Linkage Disequilibrium and Inference of Ancestral Recombination in 538 Single-Nucleotide Polymorphism Clusters across the Human Genome

Abstract

The prospect of using linkage disequilibrium (LD) for fine-scale mapping in humans has attracted considerable attention, and, during the validation of a set of single-nucleotide polymorphisms (SNPs) for linkage analysis, a set of data for 4,833 SNPs in 538 clusters was produced that provides a rich picture of local attributes of LD across the genome. LD estimates may be biased depending on the means by which SNPs are first identified, and a particular problem of ascertainment bias arises when SNPs identified in small heterogeneous panels are subsequently typed in larger population samples. Understanding and correcting ascertainment bias is essential for a useful quantitative assessment of the landscape of LD across the human genome. Heterogeneity in the population recombination rate, rho=4Nr, along the genome reflects how variable the density of markers will have to be for optimal coverage. We find that ascertainment-corrected rho varies along the genome by more than two orders of magnitude, implying great differences in the recombinational history of different portions of our genome. The distribution of rho is unimodal, and we show that this is compatible with a wide range of mixtures of hotspots in a background of variable recombination rate. Although rho is significantly correlated across the three population samples, some regions of the genome exhibit population-specific spikes or troughs in rho that are too large to be explained by sampling. This result is consistent with differences in the genealogical depth of local genomic regions, a finding that has direct bearing on the design and utility of LD mapping and on the National Institutes of Health HapMap project.

Meta-Analysis Suggests Association of L- myc Eco RI Polymorphism with Cancer Prognosis

“…The distance over which significant linkage disequilibrium is maintained between single nucleotide polymorphisms in the human population remains controversial, with estimates ranging from 5 kb (22) to 500 kb (23). The distribution of LD is, however, highly irregular and populationspecific LD patterns may be observed (24) and may provide an explanation for the difficulty in replicating association studies.…”

Inference from the relationships between linkage disequilibrium and allele frequency distributions of 240 candidate SNPs in 109 drug-related genes in four Asian populations

“…In fact, this may most possibly result from the ascertainment bias during SNP discovery. Since the investigated sites were previously discovered by using only 48 individuals of Japanese descent (Iida et al 2001a(Iida et al ,b,c, 2002aSaito et al 2001aSaito et al ,b, 2002aSaito et al ,b,c,d, 2003; Unpublished data of Laboratory for Genotyping, SRC) and then scored in 752 Japanese individuals (Kamatani et al 2004; Unpublished data of Laboratory for Genotyping, SRC), more often than not, they tend to have higher population frequencies (Clark et al 2003). Furthermore, since they were genotyped but not resequenced in the other three Malaysian populations, there is a tendency to introduce a bias toward lower frequencies in other populations (Weiss and Clark 2002).…”

Estimation of individual admixture: Analytical and study design considerations

“…African-Americans and 30 European Americans Clark et al 2003). The absolute allele frequency difference, referred to as the δ-values, between these two samples is shown in Figure 1, and is used to approximate the allele frequency difference between our simulated ancestral populations.…”