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Mapping and sequencing of structural variation from eight human genomes

Naturevolume 453, pages56–64 (2008)Cite this article

Abstract

Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale—particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation—a standard for genotyping platforms and a prelude to future individual genome sequencing projects.

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Figure 1:Map of structural variation in the human genome.
Figure 2:Frequency distribution.
Figure 3:Discovery of novel human sequences that are CNV.
Figure 4:Sequence resolution of human structural variation.
Figure 5:Regions of enriched SNP density.

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Acknowledgements

We thank the staff from the University of Washington Genome Center and the Washington University Genome Sequencing Center for technical assistance. J.M.K. is supported by a National Science Foundation Graduate Research Fellowship. G.M.C. is supported by a Merck, Jane Coffin Childs Memorial Fund Postdoctoral Fellowship. This work was supported by National Institutes of Health grants HG004120 to E.E.E., D.A.N. and M.V.O., and 3 U54 HG002043 to M.V.O. E.E.E. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions J.M.K., G.M.C., M.V.O, D.A.N, and E.E.E. contributed to the writing of this paper. The study was coordinated by L.B., M.V.O, R.K., D.R.S., J.M.K. and E.E.E. A.B., D.R.S., D.Sa., E.G., H.M.E., K.M., N.T., R.D., W.F.D. and W.T. performed library construction and end sequencing. E.H., H.S.H., K.A.P., M.V.O., R.K., R.K.W., T.G. and W.G. performed clone insert validation and sequencing. C.A., D.A.N., E.T., J.D.S., J.S., L.C., M.D., M.M., M.W., T.L.N. and Z.C. provided technical and analytical support. D.A.P., D.A.A., J.M.Ko. and S.A.M. contributed variation data. G.M.C., J.M.K., L.B., N.A.Y., N.S. and P.T. designed and analysed array CGH experiments. G.M.C. and T.Z. performed the genotype analysis. F.A. performed FISH experiments. B.T. and D.S. performed optical mapping experiments. E.E.E., J.M.K. and L.C. analysed sequenced clones. J.C.M. and N.H. identified SNPs and indels.

Author information

Authors and Affiliations

  1. Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA,

    Jeffrey M. Kidd, Gregory M. Cooper, Can Alkan, Francesca Antonacci, Troy Zerr, Tera L. Newman, Eray Tüzün, Ze Cheng, Molly Weaver, Lin Chen, Maika Malig, Joshua D. Smith, Michael Dorschner, John Stamatoyannopoulos, Deborah A. Nickerson & Evan E. Eichler

  2. Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA ,

    William F. Donahue, Heather M. Ebling, Nadeem Tusneem, Robert David, David Saranga, Adrianne Brand, Wei Tao, Erik Gustafson, Kevin McKernan & Douglas R. Smith

  3. Division of Medical Genetics, Department of Medicine, and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA,

    Hillary S. Hayden, Eric Haugen, Will Gillett, Karen A. Phelps, Maynard V. Olson & Rajinder Kaul

  4. Agilent Technologies, Santa Clara, California 95051, USA ,

    Nick Sampas, N. Alice Yamada, Peter Tsang & Laurakay Bruhn

  5. Washington University Genome Sequencing Center, School of Medicine, St Louis, Missouri 63108, USA ,

    Tina Graves & Richard K. Wilson

  6. Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA ,

    Nancy Hansen & James C. Mullikin

  7. Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA ,

    Brian Teague & David Schwartz

  8. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA ,

    Joshua M. Korn, Steven A. McCarroll & David A. Altshuler

  9. Illumina, Inc., 9885 Towne Centre Drive, San Diego, California 92121, USA ,

    Daniel A. Peiffer

Authors
  1. Jeffrey M. Kidd
  2. Gregory M. Cooper
  3. William F. Donahue
  4. Hillary S. Hayden
  5. Nick Sampas
  6. Tina Graves
  7. Nancy Hansen
  8. Brian Teague
  9. Can Alkan
  10. Francesca Antonacci
  11. Eric Haugen
  12. Troy Zerr
  13. N. Alice Yamada
  14. Peter Tsang
  15. Tera L. Newman
  16. Eray Tüzün
  17. Ze Cheng
  18. Heather M. Ebling
  19. Nadeem Tusneem
  20. Robert David
  21. Will Gillett
  22. Karen A. Phelps
  23. Molly Weaver
  24. David Saranga
  25. Adrianne Brand
  26. Wei Tao
  27. Erik Gustafson
  28. Kevin McKernan
  29. Lin Chen
  30. Maika Malig
  31. Joshua D. Smith
  32. Joshua M. Korn
  33. Steven A. McCarroll
  34. David A. Altshuler
  35. Daniel A. Peiffer
  36. Michael Dorschner
  37. John Stamatoyannopoulos
  38. David Schwartz
  39. Deborah A. Nickerson
  40. James C. Mullikin
  41. Richard K. Wilson
  42. Laurakay Bruhn
  43. Maynard V. Olson
  44. Rajinder Kaul
  45. Douglas R. Smith
  46. Evan E. Eichler

Corresponding author

Correspondence toEvan E. Eichler.

Ethics declarations

Competing interests

Daniel A. Peiffer is currently an employee of Illumina, Inc.; Kevin McKernan and Robert David are currently employed by Applied Biosystems, a manufacturer of DNA-sequencing reagents and instruments; and Laurakay Bruhn, Nick Sampas, Peter Tsang and N. Alice Yamada are employees of Agilent Technologies, Inc.

Supplementary information

Supplementary Information

The file contains extensive Supplementary Information with Supplementary Figures S1-S2, S4-S9. Supplementary Figures S3 and S10 are included in separate files. (PDF 9427 kb)

Supplementary Figure S2

The file contains Supplementary Figure S2 with end-sequence mapping of fosmids against the human genome. All discordant fosmids mapping to the human genome are displayed individually for each library using the following color scheme: ABC7=green, ABC8=forestgreen, ABC10=blue, ABC13=cyan, G248=black, ABC9=purple, ABC11=red, ABC12=orange, and ABC14=hotpink. The end-sequence placements are mapped in the context of gaps within the assembly (purple) and segmental duplications (grey bars). (PDF 4463 kb)

Supplementary Figure S3

The file contains Supplementary Figure S3 with end-sequence mapping of fosmids against the human genome. All discordant fosmids mapping to the human genome are displayed individually for each library using the following color scheme: ABC7=green, ABC8=forestgreen, ABC10=blue, ABC13=cyan, G248=black, ABC9=purple, ABC11=red, ABC12=orange, and ABC14=hotpink. The end-sequence placements are mapped in the context of gaps within the assembly (purple) and segmental duplications (grey bars). (PDF 6227 kb)

Supplementary Figure S4

The file contains Supplementary Figure S4 with end-sequence mapping of fosmids against the human genome. All discordant fosmids mapping to the human genome are displayed individually for each library using the following color scheme: ABC7=green, ABC8=forestgreen, ABC10=blue, ABC13=cyan, G248=black, ABC9=purple, ABC11=red, ABC12=orange, and ABC14=hotpink. The end-sequence placements are mapped in the context of gaps within the assembly (purple) and segmental duplications (grey bars). (PDF 3489 kb)

Supplementary Figure S10

The file contains Supplementary Figure S10 with sequenced Structural Variation and Gene Structure. A graphical representation for sequenced sites (n=266) of structural variation (miropeats view) is provided. Each alignment compares the human reference genome (top) with the sequenced structure of the fosmid clone. (PDF 3571 kb)

Supplementary Table S1

The file contains Supplementary Table S1 showing concordant vs. discordant clone placement summary statistics. (XLS 22 kb)

Supplementary Table S2

The file contains Supplementary Table S2 showing one-end anchored (OEA) clone statistics. (XLS 14 kb)

Supplementary Table S3

The file contains Supplementary Table S3 with All ESP predicted sites of insertions and deletions with associated experimental validation (See Supplementary Material Section 12 for description of column headers) (XLS 5072 kb)

Supplementary Table S4

The file contains Supplementary Table S4 with ESP predicted sites of insertion and deletion loci (non-redundant) across the fosmid libraries (See Supplementary Material Section 12 for description of column headers) (XLS 4106 kb)

Supplementary Table S5

The file contains Supplementary Table S5 with genotyping results for a subset of ESP deletion variants based on analysis of genotypes from the llumina Human1M BeadChip (XLS 38 kb)

Supplementary Table S6

The file contains Supplementary Table S6 with ESP predicted inversion breakpoints (XLS 308 kb)

Supplementary Table S7

The file contains Supplementary Table S7 with merged inversion loci (non-redundant). (XLS 63 kb)

Supplementary Table S8

The file contains Supplementary Table S8 with large insertions of novel sequence confirmed by optical mapping. (XLS 16 kb)

Supplementary Table S9

The file contains Supplementary Table S9 with genbank accession IDs of sequenced clones. (XLS 73 kb)

Supplementary Table S10

The file contains Supplementary Table S10 with sequenced structural variants that affect exons of genes. (XLS 26 kb)

Supplementary Table S11

The file contains Supplementary Table S11 with summary statistics of fosmid end sequences. (XLS 17 kb)

Supplementary Table S12

The file contains Supplementary Table S12 with genotypes based on custom GoldenGate Assay and qPCR. (XLS 78 kb)

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Kidd, J., Cooper, G., Donahue, W.et al. Mapping and sequencing of structural variation from eight human genomes.Nature453, 56–64 (2008). https://doi.org/10.1038/nature06862

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Editorial Summary

Pieces of eight genomes

Clone-based sequencing of the genomes of eight unrelated individuals — four African and four non-African — has been used to build a picture of human genetic variation. The study concentrated on intermediate-scale variations a few thousand to a few million base pairs long. The results confirm the finding that African genomes are more diverse than other groups, and suggest that previous estimates of the incidence of 'copy-number variant' base pairs have been too high. The data suggest that, despite recent evidence to the contrary, non-allelic homologous recombination is the dominant process in promoting structural variation in the genome. Studies of this type provide benchmarks for the many genome sequences that will be generated by next-generation technologies.

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