Fine-scale structural variation of the human genome

Abstract

Inversions, deletions and insertions are important mediators of disease and disease susceptibility1. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.

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Figure 1: Detection of structural variation.
Figure 2: Structural variation map.
Figure 3: Sequence analysis of structural variants.
Figure 4: Genotyping analysis of structural variants.

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Acknowledgements

We thank C. Alkan, J. Sprague, C. Gulden, D. Locke, S. McGrath and Z. Cheng for technical assistance and A. Chakravarti and B. Waterston for comments. This work was supported, in part, by a grant from the US National Institutes of Health to E.E.E.

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Correspondence to Evan E Eichler.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Fosmid size distribution. (PDF 46 kb)

Supplementary Fig. 2

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 458 kb)

Supplementary Fig. 3

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 452 kb)

Supplementary Fig. 4

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 368 kb)

Supplementary Fig. 5

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 370 kb)

Supplementary Fig. 6

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 345 kb)

Supplementary Fig. 7

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 320 kb)

Supplementary Fig. 8

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 326 kb)

Supplementary Fig. 9

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 267 kb)

Supplementary Fig. 10

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 250 kb)

Supplementary Fig. 11

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 264 kb)

Supplementary Fig. 12

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 252 kb)

Supplementary Fig. 13

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 260 kb)

Supplementary Fig. 14

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 197 kb)

Supplementary Fig. 15

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 180 kb)

Supplementary Fig. 16

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 193 kb)

Supplementary Fig. 17

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 178 kb)

Supplementary Fig. 18

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 184 kb)

Supplementary Fig. 19

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 144 kb)

Supplementary Fig. 20

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 149 kb)

Supplementary Fig. 21

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 115 kb)

Supplementary Fig. 22

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 81 kb)

Supplementary Fig. 23

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 90 kb)

Supplementary Fig. 24

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 297 kb)

Supplementary Fig. 25

Chromosomal views of structural variation (chromosomes 1 through Y inclusive). (PDF 80 kb)

Supplementary Fig. 26

Sequence properties of segmental duplications associated with structural variants. (PDF 15 kb)

Supplementary Fig. 27

L1 HS insertions and deletions. (PDF 54 kb)

Supplementary Fig. 28

Validated structural polymorphisms. (PDF 152 kb)

Supplementary Table 1

Summary details of detected structural variants and fosmid pairs spanning gaps within the sequence assembly. (XLS 303 kb)

Supplementary Table 2

Array CGH using BAC surrogates over sites of structural variation detected by fosmid paired-ends. (XLS 1274 kb)

Supplementary Table 3

Summary of fosmid sequencing. (XLS 31 kb)

Supplementary Table 4

PCR genotyping assays for structural variation. (XLS 19 kb)

Supplementary Table 5

Allele frequencies for seven structural polymorphisms validated by PCR. (XLS 19 kb)

Supplementary Note (PDF 108 kb)

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Tuzun, E., Sharp, A., Bailey, J. et al. Fine-scale structural variation of the human genome. Nat Genet 37, 727–732 (2005). https://doi.org/10.1038/ng1562

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