Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics
Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics
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DOI：
10.1016/j.ajhg.2014.08.010
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发表时间：
2014-10-02
影响因子：
9.8
通讯作者：
Shaw, Chad A.
中科院分区：
文献类型：
--
作者：
Campbell, Ian M.;Stewart, Jonathan R.;Shaw, Chad A.
据观察，大多数新突变发生在父亲身上，父亲年龄的增加与新突变的风险呈正相关。有趣的是，X连锁隐性遗传病的新突变显示出家族复发率升高。在男性后代中，这些突变必须遗传自母亲。我们之前开发了一个模拟模型，将亲本嵌合视为遗传突变的来源。在本文中，我们扩展并形式化了模型以提供分析结果和灵活的公式。结果表明，起源父母和父母嵌合体是复发风险的中心变量。与经验数据一致，我们的模型预测父亲中会出现更多的遗传突变，并且这种趋势随着父亲年龄的增长而增加。值得注意的是，雄性种系后期缺乏扩增决定了突变体比例的方差相对较低，并且随着父亲年龄的增长而减少。随后，对传播突变的观察对未来后代的预期风险影响较小。相反，对于在早期发育中克隆扩增后停滞的雌性种系，突变比例的方差较高，并且观察到传递的突变会显着增加另一次妊娠中复发的预期风险。父母体细胞嵌合体大大增加了父母双方的风险。这些发现对于遗传咨询和了解传播遗传学的复发模式具有重要意义。我们提供了一个方便的在线工具和源代码来实现我们的分析结果。这些工具允许改变影响复发风险的基本参数，并且可用于分析不同家庭结构的风险。
Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers' age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.