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. 2007 Feb;17(2):219-30.
doi: 10.1101/gr.5774507. Epub 2006 Dec 21.

Evidence for large inversion polymorphisms in the human genome from HapMap data

Vikas Bansal  1 , Ali Bashir, Vineet Bafna
Affiliations

Evidence for large inversion polymorphisms in the human genome from HapMap data

Vikas Bansal et al. Genome Res. 2007 Feb.

Abstract

Knowledge about structural variation in the human genome has grown tremendously in the past few years. However, inversions represent a class of structural variation that remains difficult to detect. We present a statistical method to identify large inversion polymorphisms using unusual Linkage Disequilibrium (LD) patterns from high-density SNP data. The method is designed to detect chromosomal segments that are inverted (in a majority of the chromosomes) in a population with respect to the reference human genome sequence. We demonstrate the power of this method to detect such inversion polymorphisms through simulations done using the HapMap data. Application of this method to the data from the first phase of the International HapMap project resulted in 176 candidate inversions ranging from 200 kb to several megabases in length. Our predicted inversions include an 800-kb polymorphic inversion at 7p22, a 1.1-Mb inversion at 16p12, and a novel 1.2-Mb inversion on chromosome 10 that is supported by the presence of two discordant fosmids. Analysis of the genomic sequence around inversion breakpoints showed that 11 predicted inversions are flanked by pairs of highly homologous repeats in the inverted orientation. In addition, for three candidate inversions, the inverted orientation is represented in the Celera genome assembly. Although the power of our method to detect inversions is restricted because of inherently noisy LD patterns in population data, inversions predicted by our method represent strong candidates for experimental validation and analysis.

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Figures

Figure 1.
Figure 1.
Unusual LD observed in SNP data when the inverted haplotype (with respect to the reference sequence) has very high frequency. SNPs are “mapped” to the reference sequence using the flanking sequence (denoted by shaded boxes). Therefore, close SNPs in high LD are mapped to distant regions 1 and 3 (the shaded boxes). Consequently, the two regions show unusually high LD for that distance.
Figure 2.
Figure 2.
(A) Power of our method to detect inversion polymorphisms in the three HapMap analysis panels. Inversions of varying frequency (100%–50%) of a fixed length (500 kb) were simulated using the HapMap data for the three analysis panels separately (YRI, CEU, and CHB + JPT). The y-axis represents the fraction of simulated inversions for which there was at least one pair of predicted breakpoints with P-value ≤0.02 matching the breakpoints of the simulated inversion. (B) Power to detect inversions of four different lengths in the YRI analysis panel.
Figure 3.
Figure 3.
Genomic overview of a 1.4-Mb region at 16p12 predicted to have an inversion in both the CEU and YRI analysis panels. The left predicted breakpoint (the dotted line) overlaps with an ≈80-kb-long segment that is highly homologous to a segment (in the inverted orientation) near the other breakpoint. The region contains several disease-related genes (from the OMIM database).
Figure 4.
Figure 4.
Overview of an ≈1.2-Mb-long inversion on chromosome 10 predicted in the CHB + JPT analysis panel. Also shown are two fosmid pairs (discordant by orientation) whose one end maps to before the predicted left breakpoint and the other end maps to a region before the right breakpoint. These discordant mappings support the predicted inversion breakpoints. In this region, there is another overlapping inversion predicted in the CHB + JPT analysis panel. The region has several genes proximal to the left breakpoint, one of which is known to be overexpressed in tumor cells (Sampath et al. 2003).
Figure 5.
Figure 5.
A predicted YRI inversion polymorphism on chromosome 6 overlaps with the TCBA1 gene. The dashed line describes the location of the predicted breakpoints. The previously mapped breakpoints of the gene in T-cell lymphoma/leukemia cell lines are also shown.
Figure 6.
Figure 6.
Splice isoforms of the ICA1 gene that are approximately consistent with a predicted YRI inversion breakpoint on chromosome 7. The region of the left insertion breakpoint is denoted by a dashed line. The exons are not drawn to scale.
Figure 7.
Figure 7.
Length distribution of predicted inversions in the YRI analysis panel. For this plot, we consider inversions with length in the range 200 kb to 10 Mb.
Figure 8.
Figure 8.
The P-value distribution for predicted inversions having P-value ≤0.02.
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References

    1. Andolfatto P., Depaulis F., Navarro A., Depaulis F., Navarro A., Navarro A. Inversion polymorphisms and nucleotide variability in Drosophila. Genet. Res. 2001;77:1–8. - PubMed
    1. Bagnall R.D., Waseem N., Green P.M., Giannelli F., Waseem N., Green P.M., Giannelli F., Green P.M., Giannelli F., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002;99:168–174. - PubMed
    1. Conrad D., Andrews T., Carter N., Hurles M., Pritchard J., Andrews T., Carter N., Hurles M., Pritchard J., Carter N., Hurles M., Pritchard J., Hurles M., Pritchard J., Pritchard J. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 2006;38:75–81. - PubMed
    1. Crawford D., Bhangale T., Li N., Hellenthal G., Rieder M., Nickerson D., Stephens M., Bhangale T., Li N., Hellenthal G., Rieder M., Nickerson D., Stephens M., Li N., Hellenthal G., Rieder M., Nickerson D., Stephens M., Hellenthal G., Rieder M., Nickerson D., Stephens M., Rieder M., Nickerson D., Stephens M., Nickerson D., Stephens M., Stephens M. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat. Genet. 2004;36:700–706. - PubMed
    1. Deutz-Terlouw P.P., Losekoot M., Olmer R., Pieneman W.C., de Vries-v d Weerd S., Briët E., Bakker E., Losekoot M., Olmer R., Pieneman W.C., de Vries-v d Weerd S., Briët E., Bakker E., Olmer R., Pieneman W.C., de Vries-v d Weerd S., Briët E., Bakker E., Pieneman W.C., de Vries-v d Weerd S., Briët E., Bakker E., de Vries-v d Weerd S., Briët E., Bakker E., Briët E., Bakker E., Bakker E. Inversions in the factor VIII gene: Improvement of carrier detection and prenatal diagnosis in Dutch haemophilia A families. J. Med. Genet. 1995;32:296–300. - PMC - PubMed