Hattori Atsushi, Fukami Maki
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Division of Diversity Research, National Research Institute for Child Health and Development, Tokyo, Japan.
Methods Mol Biol. 2025;2968:509-520. doi: 10.1007/978-1-0716-4750-9_30.
Usually, the human genome acquires one or fewer de novo genomic structural variants (SVs) per generation. However, in rare cases, multiple de novo SVs occur independently on different chromosomes. Typical examples are multiple de novo copy number variants (MdnCNVs) and multifocal genomic crises, collectively termed "multifocal genomic reconstruction." MdnCNVs are characterized by multiple copy number gains on different chromosomes, which can be ascribed to replication-based errors. MdnCNV phenomenon is thought to persist during oogenesis and shortly after fertilization because of maternal factors that predispose oocytes and early embryos to genomic instability. In contrast, multifocal genomic crises result in various SVs such as deletions, duplications, inversions, and chromothriptic SVs, which are likely to be facilitated by replication-based errors and erroneous non-homologous repairs. Multifocal genomic crises appear to be restricted to spermatogenesis and may be influenced by several factors, such as paternal age, genetic background, and environmental exposures. Molecular methods useful for identifying multifocal genomic reconstruction include G-banding, multicolor fluorescence in situ hybridization, chromosomal microarray analysis, short- and long-read next-generation sequencing, and optical genome mapping. These analyses can identify undiscovered cases and lead to a better understanding of the basis of multifocal genomic reconstruction.
通常情况下，人类基因组每代获得一个或更少的新生基因组结构变异（SVs）。然而，在罕见情况下，多个新生SVs会独立出现在不同染色体上。典型例子有多新生拷贝数变异（MdnCNVs）和多灶性基因组危机，统称为“多灶性基因组重建”。MdnCNVs的特征是不同染色体上有多个拷贝数增加，这可归因于基于复制的错误。由于母体因素使卵母细胞和早期胚胎易发生基因组不稳定，MdnCNV现象被认为在卵子发生过程中及受精后不久持续存在。相比之下，多灶性基因组危机导致各种SVs，如缺失、重复、倒位和染色体碎裂性SVs，这些可能由基于复制的错误和错误的非同源修复促成。多灶性基因组危机似乎仅限于精子发生，可能受多种因素影响，如父亲年龄、遗传背景和环境暴露。用于识别多灶性基因组重建的分子方法包括G显带、多色荧光原位杂交、染色体微阵列分析、短读长和长读长下一代测序以及光学基因组图谱绘制。这些分析可以识别未被发现 的病例，并有助于更好地理解多灶性基因组重建的基础。
