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Sampling SNPs

Nature Genetics volume 26, pages 13–14 (2000)Cite this article

Several major single-nucleotide polymorphism (SNP) discovery projects have been launched recently1. The SNP Consortium alone has released 102,719 SNPs (http://snp.cshl.org). More recently, 664,846 SNPs based on the clone overlaps2 from the Human Genome Project were submitted by groups at the Sanger Center and at Washington University. So far, few of these SNPs have been validated. Moreover, validation rates have been derived by re-sequencing the same DNA samples used for the initial discovery. This approach controls for experimental artefacts in the discovery process, but does not control for the presence of segregating sites with rare alleles. Because such sites comprise most of the sites that vary in the human population, they may represent a significant fraction of all sites detected as ‘SNPs’. The rare alleles are unlikely to be observed again in a second sample, and therefore these sites will not be useful for genetic studies.

To investigate this phenomenon, we surveyed the expressed sequence tag (EST) databases3 for high-quality discrepancies (HQDs), designed PCR primers to amplify these putative SNPs from genomic DNA and re-sequenced them in a second DNA sample4. We applied stringent data quality restrictions on the HQDs to minimize the number of sequencing artefacts. Almost all selected HQDs had two or more high-quality EST reads for both alleles, with an overall Phred quality5,6 of greater than or equal to Q30 (that is, an expected error rate ≤10−3). We also inspected the EST traces visually. After PCR testing, 436 putative SNPs were available. These were re-sequenced in an average of 11 individuals. In this sample, 2 or 3 genotypes were observed for 314 of the sites. For the remaining 122 sites (28%), we observed a single homozygous genotype—the site was monomorphic in this second sample.

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Figure 1: Polymorphism rate in second sample, plotted against Phred quality (a) and number of libraries in HQD (b).

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Author notes

  1. Zhiyong Yang, Gane Ka-Shu Wong and Michael A. Eberle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Human Genome Center, University of Washington, Seattle, Washington, USA

    Zhiyong Yang, Gane Ka-Shu Wong, Miho Kibukawa, Douglas A. Passey, William R. Hughes & Jun Yu

  2. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Michael A. Eberle & Leonid Kruglyak

  3. Howard Hughes Medical Institute,

    Leonid Kruglyak

Authors
  1. Zhiyong Yang
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  2. Gane Ka-Shu Wong
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  3. Michael A. Eberle
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  4. Miho Kibukawa
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  5. Douglas A. Passey
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  6. William R. Hughes
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  7. Leonid Kruglyak
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  8. Jun Yu
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Corresponding author

Correspondence to Jun Yu.

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Yang, Z., Ka-Shu Wong, G., Eberle, M. et al. Sampling SNPs. Nat Genet 26, 13–14 (2000). https://doi.org/10.1038/79113

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