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A high-resolution survey of deletion polymorphism in the human genome

Nature Genetics volume 38, pages 75–81 (2006)Cite this article

Abstract

Recent work has shown that copy number polymorphism is an important class of genetic variation in human genomes1,2,3,4. Here we report a new method that uses SNP genotype data from parent-offspring trios to identify polymorphic deletions. We applied this method to data from the International HapMap Project5 to produce the first high-resolution population surveys of deletion polymorphism. Approximately 100 of these deletions have been experimentally validated using comparative genome hybridization on tiling-resolution oligonucleotide microarrays. Our analysis identifies a total of 586 distinct regions that harbor deletion polymorphisms in one or more of the families. Notably, we estimate that typical individuals are hemizygous for roughly 30–50 deletions larger than 5 kb, totaling around 550–750 kb of euchromatic sequence across their genomes. The detected deletions span a total of 267 known and predicted genes. Overall, however, the deleted regions are relatively gene-poor, consistent with the action of purifying selection against deletions. Deletion polymorphisms may well have an important role in the genetics of complex traits; however, they are not directly observed in most current gene mapping studies. Our new method will permit the identification of deletion polymorphisms in high-density SNP surveys of trio or other family data.

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Figure 1: Examples of four of the seven types of trio genotype configurations used in this analysis.
Figure 2: Comparison of high-resolution CGH results (top) with haplotype patterns (bottom) for two regions containing deletions.
Figure 3: Cumulative length of hemizygous sequence detected within the 30 children in each sample.
Figure 4: Observed and predicted distributions of deletion sizes in the CEU and YRI samples.
Figure 5: Power to detect a single deletion transmitted from parent to child, in HapMap Release 16c.1, as a function of deletion size (see Methods).

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Acknowledgements

We thank G. Coop, D. Cutler, A. DiRienzo, H. Fiegler, M. Przeworski, G. Raca, C. Tyler-Smith and D. Vetrie for comments and discussions; R. Redon for managing the genomic DNA collection; B. Voight for extracting the SNP classifications; S. Das, A. DiRienzo and C. Ober for lab space and equipment and the members of the International HapMap Consortium for their work in creating this dataset. This work was supported by a grant to J.K.P. from the Packard Foundation. D.F.C. was supported in part by US National Institutes of Health/National Institute of General Medical Sciences Genetics and Regulation Training Grant GM07197. Additional funding was provided by the Wellcome Trust.

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Authors and Affiliations

  1. Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, 60637, Illinois, USA

    Donald F Conrad & Jonathan K Pritchard

  2. Genome Dynamics and Evolution Group, The Wellcome Trust, Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

    T Daniel Andrews, Nigel P Carter & Matthew E Hurles

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  1. Donald F Conrad
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  2. T Daniel Andrews
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Correspondence to Jonathan K Pritchard.

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Supplementary information

Supplementary Table 1

List of deletions. (XLS 48 kb)

Supplementary Table 2

List of deletions. (XLS 72 kb)

Supplementary Table 3

List of CGH validation results. (XLS 48 kb)

Supplementary Table 4

List of genes involved. (XLS 90 kb)

Supplementary Methods (PDF 1044 kb)

Supplementary Note (PDF 1715 kb)

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Conrad, D., Andrews, T., Carter, N. et al. A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38, 75–81 (2006). https://doi.org/10.1038/ng1697

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