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Automating resequencing-based detection of insertion-deletion polymorphisms


Structural and insertion-deletion (indel) variants have received considerable recent attention, partly because of their phenotypic consequences. Among these variants, the most common are small indels (1–30 bp). Identifying and genotyping indels using sequence traces obtained from diploid samples requires extensive manual review, which makes large-scale studies inconvenient. We report a new algorithm, implemented in available software (PolyPhred version 6.0), to help automate detection and genotyping of indels from sequence traces. The algorithm identifies heterozygous individuals, which permits the discovery of low-frequency indels. It finds 80% of all indel polymorphisms with almost no false positives and finds 97% with a false discovery rate of 10%. Additionally, genotyping accuracy exceeds 99%, and it correctly infers indel length in 96% of the cases. Using this approach, we identify indels in the HapMap ENCODE regions, providing the first report of these polymorphisms in this data set.

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Figure 1: An example of how our algorithm identifies a heterozygous indel trace.
Figure 2: Indel detection and genotyping accuracy.

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The authors thank the past and present members of the SeattleSNPs team for their efforts in variation discovery and the PolyPhred development team, including J. Sloan and P. Robertson. This work was supported by grants from the US National Institute of Health (HL66682 to D.A.N. and HG/LM02585 to M.S.).

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Correspondence to Tushar R Bhangale or Deborah A Nickerson.

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Competing interests

PolyPhred is freely available for academic purposes, but a licensing fee is charged for commercial use, which predominantly funds further software and methods development.

Supplementary information

Supplementary Fig. 1

Trace signal patterns. (PDF 76 kb)

Supplementary Fig. 2

Lengths and LD characteristics of ENCODE indels. (PDF 285 kb)

Supplementary Fig. 3

Application of the DPA. (PDF 225 kb)

Supplementary Table 1

ENCODE indels found in different functional regions of genes. (PDF 49 kb)

Supplementary Table 2

Chromosomal locations of the 1,125 indels identified in the ENCODE regions. (PDF 200 kb)

Supplementary Table 3

The independent variables and their estimated effect parameters in the logistic regression model used for identifying heterozygous indel traces. (PDF 86 kb)

Supplementary Table 4

The independent variables and their estimated effect parameters in the logistic regression model used for identifying indel loci. (PDF 83 kb)

Supplementary Methods (PDF 101 kb)

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Bhangale, T., Stephens, M. & Nickerson, D. Automating resequencing-based detection of insertion-deletion polymorphisms. Nat Genet 38, 1457–1462 (2006).

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