Department of Psychological Medicine and Neurology, Medical Research Council, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Biol Psychiatry. 2011 Dec 15;70(12):1109-14. doi: 10.1016/j.biopsych.2011.07.011. Epub 2011 Aug 19.
At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia and other neurodevelopmental disorders. Because such conditions are associated with reduced fecundity, these pathogenic CNVs should be filtered out from the population by selection and must be replenished by de novo events.
To estimate the mutation rate (μ) for these CNVs and the selection pressure (s) against them, we first conducted a literature review on the rate of each of these CNVs in the population and the rate of their de novo occurrence. In each generation, the number of CNVs lost because of reduced fertility must be replenished by the same number of de novo CNVs. Therefore, the observed ratio of de novo versus all (inherited + de novo) CNVs approximates the selection coefficient (s) of that CNV. The mutation rate approximates to μ = s × q, where q is the frequency of the CNV in the population.
High selection pressure operates at all these loci (s = .12 - .88), suggesting that following de novo occurrence, each of these CNVs persists in the population in only a few generations. The mutation rate for each CNV is high, affecting between 1:3500 and 1:30,000 individuals. The rarest CNVs have the highest selection coefficients.
The CNVs that increase risk to develop schizophrenia are caused by recent de novo mutations and are under strong selection pressure. They persist in the population because of high mutation rates.
至少有 10 个大型且罕见的重复 DNA 拷贝数变异（CNVs）已被确定为精神分裂症和其他神经发育障碍的风险因素。由于这些情况与生育能力降低有关，因此这些致病性 CNVs 应该通过选择从人群中过滤掉，并且必须通过新生事件来补充。
为了估计这些 CNVs 的突变率（μ）和对它们的选择压力（s），我们首先对这些 CNVs 在人群中的发生率和新生发生率进行了文献综述。在每一代中，由于生育力降低而丢失的 CNV 数量必须通过相同数量的新生 CNV 来补充。因此，观察到的新生 CNV 与所有（遗传+新生）CNV 的比例近似于该 CNV 的选择系数（s）。突变率近似于 μ = s × q，其中 q 是 CNV 在人群中的频率。
所有这些位点都存在高选择压力（s =.12 -.88），表明在新生发生后，这些 CNV 中的每一个在人群中仅能维持几个世代。每个 CNV 的突变率都很高，影响了 1：3500 到 1：30,000 个人中的一个。最罕见的 CNVs 具有最高的选择系数。
增加患精神分裂症风险的 CNVs 是由最近的新生突变引起的，并且受到强烈的选择压力的影响。由于高突变率，它们在人群中得以维持。
