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Complex SNP-related sequence variation in segmental genome duplications

Nature Genetics volume 36, pages 861–866 (2004)Cite this article

Abstract

There is uncertainty about the true nature of predicted single-nucleotide polymorphisms (SNPs) in segmental duplications (duplicons) and whether these markers genuinely exist at increased density as indicated in public databases. We explored these issues by genotyping 157 predicted SNPs in duplicons and control regions in normal diploid genomes and fully homozygous complete hydatidiform moles. Our data identified many true SNPs in duplicon regions and few paralogous sequence variants. Twenty-eight percent of the polymorphic duplicon sequences we tested involved multisite variation, a new type of polymorphism representing the sum of the signals from many individual duplicon copies that vary in sequence content due to duplication, deletion or gene conversion. Multisite variations can masquerade as normal SNPs when genotyped. Given that duplicons comprise at least 5% of the genome and many are yet to be annotated in the genome draft, effective strategies to identify multisite variation must be established and deployed.

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Figure 1: Genotyping patterns identifying evolutionary sequence states.
Figure 2: Summarized genotyping results.
Figure 3: MLPA data for eight CHMs across three consecutive loci.

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Acknowledgements

We thank R.J. Fisher and M. Seckl for CHM DNA samples and R.A. Clark, S. Sawyer and C. Lagerberg for technical assistance. Funding was provided by Pfizer Corporation and Stiftelsen för Kompetens-och Kunskapsutveckling (to D.F. and A.J.B.) and by the US National Institutes of Health (to E.E.E.).

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Author notes

  1. Anthony J Brookes

    Present address: Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH, UK

Authors and Affiliations

  1. Center for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35, Stockholm, S-171 77, Sweden

    David Fredman, Susanna Potter & Anthony J Brookes

  2. Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, Leiden, 2333 AL, The Netherlands

    Stefan J White & Johan T Den Dunnen

  3. Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Evan E Eichler

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Correspondence to Anthony J Brookes.

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A.J.B. declares share interests in Dynametrix Ltd.

Supplementary information

Supplementary Fig. 1

Average raw MLPA signal strength correlates with target sequence copy number. (PDF 198 kb)

Supplementary Fig. 2

MLPA and DASH correlation. (PDF 208 kb)

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Fredman, D., White, S., Potter, S. et al. Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 36, 861–866 (2004). https://doi.org/10.1038/ng1401

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