State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Sci Rep. 2017 Mar 21;7:44446. doi: 10.1038/srep44446.
Copy number variation (CNV) is of great significance in human evolution and disorders. Through tracing the parent-of-origin of de novo pathogenic CNVs, we are expected to investigate the relative contributions of germline genomic stability on reproductive health. In our study, short tandem repeat (STR) and single nucleotide polymorphism (SNP) were used to determine the parent-of-origin of 87 de novo pathogenic CNVs found in unrelated patients with intellectual disability (ID), developmental delay (DD) and multiple congenital anomalies (MCA). The results shown that there was a significant difference on the distribution of the parent-of-origin for different CNVs types (Chi-square test, p = 4.914 × 10). An apparently paternal bias existed in deletion CNVs and a maternal bias in duplication CNVs, indicating that the relative contribution of paternal germline variations is greater than that of maternal to the origin of deletions, and vice versa to the origin of duplications. By analyzing the sequences flanking the breakpoints, we also confirmed that non-allelic homologous recombination (NAHR) served as the major mechanism for the formation of recurrent CNVs whereas non-SDs-based mechanisms played a part in generating rare non-recurrent CNVs and might relate to the paternal germline bias in deletion CNVs.
拷贝数变异（CNV）在人类进化和疾病中具有重要意义。通过追踪新生致病性 CNV 的亲本来源，我们有望研究生殖健康中种系基因组稳定性的相对贡献。在我们的研究中，短串联重复（STR）和单核苷酸多态性（SNP）用于确定 87 个新发致病性 CNV 的亲本来源，这些 CNV 存在于智力障碍（ID）、发育迟缓（DD）和多种先天性异常（MCA）的无关患者中。结果表明，不同 CNV 类型的亲本来源分布存在显著差异（卡方检验，p=4.914×10）。缺失 CNV 中存在明显的父系偏倚，而重复 CNV 中存在母系偏倚，这表明父系种系变异对缺失的起源的相对贡献大于母系，反之亦然对重复的起源。通过分析断点侧翼的序列，我们还证实非等位基因同源重组（NAHR）是形成反复 CNV 的主要机制，而非基于非 SD 的机制在产生罕见的非反复 CNV 中起作用，并且可能与缺失 CNV 中的父系种系偏倚有关。
