Abstract
Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1–50 kb) including insertions, deletions, inversions and their precise breakpoints, and in contrast to other methods, can resolve complex rearrangements. In total, we identified 277,243 SVs ranging in length from 1–23 kb. Validation using computational and experimental methods suggests that we achieve overall <6% false-positive rate and <10% false-negative rate in genomic regions that can be assembled, which outperforms other methods. Analysis of the SVs in the genomes of 106 individuals sequenced as part of the 1000 Genomes Project suggests that SVs account for a greater fraction of the diversity between individuals than do single-nucleotide polymorphisms (SNPs). These findings demonstrate that whole-genome de novo assembly is a feasible approach to deriving more comprehensive maps of genetic variation.
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Accession codes
Accessions
GenBank/EMBL/DDBJ
Sequence Read Archive
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Acknowledgements
This work was supported by a National Basic Research Program of China (973 program no. 2011CB809200), the National Natural Science Foundation of China (30725008; 30890032; 30811130531; 30221004), the Chinese 863 program (2006AA02Z177; 2006AA02Z334; 2006AA02A302;2009AA022707), the Shenzhen Municipal Government of China (grants JC200903190767A; JC200903190772A; ZYC200903240076A; CXB200903110066A; ZYC200903240077A; ZYC200903240076A and ZYC200903240080A) and the Ole Rømer grant from the Danish Natural Science Research Council. This project is also funded by the Shenzhen Municipal Government and the Local Government of Yantian District of Shenzhen. The 1000 Genomes Project Consortium provided the data for population analysis. AIFB is supported by Diabetes UK, the Wellcome Trust, the Medical Research Council and the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust. Thanks to X. Wang from School of Biosciences & Bioengineering, SCUT, for his excellent coordination. Thanks to J. El-Sayed Moustafa for her help analyzing the experimental validation data. L. Goodman, S. Edmunds and A. Basford edited the manuscript.
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Jun W., Jian W. and H.Y. managed the project. Jun W., Y.L., R. Luo designed the analyses. Y.L., R. Luo, R. Li, H. Zheng, H. Zhu, H.W., H.C., B.W., S.H., H.S., F.Z., H.M., S.F., A.J.d.S., A.I.F.B., W.Z., H.D., L.J.M.C., S.L., L.B. and K.K. performed the data analyses. G.T., J.L. and X.Z. performed the sequencing. Jun W., Y.L. and R. Luo wrote the paper.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Notes (PDF 1037 kb)
Supplementary Table 1
Primers, sequences of randomly selected structural variations and Sanger capillary sequencing results for PCR validation. (XLS 111 kb)
Supplementary Table 2
Summary of Fosmid sequences validation results. (XLS 144 kb)
Supplementary Table 3
Structural variations predicted on the YH and NA18507 genome were, respectively, compared to sets of variants discovered by alternative approaches. (XLS 17 kb)
Supplementary Table 5
Classification of those strongly conserved (dN/dS ⩽ 0.1) genes containing SVs. (XLS 48 kb)
Supplementary Data Set 1
Souce code (ZIP 5936 kb)
Supplementary Data Set 2
Supplementary array CGH results (TXT 38 kb)
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Li, Y., Zheng, H., Luo, R. et al. Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly. Nat Biotechnol 29, 723–730 (2011). https://doi.org/10.1038/nbt.1904
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DOI: https://doi.org/10.1038/nbt.1904
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