PSCC: sensitive and reliable population-scale copy number variation detection method based on low coverage sequencing.
BACKGROUND
Copy number variations (CNVs) represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS) we have developed an effective population-scale CNV calling (PSCC) method.


RESULTS
In our novel method, two-step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100% and 98.6%/100% sensitivity and specificity for over 300 kb CNV calling in the condition of LCS (∼2×) and ultra LCS (∼0.2×), respectively. Finally, we applied this novel method to analyze 34 clinical samples with an average of 2× LCS. In the final results, all the 31 pathogenic CNVs identified by aCGH were successfully detected. In addition, the performance comparison revealed that our method had significant advantages over existing methods using ultra LCS.


CONCLUSIONS
Our study showed that PSCC can sensitively and reliably detect CNVs using low coverage or even ultra-low coverage data through population-scale sequencing.
BGI-Shenzhen, Shenzhen, China.
Xuchao
X
Li
BGI-Shenzhen, Shenzhen, China ; State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
Shengpei
S
Chen
BGI-Shenzhen, Shenzhen, China.
Weiwei
W
Xie
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Ida
I
Vogel
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Kwong Wai
KW
Choy
BGI-Shenzhen, Shenzhen, China.
Fang
F
Chen
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Rikke
R
Christensen
BGI-Shenzhen, Shenzhen, China.
Chunlei
C
Zhang
BGI-Shenzhen, Shenzhen, China.
Huijuan
H
Ge
BGI-Shenzhen, Shenzhen, China ; State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
Haojun
H
Jiang
BGI-Shenzhen, Shenzhen, China.
Chang
C
Yu
Guangzhou Children's Social Welfare Home, Guangzhou, China.
Fang
F
Huang
BGI-Shenzhen, Shenzhen, China ; Clinical laboratory of BGI Health, Shenzhen, China.
Wei
W
Wang
BGI-Shenzhen, Shenzhen, China.
Hui
H
Jiang
BGI-Shenzhen, Shenzhen, China ; The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.
Xiuqing
X
Zhang
D000465:Algorithms; D056915:DNA Copy Number Variations; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000706:statistics & numerical data*; D006801:Humans; D012680:Sensitivity and Specificity