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The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.

Original publication

DOI

10.1038/sj.gene.6364022

Type

Journal article

Journal

Genes and immunity

Publication Date

10/2003

Volume

4

Pages

506 - 514

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. dburgner@paed.uwa.edu.au

Keywords

Humans, Genetic Markers, Genetics, Population, Microsatellite Repeats, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Gambia, Nitric Oxide Synthase, Promoter Regions, Genetic, Genetic Variation