Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Hum Mutat. 2011 Aug;32(8):947-55. doi: 10.1002/humu.21524. Epub 2011 Jul 20.
In the past few years the number of copy number variants (CNVs) identified in the human genome has increased significantly, but our understanding of the functional impact of CNVs is still limited. Clinically significant variations cannot easily be distinguished from benign, complicating interpretation of patient data. Multiple studies have focused on analysis of regions that vary in copy number in specific disorders. Here we use the opposite strategy and focus our analysis on regions that never seem to vary in the general population, hypothesizing that these are copy number stable because variations within them are deleterious. Our results show that copy number stable regions are characterized by correlation with a number of genomic features, allowing us to define a list of genomic regions that are dosage sensitive in humans. We find that these dosage-sensitive regions show significant overlap with de novo CNVs identified in patients with intellectual disability or autism. There is also a significant association between copy number stable regions and rare inherited variants in autism patients, but not in controls. Based on this predictive power, we propose that copy number stable regions can be used to complement maps of known CNVs to facilitate interpretation of patient data.
在过去的几年中，人类基因组中鉴定出的拷贝数变异（CNVs）数量显著增加，但我们对 CNVs 功能影响的理解仍然有限。临床上重要的变异与良性变异难以区分，这使得患者数据的解释变得复杂。多项研究集中在分析特定疾病中拷贝数发生变化的区域。在这里，我们采用相反的策略，将分析重点放在人群中似乎从未发生过变化的区域上，假设这些区域的拷贝数是稳定的，因为其内部的变异是有害的。我们的研究结果表明，拷贝数稳定的区域与许多基因组特征相关，这使我们能够定义一组在人类中剂量敏感的基因组区域。我们发现，这些剂量敏感区域与智力障碍或自闭症患者中新发现的 CNVs 有显著重叠。在自闭症患者中，拷贝数稳定区域与罕见的遗传性变异之间也存在显著关联，但在对照组中没有。基于这种预测能力，我们提出拷贝数稳定区域可以用于补充已知 CNVs 图谱，以促进患者数据的解释。
