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. 2012;7(7):e40294.
doi: 10.1371/journal.pone.0040294. Epub 2012 Jul 11.

Limitations of the human reference genome for personalized genomics

Jeffrey A Rosenfeld  1 , Christopher E Mason, Todd M Smith
Affiliations

Limitations of the human reference genome for personalized genomics

Jeffrey A Rosenfeld et al. PLoS One. 2012.

Abstract

Data from the 1000 genomes project (1KGP) and Complete Genomics (CG) have dramatically increased the numbers of known genetic variants and challenge several assumptions about the reference genome and its uses in both clinical and research settings. Specifically, 34% of published array-based GWAS studies for a variety of diseases utilize probes that overlap unanticipated single nucleotide polymorphisms (SNPs), indels, or structural variants. Linkage disequilibrium (LD) block length depends on the numbers of markers used, and the mean LD block size decreases from 16 kb to 7 kb,when HapMap-based calculations are compared to blocks computed from1KGP data. Additionally, when 1KGP and CG variants are compared, 19% of the single nucleotide variants (SNVs) reported from common genomes are unique to one dataset; likely a result of differences in data collection methodology, alignment of reads to the reference genome, and variant-calling algorithms. Together these observations indicate that current research resources and informatics methods do not adequately account for the high level of variation that already exists in the human population and significant efforts are needed to create resources that can accurately assess personal genomics for health, disease, and predict treatment outcomes.

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Conflict of interest statement

Competing Interests: TS is an employee of Perkin Elmer. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Location of SNPs relative to the probed base in microarrays.
Histogram showing the number of SNPs in upstream and downstream positions relative to the probed SNP on the Illumina1 M array. The red line indicates the location of the probed SNP.
Figure 2
Figure 2. Problematic probes on microarrays.
The number of probes on the Affymetrix Axiom CEU (blue) and Illumina 2.5 M(red) arrays that are found to contain an un-probed SNP for sub-samples of the 1KGP SNPs.
Figure 3
Figure 3. LD block lengths.
The mean length of LD blocks as the number of genotyped markers increases.
Figure 4
Figure 4. The LD block structure of two genes for the HapMap data and the 1KGP data.
A. The BRCA1 gene using the HapMap data. B. The BRCA1 gene using the 1KGP data. C. The JAK2 gene using the HapMap data. D. The Jak2 gene using the 1KGP data.
Figure 5
Figure 5. Venn diagrams illustrating the overlap in SNP calls between the 1KGP and CG.
A. For the full call sets. B. For the matched set of 32 genomes.
See this image and copyright information in PMC

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