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The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster

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Abstract

While there is considerable appeal to the idea of selecting a few SNPs to represent all, or much, of the DNA sequence variability in a local chromosomal region, it is also important to quantify what detail is lost in adopting such an approach. To address this issue, we compared high- and low-resolution depictions of sequence diversity for the same genomic region, the APOA1/C3/A4/A5 gene cluster on chromosome 11. First, extensive re-sequencing identified all nucleotide and sequence haplotype variation of the linked apolipoprotein genes in 72 individuals from three populations: African-Americans from Jackson, Miss., Europeans from North Karelia, Finland, and European-Americans from Rochester, Minn.. We identified 124 SNPs in 17.7 kb and significant differences in variation among genes. APOC3 gene diversity was particularly distinctive at high resolution, showing large allele frequency differences (F ST values >0.250) between Jackson and the other two samples, and divergent population-specific haplotype lineages. Next, we selected haplotype-tagging SNPs (htSNPs) for each gene, at a density of approximately one SNP per kb, using an algorithm suggested by Stram et al. (2003). The 17 htSNPs identified were then used to reconstruct low-resolution haplotypes, from which inferences about the structure of variation were also drawn. This comparison showed that while the htSNPs successfully tagged common haplotype variation, they also left much underlying sequence diversity undetected and failed, in some cases, to co-classify groups of closely related haplotypes. The implications of these findings for other haplotype-based descriptions of human variation are discussed.

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Acknowledgements

We thank D. J. Matthews and M. D. Shriver for comments on an earlier version of the manuscript. This research was supported by grants from the National Heart, Lung, and Blood Institute: HL39107, HL58238, HL58239, HL58240, and HL66682.

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Authors and Affiliations

  1. Department of Anthropology, Penn State University, 409 Carpenter Bldg., University Park, PA, 16802, USA

    Stephanie M. Fullerton, Anne V. Buchanan, Vibhor A. Sonpar & Kenneth M. Weiss

  2. Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA

    Scott L. Taylor, Joshua D. Smith, Christopher S. Carlson & Deborah A. Nickerson

  3. Department of Epidemiology and Health Promotion, KTL-National Public Health Institute, Helsinki, Finland

    Veikko Salomaa & Jari H. Stengård

  4. Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, 77225, USA

    Eric Boerwinkle

  5. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA

    Andrew G. Clark

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  1. Stephanie M. Fullerton
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  2. Anne V. Buchanan
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  3. Vibhor A. Sonpar
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Correspondence to Stephanie M. Fullerton.

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Fullerton, S.M., Buchanan, A.V., Sonpar, V.A. et al. The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster. Hum Genet 115, 36–56 (2004). https://doi.org/10.1007/s00439-004-1106-x

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