Guidelines for genotyping in genomewide linkage studies: single-nucleotide-polymorphism maps versus microsatellite maps

Abstract

Genomewide linkage scans have traditionally employed panels of microsatellite markers spaced at intervals of approximately 10 cM across the genome. However, there is a growing realization that a map of closely spaced single-nucleotide polymorphisms (SNPs) may offer equal or superior power to detect linkage, compared with low-density microsatellite maps. We performed a series of simulations to calculate the information content associated with microsatellite and SNP maps across a range of different marker densities and heterozygosities for sib pairs (with and without parental genotypes), sib trios, and sib quads. In the case of microsatellite markers, we varied density across 11 levels (1 marker every 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cM) and marker heterozygosity across 6 levels (2, 3, 4, 5, 10, or 20 equally frequent alleles), whereas, in the case of SNPs, we varied marker density across 4 levels (1 marker every 0.1, 0.2, 0.5, or 1 cM) and minor-allele frequency across 7 levels (0.5, 0.4, 0.3, 0.2, 0.1, 0.05, and 0.01). When parental genotypes were available, a map consisting of microsatellites spaced every 2 cM or a relatively sparse map of SNPs (i.e., at least 1 SNP/cM) was sufficient to extract most of the inheritance information from the map (>95% in most cases). However, when parental genotypes were unavailable, it was important to use as dense a map of markers as possible to extract the greatest amount of inheritance information. It is important to note that the information content associated with a traditional map of microsatellite markers (i.e., 1 marker every ~10 cM) was significantly lower than the information content associated with a dense map of SNPs or microsatellites. These results strongly suggest that previous linkage studies that employed sparse microsatellite maps could benefit substantially from reanalysis by use of a denser map of markers.

Figure 1

Information content for microsatellites, as a function of marker density (X-axis) and marker heterozygosity (colored lines). Information content is calculated at the middle marker of the chromosome (A) and halfway between the two middle markers (B).

Figure 2

Information content associated with a single 100-cM simulated region for a variety of SNP and microsatellite panels. Each line is representative of a marker panel currently available. Broken lines represent sparse marker densities (1 SNP/0.5 cM or 1 microsatellite/10 cM), and unbroken lines represent dense maps (1 SNP/0.2 cM or 1 microsatellite/3 cM). All simulations were conducted for one sib pair per family; color coding shows the presence or absence of parental genotypes, as labeled in the margin. All SNPs had MAFs of 30%, and all microsatellites had five equally frequent alleles (or heterozygosities of 0.80).