伤和易错修复在靶向 Ig 序列时表现出内在偏差。SHM 靶向的计算模型通常以基于基序的方式模拟核苷酸的靶向概率，假设相同的 DNA 基序同样有可能被靶向，而不管其沿 Ig 序列的位置。然而，这一假设的有效性尚未在体内进行严格研究。在这项研究中，通过分析 956,157 个人类 Ig 序列的大量集合，同时控制选择的混杂影响，我们表明 SHM 靶向 DNA 5 聚体基序的可能性在同一 Ig 的不同位置上是不同的顺序。我们发现位置依赖性差异 SHM 靶向分别使用生产性和非生产性 Ig 序列分析的 292 和 1912 基序-等位基因对中的一半以上的 38 和 269 个独特基序中的大约四分之三。差异 SHM 靶向的方向在 IgH 可变基因家族内没有等位基因特异性效应的个体之间很大程度上是保守的，但与 SHM 靶向随着距转录起始位点距离增加的一般衰减不一致。然而，SHM 靶向确实与围绕基序的更广泛序列邻域的可变性呈正相关。这些发现为模拟 SHM 的计算工作提供了见解和未来方向。