Risch N, Reich E W, Wishnick M M, McCarthy J G
Am J Hum Genet. 1987 Aug;41(2):218-48.
A statistical analysis of parental age and the incidence of new mutation has been performed. Some new data on Apert, Crouzon, and Pfeiffer syndromes is presented and combined with all available data from the literature on parental age and new mutation. Significant heterogeneity among syndromes for the rate of increase in incidence with parental age was found. A parsimonious conclusion is that mutations fall into two groups, one with a high rate of increase with age and the other with a low rate of increase with age. For the high-rate-of-increase group, a linear model relating incidence to age is rejected, while an exponential model is not. In addition, for this group, increased paternal age cannot account for the observed increase in maternal age--that is, increased maternal age also contributes to the incidence of new mutations. For the low-rate-of-increase group, increased paternal age alone can account for the observed increase in maternal ages; also, either a linear or exponential model is acceptable. In addition, there is no evidence for a mixture of parental age-independent cases with parental age-dependent cases for any of the syndromes examined. The curves reflecting incidence of new mutation and paternal age for two syndromes, Apert and neurofibromatosis, have an anomalous shape. In both cases the curve increases up to age 37 and drops at age 42 before increasing again at age 47. The usual explanation for the effect of parental age on new mutations is the mechanism of "copy-error" at mitotic division in male sperone that specifies an increased probability of mutation with time spent by a spermatozoon or ovum in a haploid state, a period of time that may also increase with age of the parent. A firm answer to the question of parental age and new mutation awaits identification of the molecular defect underlying some of these syndromes; we will then be in a position to determine in which parent the mutation occurred and at what age it did so.
已对父母年龄与新突变发生率进行了统计分析。本文呈现了一些关于Apert综合征、Crouzon综合征和Pfeiffer综合征的新数据，并将其与文献中所有关于父母年龄和新突变的可用数据相结合。研究发现，不同综合征的发病率随父母年龄增长的速率存在显著异质性。一个简约的结论是，突变分为两组，一组随年龄增长的速率较高，另一组随年龄增长的速率较低。对于高增长速率组，将发病率与年龄相关联的线性模型被否定，而指数模型则未被否定。此外，对于该组，父亲年龄的增加并不能解释观察到的母亲年龄的增加，也就是说，母亲年龄的增加也会导致新突变的发生率上升。对于低增长速率组，仅父亲年龄的增加就能解释观察到的母亲年龄的增加；同样，线性模型或指数模型都是可以接受的。此外，在所研究的任何综合征中，均未发现与父母年龄无关的病例和与父母年龄有关的病例混合存在的证据。反映Apert综合征和神经纤维瘤病这两种综合征新突变发生率与父亲年龄关系的曲线呈现出异常形状。在这两种情况下，曲线在37岁之前上升，在42岁时下降，然后在47岁时再次上升。关于父母年龄对新突变影响的通常解释是男性精子有丝分裂过程中的“复制错误”机制，该机制表明随着精子或卵子处于单倍体状态的时间增加，发生突变的概率也会增加，而这段时间也可能随着父母年龄的增长而增加。关于父母年龄与新突变问题的确切答案，有待于确定这些综合征背后的分子缺陷；届时我们将能够确定突变发生在哪一位父母身上以及发生时的年龄。
