Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington School of Medicine, 3720 15th Avenue NE, Seattle, WA 98195, USA.
Hum Mol Genet. 2010 Oct 15;19(R2):R176-87. doi: 10.1093/hmg/ddq366. Epub 2010 Aug 31.
The duplication architecture of the human genome predisposes our species to recurrent copy number variation and disease. Emerging data suggest that this mechanism of mutation contributes to both common and rare diseases. Two features regarding this form of mutation have emerged. First, common structural polymorphisms create susceptible and protective chromosomal architectures. These structural polymorphisms occur at varying frequencies in populations, leading to different susceptibility and ethnic predilection. Second, a subset of rearrangements shows extreme variability in expressivity. We propose that two types of genomic disorders may be distinguished: syndromic forms where the phenotypic features are largely invariant and those where the same molecular lesion associates with a diverse set of diagnoses including epilepsy, schizophrenia, autism, intellectual disability and congenital malformations. Copy number variation analyses of patient genomes reveal that disease type and severity may be explained by the occurrence of additional rare events and their inheritance within families. We propose that the overall burden of copy number variants creates differing sensitized backgrounds during development leading to different thresholds and disease outcomes. We suggest that the accumulation of multiple high-penetrant alleles of low frequency may serve as a more general model for complex genetic diseases, posing a significant challenge for diagnostics and disease management.
人类基因组的重复结构使我们的物种容易发生反复的拷贝数变异和疾病。新出现的数据表明，这种突变机制导致了常见和罕见疾病的发生。这种突变形式有两个特征。首先，常见的结构多态性会产生易感和保护的染色体结构。这些结构多态性在不同人群中的发生频率不同，导致不同的易感性和种族倾向。其次，一部分重排显示出极高的表型变异性。我们提出，可能区分两种类型的基因组疾病：综合征形式，其表型特征基本不变，以及同一种分子病变与多种诊断相关联，包括癫痫、精神分裂症、自闭症、智力障碍和先天性畸形。对患者基因组的拷贝数变异分析表明，疾病类型和严重程度可以通过额外的罕见事件的发生及其在家族中的遗传来解释。我们提出，拷贝数变异的总体负担在发育过程中产生了不同的敏感背景，导致了不同的阈值和疾病结果。我们认为，多个低频率的高外显率等位基因的积累可能是复杂遗传疾病的更普遍模型，这对诊断和疾病管理构成了重大挑战。
