Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sci Rep. 2020 Jul 22;10(1):12235. doi: 10.1038/s41598-020-69134-4.
The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.
人类最常见的微缺失发生在 22q11.2，这是一个富含染色体特异性低拷贝重复序列（LCR22）的区域。由于其大小、区域复杂性和单倍型多样性，该区域的结构难以阐明，并且在人类基因组参考中没有很好地表示。大多数 22q11.2 缺失综合征（22q11.2DS）患者携带由 LCR22 介导的非等位基因同源重组（NAHR）产生的约 3 Mbp 的从头半合子缺失。在这项研究中，光学作图已被用于阐明 30 个 22q11.2DS 家族中的 88 个人的 LCR22 结构和变异，以揭示导致 22q11.2DS 后代的生殖系重排的潜在风险因素。对家族进行光学作图以表征 LCR22 结构、NAHR 位置和与缺失相关的基因组特征。生物信息学分析显示正常和缺失等位基因之间的 LCR22 结构有明显的划分。尽管没有明确的整个单倍型易位构型被识别，但所有的 NAHR 事件都包含 FAM230 基因成员的片段重复，表明存在优先的重组序列。缺失断点的分析表明，优先的重组发生在 FAM230 和 LCR22A 和 LCR22D 内的特定片段重复取向之间，最终导致 NAHR。这项工作代表了对 22q11.2DS NAHR 事件的最全面分析，证明了围绕和在缺失断点内的完全连续的 LCR22 结构。
