Application of genome-wide single nucleotide polymorphism typing: simple association and beyond

Abstract

The International HapMap Project and the arrival of technologies that type more than 100,000 SNPs in a single experiment have made genome-wide single nucleotide polymorphism (GW-SNP) assay a realistic endeavor. This has sparked considerable debate regarding the promise of GW-SNP typing to identify genetic association in disease. As has already been shown, this approach has the potential to localize common genetic variation underlying disease risk. The data provided from this technology also lends itself to several other lines of investigation; autozygosity mapping in consanguineous families and outbred populations, direct detection of structural variation, admixture analysis, and other population genetic approaches. In this review we will discuss the potential uses and practical application of GW-SNP typing including those above and beyond simple association testing.

Figure 1. Multiple Regions of Extended Homozygosity within a Single Subject Born from a First Cousin Marriage

The regions of extended homozygosity on Chromosomes 3 (upper panel) and 18 (lower panel) are outlined in red. Homozygosity is shown by a lack of A/B genotype calls (corresponding to a B allele frequency of 0.5) coupled with a normal copy number, indicated by an average log R ratio of 0.

Figure 2. Log R Ratio and B Allele plots for Two Samples Showing Genomic Duplication

Genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside of the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A). (A) Shows duplication of a small segment on Chromosome 1 (red arrow). (B) Shows duplication of a region of approximately 7 Mb on Chromosome 21, outlined in red. This region contains APP, and the duplication mutation results in a neurodegenerative phenotype (courtesy of J. Hardy).

Figure 3. GW-SNP Assay Using the Illumina Infinium II Arrays Reveals Structural Variation in Chromosomes

(A) Common laboratory cell line HEK293. (B) Common laboratory cell line M17. (C) Human embryonic stem cell line 293F7. (D) Human embryonic stem cell line Bg01P3SFF2. These include apparent multiplication and deletion mutations in the M17 and HEK293 lines, multiplication mutations across line 293F7, and duplication Chromosome 17 in line Bg01P3SFF2.