Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
DNA Res. 2024 Oct 1;31(5). doi: 10.1093/dnares/dsae028.
Monozygotic (MZ) twins originate from a single fertilized egg, making them genetically identical at the time of conception. However, postzygotic somatic mutations (PZMs) can introduce genetic differences after separation. Although whole-genome sequencing (WGS) sheds light on somatic mutations in cancer genomics, its application in genomic studies of MZ twins remains limited. In this study, we investigate PZMs in 30 healthy MZ twin pairs from the Osaka University Center for Twin Research using WGS (average depth = 23.8) and a robust germline-calling algorithm. We find high genotype concordance rates (exceeding 99%) in MZ twins. We observe an enrichment of PZMs with variant allele frequency around 0.5 in twins with highly concordant genotypes. These PZMs accumulate more frequently in non-coding regions compared with protein-coding regions, which could potentially influence gene expression. No significant association is observed between the number of PZMs and age or sex. Direct sequencing confirms a missense mutation in the ANKRD35 gene among the PZMs. By applying a genome-wide mutational signature pattern technique, we detect an age-related clock-like signature in these early postzygotic somatic mutations in MZ twins. Our study provides insights that contribute to a deeper understanding of genetic variation in MZ twins.
同卵（MZ）双胞胎起源于一个受精卵，因此在受孕时具有完全相同的遗传基因。然而，合子后体突变（PZMs）在分离后会引入遗传差异。尽管全基因组测序（WGS）揭示了癌症基因组中的体细胞突变，但它在 MZ 双胞胎的基因组研究中的应用仍然有限。在这项研究中，我们使用 WGS（平均深度为 23.8）和一种稳健的种系调用算法，对来自大阪大学双胞胎研究中心的 30 对健康 MZ 双胞胎进行了 PZMs 研究。我们发现 MZ 双胞胎之间的基因型一致性非常高（超过 99%）。我们观察到，在高度一致的基因型的双胞胎中，等位基因频率在 0.5 左右的 PZMs 富集。与编码区相比，这些 PZMs 更频繁地积累在非编码区，这可能会影响基因表达。我们没有观察到 PZMs 的数量与年龄或性别之间存在显著关联。直接测序证实了 PZMs 中存在 ANKRD35 基因的错义突变。通过应用全基因组突变特征模式技术，我们在 MZ 双胞胎的这些早期合子后体突变中检测到了一种与年龄相关的时钟样特征。我们的研究提供了有助于深入了解 MZ 双胞胎遗传变异的见解。
