Large-scale genotyping of complex DNA (original) (raw)

• Letter
• Published: 07 September 2003
• Hajime Matsuzaki1,
• Shoulian Dong1,
• Wei-min Liu1,
• Jing Huang1,
• Guoying Liu1,
• Xing Su1 nAff4,
• Manqiu Cao1,
• Wenwei Chen1,
• Jane Zhang1,
• Weiwei Liu1,
• Geoffrey Yang1,
• Xiaojun Di1,
• Thomas Ryder1,
• Zhijun He1,
• Urvashi Surti2,
• Michael S Phillips3,
• Michael T Boyce-Jacino3,
• Stephen PA Fodor1 &
• …
• Keith W Jones1

Nature Biotechnology volume 21, pages 1233–1237 (2003)Cite this article

• 1775 Accesses
• 411 Citations
• 9 Altmetric
• Metrics details

Abstract

Genetic studies aimed at understanding the molecular basis of complex human phenotypes require the genotyping of many thousands of single-nucleotide polymorphisms (SNPs) across large numbers of individuals1. Public efforts have so far identified over two million common human SNPs2; however, the scoring of these SNPs is labor-intensive and requires a substantial amount of automation. Here we describe a simple but effective approach, termed whole-genome sampling analysis (WGSA), for genotyping thousands of SNPs simultaneously in a complex DNA sample without locus-specific primers or automation. Our method amplifies highly reproducible fractions of the genome across multiple DNA samples and calls genotypes at >99% accuracy. We rapidly genotyped 14,548 SNPs in three different human populations and identified a subset of them with significant allele frequency differences between groups. We also determined the ancestral allele for 8,386 SNPs by genotyping chimpanzee and gorilla DNA. WGSA is highly scaleable and enables the creation of ultrahigh density SNP maps for use in genetic studies.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

• Log in
• Learn about institutional subscriptions
• Read our FAQs
• Contact customer support

Similar content being viewed by others

References

1. Ardlie, K.G., Kruglyak, L. & Seielstad, M. Patterns of linkage disequilibrium in the human genome. Nat. Rev. Genet. 3, 299–309 (2002).
   Article CAS Google Scholar
2. Sachidanandam, R. et al. The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).
   Article CAS Google Scholar
3. Kwok, P.-Y. Methods for genotyping single nucleotide polymorphisms. Annu. Rev. Genomics Hum. Genet. 2, 235–258 (2001).
   Article CAS Google Scholar
4. Syvanen, A.-C. Accessing genetic variation: genotyping single nucleotide polymorphisms Nat. Rev. Genet. 2, 930–942 (2001).
   Article CAS Google Scholar
5. Lipshutz, R.J., Fodor, S.P., Gingeras, T.R. & Lockhart, D.J. High density synthetic oligonucleotide arrays. Nat. Genet. 21(1 Suppl), 20–24 (1999).
   Article CAS Google Scholar
6. Lisitsyn, N., Lisitsyn, N. & Wigler, M. Cloning the differences between two complex genomes. Science 259, 946–51 (1993).
   Article CAS Google Scholar
7. Lucito, R. et al. Genetic analysis using genomic representations. Proc. Natl. Acad. Sci. USA 95, 4487–4492 (1998).
   Article CAS Google Scholar
8. Vos, P. et al. AFLP: a new technique for DNA fingerprinting. Nucleic Acids Res. 23, 4407–4414 (1995).
   Article CAS Google Scholar
9. Altshuler, D. et al. An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516 (2000).
   Article CAS Google Scholar
10. Dong, S. et al. Flexible use of high-density oligonucleotide arrays for single-nucleotide polymorphism discovery and validation. Genome Res. 11, 1418–1424 (2001).
    Article CAS Google Scholar
11. Liu, W.-m. et al. Algorithms for large scale genotyping microarrays. Bioinformatics, (2003), in the press.
12. Weir, B.S. Genetic Data Analysis II (Sinauer Associates, Sunderland, Massachusetts, 1996).
    Google Scholar
13. Bowcock, A.M. et al. Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. Proc. Nat. Acad. Sci. USA 88, 839–843 (1991).
    Article CAS Google Scholar
14. Collins-Schramm, H. et al. Ethnic-difference markers for use in mapping by admixture linkage disequilibrium. Am. J. Hum. Genet. 70, 737–750 (2002).
    Article CAS Google Scholar
15. Briscoe, D., Stephens, J.C. & O'Brien, S.J. Linkage disequilibrium in admixed populations: applications in gene mapping. J. Hered. 85, 59–63 (1994).
    CAS PubMed Google Scholar
16. Parra, E.J. et al. Estimating African-American admixture proportions by use of population-specific alleles. Am. J. Hum. Genet. 63, 1839–1851 (1998).
    Article CAS Google Scholar
17. McKeigue, P.M., Carpenter, J.R., Parra, E.J. & Shriver, M.D. Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations. Ann. Hum. Genet. 64, 171–186 (2000).
    Article CAS Google Scholar
18. Hacia, J.G. Genome of the apes. Trends Genet. 17, 637–645 (2001).
    Article CAS Google Scholar
19. Hacia, J.G. et al. Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays. Nat. Genet. 22, 164–167 (1999).
    Article CAS Google Scholar
20. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 (1999).
    Article CAS Google Scholar
21. Watterson, G.A. & Guess, H.A. Is the most frequent allele the oldest? Theor. Pop. Biol. 11, 141–160 (1977).
    Article CAS Google Scholar
22. Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes (Princeton University Press, Princeton, NJ, 1994).
    Google Scholar
23. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).
    Article CAS Google Scholar
24. Lindblad-Toh, K. et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat. Biotechnol. 18, 1001–1005 (2000).
    Article CAS Google Scholar
25. Liu, W.-m. et al. Rank-based algorithms for analysis of microarrays. in Microarrays: Optical Technologies and Informatics (eds. Bittner, M.L., Chen, Y., Dorsel, A.N. & Dougherty, E.R.) Proc. SPIE 4266, 56–67 (2001).
    Book Google Scholar
26. Collins, F.S., Brooks, L.D. & Chakravarti, A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998).
    Article CAS Google Scholar
27. Rousseeuw, P.J. Silhouettes: a graphical aid to the interpretation and validation of cluster analysis. J. Comput. Appl. Math. 20, 53–65 (1987).
    Article Google Scholar
28. Picoult-Newberg, L. et al. Mining SNPs from EST databases. Genome Res. 9, 167–174 (1999).
    CAS PubMed Google Scholar
29. Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001).
    Article CAS Google Scholar
30. Fan, J.-B. et al. Paternal origins of complete hydatidiform moles proven by whole genome single-nucleotide phaplotyping. Genomics 79, 58–62 (2002).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank David Altshuler, Eric Lander, Thomas Gingeras, Richard Rava, Michael Shapero and Jon McAuliffe for helpful suggestions and critical reading of the manuscript.

Author information

Author notes

1. Xing Su
   Present address: Biotechnology Research Group, Intel Corporation, 3065 Bowers Ave., Santa Clara, California, 95054, USA

Authors and Affiliations

1. Affymetrix, 3380 Central Expressway, Santa Clara, 95051, California, USA
   Giulia C Kennedy, Hajime Matsuzaki, Shoulian Dong, Wei-min Liu, Jing Huang, Guoying Liu, Xing Su, Manqiu Cao, Wenwei Chen, Jane Zhang, Weiwei Liu, Geoffrey Yang, Xiaojun Di, Thomas Ryder, Zhijun He, Stephen PA Fodor & Keith W Jones
2. Departments of Pathology and Genetics, Magee Women's Hospital, 300 Halket St., Pittsburgh, 15213-3180, Pennsylvania, USA
   Urvashi Surti
3. Orchid BioSciences, Inc., 303 College Road East, Princeton, 08540, New Jersey, USA
   Michael S Phillips & Michael T Boyce-Jacino

Authors

1. Giulia C Kennedy
   You can also search for this author inPubMed Google Scholar
2. Hajime Matsuzaki
   You can also search for this author inPubMed Google Scholar
3. Shoulian Dong
   You can also search for this author inPubMed Google Scholar
4. Wei-min Liu
   You can also search for this author inPubMed Google Scholar
5. Jing Huang
   You can also search for this author inPubMed Google Scholar
6. Guoying Liu
   You can also search for this author inPubMed Google Scholar
7. Xing Su
   You can also search for this author inPubMed Google Scholar
8. Manqiu Cao
   You can also search for this author inPubMed Google Scholar
9. Wenwei Chen
   You can also search for this author inPubMed Google Scholar
10. Jane Zhang
    You can also search for this author inPubMed Google Scholar
11. Weiwei Liu
    You can also search for this author inPubMed Google Scholar
12. Geoffrey Yang
    You can also search for this author inPubMed Google Scholar
13. Xiaojun Di
    You can also search for this author inPubMed Google Scholar
14. Thomas Ryder
    You can also search for this author inPubMed Google Scholar
15. Zhijun He
    You can also search for this author inPubMed Google Scholar
16. Urvashi Surti
    You can also search for this author inPubMed Google Scholar
17. Michael S Phillips
    You can also search for this author inPubMed Google Scholar
18. Michael T Boyce-Jacino
    You can also search for this author inPubMed Google Scholar
19. Stephen PA Fodor
    You can also search for this author inPubMed Google Scholar
20. Keith W Jones
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toGiulia C Kennedy.

Ethics declarations

Competing interests

G.C.K., H.M., S.D., W.-M.L., J.H., G.L., X.S., M.C., W.C., J.Z., W.L., G.Y., X.D., T.R., Z.H., S.P.A.F. & K.W.J. are or were employed by Affymetrix, a commercial entity that manufactures and sells synthetic DNA microarrays based on the technology described in this paper.

Supplementary information

Rights and permissions

About this article

Cite this article

Kennedy, G., Matsuzaki, H., Dong, S. et al. Large-scale genotyping of complex DNA.Nat Biotechnol 21, 1233–1237 (2003). https://doi.org/10.1038/nbt869

Download citation

• Received: 07 January 2003
• Accepted: 16 July 2003
• Published: 07 September 2003
• Issue Date: 01 October 2003
• DOI: https://doi.org/10.1038/nbt869

This article is cited by