Linkage analysis of the GAW14 simulated dataset with microsatellite and single-nucleotide polymorphism markers in large pedigrees

Kimberly F Kerstann,Kevin Jacobs,Xiaohong Yang,Alisa M Goldstein,Andrew W Bergen,Lynn R Goldin

doi:10.1186/1471-2156-6-s1-s14

Abstract

Recent studies have suggested that a high-density single nucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for gene mapping by linkage. The focus of this study was to compare results obtained from linkage analyses involving extended pedigrees with STR and single-nucleotide polymorphism (SNP) marker sets. We also wanted to compare the performance of current linkage programs in the presence of high marker density and extended pedigree structures. One replicate of the Genetic Analysis Workshop 14 (GAW14) simulated extended pedigrees (n = 50) from New York City was analyzed to identify the major gene D2. Four marker sets with varying information content and density on chromosome 3 (STR [7.5 cM]; SNP [3 cM, 1 cM, 0.3 cM]) were analyzed to detect two traits, the original affection status, and a redefined trait more closely correlated with D2. Multipoint parametric and nonparametric linkage analyses (NPL) were performed using programs GENEHUNTER, MERLIN, SIMWALK2, and S.A.G.E. SIBPAL. Our results suggested that the densest SNP map (0.3 cM) had the greatest power to detect linkage for the original trait (genetic heterogeneity), with the highest LOD score/NPL score and mapping precision. However, no significant improvement in linkage signals was observed with the densest SNP map compared with STR or SNP-1 cM maps for the redefined affection status (genetic homogeneity), possibly due to the extremely high information contents for all maps. Finally, our results suggested that each linkage program had limitations in handling the large, complex pedigrees as well as a high-density SNP marker set.

Highlights

Previous studies have suggested that a high-density singlenucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for genome-wide scans by linkage [1,2,3]
The weakest linkage signal was obtained from analyses using the SNP-3 cM map, which had the lowest information content among all the marker sets
Multipoint parametric HLOD scores obtained from the dense SNP maps (1 cM and 0.3 cM) by GENEHUNTER were much higher compared with those obtained from the STR and SNP-3 cM maps

Summary

Introduction

Previous studies have suggested that a high-density singlenucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for genome-wide scans by linkage [1,2,3]. The use of SNP-based linkage mapping has been explored primarily in nuclear families and sib pairs; few studies have evaluated methodological issues involved in SNP linkage using complex or extended pedigrees. This can be challenging (page number not for citation purposes)

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