Characterization of 26 deletion CNVs reveals the frequent occurrence of micro-mutations within the breakpoint-flanking regions and frequent repair of double-strand breaks by templated insertions derived from remote genomic regions

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• 作者：Ye Wang ; Peiqiang Su ; Bin Hu ; Wenjuan Zhu ; Qibin Li ; Ping Yuan…
• 刊名：Human Genetics
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：134
• 期：6
• 页码：589-603
• 全文大小：3,299 KB
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• 作者单位：Ye Wang (1) (2)
  Peiqiang Su (2)
  Bin Hu (1)
  Wenjuan Zhu (3)
  Qibin Li (3)
  Ping Yuan (1) (4)
  Jiangchao Li (5) (6)
  Xinyuan Guan (5) (7)
  Fucheng Li (1)
  Xiangyi Jing (1) (8)
  Ru Li (8)
  Yongling Zhang (8)
  Claude Férec (10) (11) (12) (9)
  David N. Cooper (13)
  Jun Wang (14) (3)
  Dongsheng Huang (15)
  Jian-Min Chen (10) (11) (9)
  Yiming Wang (1) (3)
  
  1. Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-Sen University, Guangzhou, 510080, China
  2. Department of Orthopedics, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
  3. Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, 518083, China
  4. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
  5. State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, 510060, China
  6. Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, 510006, China
  7. Department of Clinical Oncology, The University of Hong Kong, Hong Kong, 999077, China
  8. Prenatal Diagnostic Center, Guangzhou Women and Children Medical Center affiliated to Guangzhou Medical University, Guangzhou, 510623, China
  10. Etablissement Fran?ais du Sang (EFS) - Bretagne, 29218, Brest, France
  11. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), 29238, Brest, France
  12. Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, H?pital Morvan, 29609, Brest, France
  9. Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, 29218, Brest, France
  13. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
  14. Department of Biology, University of Copenhagen, Copenhagen, Denmark
  15. Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Human Genetics
  Molecular Medicine
  Internal Medicine
  Metabolic Diseases
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1203

文摘

Copy number variations (CNVs) have increasingly been reported to cause, or predispose to, human disease. However, a large fraction of these CNVs have not been accurately characterized at the single-base-pair level, thereby hampering a better understanding of the mutational mechanisms underlying CNV formation. Here, employing a composite pipeline method derived from various inference-based programs, we have characterized 26 deletion CNVs [including three novel pathogenic CNVs involving an autosomal gene (EXT2) causing hereditary osteochondromas and an X-linked gene (CLCN5) causing Dent disease, as well as 23 CNVs previously identified by inference from a cohort of Canadian autism spectrum disorder families] to the single-base-pair level of accuracy from whole-genome sequencing data. We found that breakpoint-flanking micro-mutations (within 22?bp of the breakpoint) are present in a significant fraction (5/26; 19?%) of the deletion CNVs. This analysis also provided evidence that a recently described error-prone form of DNA repair (i.e., repair of DNA double-strand breaks by templated nucleotide sequence insertions derived from distant regions of the genome) not only causes human genetic disease but also impacts on human genome evolution. Our findings illustrate the importance of precise CNV breakpoint delineation for understanding the underlying mutational mechanisms and have implications for primer design in relation to the detection of deletion CNVs in clinical diagnosis.