Clustering of SNPs along a chromosome: can the neutral model be rejected?

Single nucleotide polymorphisms (SNPs) often appear in clusters along the length of a chromosome. This is due to variation in local coalescent times caused by, for example, selection or recombination. Here we investigate whether recombination alone (within a neutral model) can cause statistically significant SNP clustering. We measure the extent of SNP clustering as the ratio between the variance of SNPs found in bins of length l, and the mean number of SNPs in such bins, σ l /μl. For a uniform SNP distribution σ 2 l /μl = 1, for clustered SNPs σ l /μl > 1. Apart from the bin length, three length scales are important when accounting for SNP clustering: The mean distance between neighboring SNPs, ∆, the mean length of chromosome segments with constant time to the most recent common ancestor, lseg, and the total length of the chromosome, L. We show that SNP clustering is observed if ∆ < lseg ≪ L. Moreover, if l ≪ lseg ≪ L, clustering becomes independent of the rate of recombination. We apply our results to the analysis of SNP data sets from mice, and human chromosomes 6 and X. Of the three data sets investigated, the human X chromosome displays the most significant deviation from neutrality. INTRODUCTION Single nucleotide polymorphisms (SNPs) are the most abundant polymorphisms in most populations. Due to their ubiquity and stability they are useful in the diagnosis of human diseases (ZHOU et al., 2002), detection of human disease genes (WILLEY et al., 2002), and gene mapping in organisms as diverse as humans (MCINNES et al., 2001), Arabidopsis thaliana (CHO et al., 1999), and Drosophila (BERGER et al., 2001). For this reason, several large-scale SNPmapping projects are currently under way in eukaryotic model organisms including A. thaliana (http://arabidopsis.org/Cereon), Drosophila (HOSKINS et al., 2001), mouse (LINDBLAD-TOH et al., 2000), and human (INTERNATIONAL HUMAN GENOME SEQUENCING CONSORTIUM, 2001; THE INTERNATIONAL SNP MAP WORKING GROUP, 2001). A central question in the analysis of data collected in the context of these projects is how SNPs