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杨晓旭. 精子嵌合变异及其对后代的影响[J]. koko体育app 学报(医学版), 2024, 55(3): 535-541. DOI:
引用本文: 杨晓旭. 精子嵌合变异及其对后代的影响[J]. koko体育app 学报(医学版), 2024, 55(3): 535-541. DOI:
YANG Xiaoxu. Sperm Mosaic Variants and Their Influence on the Offspring[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(3): 535-541. DOI:
Citation: YANG Xiaoxu. Sperm Mosaic Variants and Their Influence on the Offspring[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(3): 535-541. DOI: 🐈

精子嵌合变异及其对后代的影响

Sperm Mosaic Variants and Their Influence on the Offspring

  • 摘要: 基因组嵌合变异会导致同一个体生殖细胞和体细胞基因组不同。嵌合变异包含不同变异类型,其中新发变异指患者父母中无法检测但患者可以检测的变异,大规模人类家系基因组和遗传分析表明80%的子代新发变异来源于父方染色单体,即来源于精子嵌合变异。本文综述了精子嵌合变异的类型和已有的检测策略,同时讨论了近期有关父亲精子嵌合变异导致后代遗传疾病的原因。笔者团队的前期研究结果表明,多达5%~20%的临床表型相关的新生变异可在父亲的精子中检测为早期胚胎发育或生殖干细胞嵌合变异,并且可以作为罕见遗传病和复杂遗传病的重要预测指标。基于这些已有的研究结果,笔者认为在未来的研究中,进行大规模新发变异检测和人口水平的遗传筛查将大幅度提升对子代的遗传风险判断,并且可以有效提高人口遗传健康。在临床推广新生变异的父亲精子检测将显著提高疾病人群分层的效率并提高筛查再生育风险的效率。环境、生活因素等通过精子对后代健康的影响、对变异特征的塑造,以及实验室条件下对精子变异的定向控制将是本领域新的研究热点。  
    Abstract: Genomic mosaicism arising from mosaic variants is a phenomenon that describes the presence of a cell or cell populations with different genome compositions from the germline cells of an individual. It comprises all types of genetic variants. A large proportion of childhood genetic disorders are defined as being de novo, meaning that the disease-causing mutations are only detected in the proband, not in any of the parents. Population studies show that 80% of the de novo mutations arise from the paternal haplotype, that is, from paternal sperm mosaicism. This review provides a summary of the types and detection strategies of sperm mosaicism. In addition, it provides discussions on how recent studies demonstrated that genomic mosaic mutations in parents, especially those in the paternal sperms, could be inherited by the offspring and cause childhood disorders. According to the previous findings of the author's research team, sperm mosaicism derived from early embryogenesis and primordial germ cell stages can explain 5% to 20% of the de novo mutations related to clinical phenotypes and can serve as an important predictor of both rare and complex disorders. Sperm mosaicism shows great potential for clinical genetic diagnosis and consultations. Based on the published literature, the author suggests that, large-scale screening for de novo sperm mosaic mutations and population-based genetic screening should be conducted in future studies, which will greatly enhance the risk assessment in the offspring and effectively improve the genetic health at the population level. Implementation of direct sperm detection for de novo mutations will significantly increase the efficiency of the stratification of patient cohorts and improve recurrence risk assessment for future births. Future research in the field should be focused on the impact of environmental and lifestyle factors on the health of the offspring through sperms and their modeling of mutation signatures. In addition, targeted in vitro modeling of sperm mutations will also be a promising direction.  

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