A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set

Abstract

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set.

Figure  1

Map features. A, Distribution of sizes of autosomal map intervals. B, Distribution of sizes of SNP clusters.

Figure  2

Female and male smoothed cM/Mb ratios, plotted along chromosome 16. Data are plotted separately for the p and q arms.

Figure  3

Map distance for corresponding map intervals on the TSC SNP linkage map and the deCode interpolated SNP linkage map.

Figure  4

IC for chromosome 12, on SNP linkage maps and Marshfield screening set 10. A, Complete SNP map with 97 markers (black). B, Marshfield map with 17 markers (red). C, SNP map with 47 markers (blue).