Structure of linkage disequilibrium and phenotypic associations in the maize genome

Abstract

Association studies based on linkage disequilibrium (LD) can provide high resolution for identifying genes that may contribute to phenotypic variation. We report patterns of local and genomewide LD in 102 maize inbred lines representing much of the worldwide genetic diversity used in maize breeding, and address its implications for association studies in maize. In a survey of six genes, we found that intragenic LD generally declined rapidly with distance (r 2 < 0.1 within 1500 bp), but rates of decline were highly variable among genes. This rapid decline probably reflects large effective population sizes in maize during its evolution and high levels of recombination within genes. A set of 47 simple sequence repeat (SSR) loci showed stronger evidence of genome-wide LD than did single-nucleotide polymorphisms (SNPs) in candidate genes. LD was greatly reduced but not eliminated by grouping lines into three empirically determined subpopulations. SSR data also supplied evidence that divergent artificial selection on flowering time may have played a role in generating population structure. Provided the effects of population structure are effectively controlled, this research suggests that association studies show great promise for identifying the genetic basis of important traits in maize with very high resolution. In plant genetic studies, recombinant inbred lines have been very successful for mapping quantitative trait loci (QTLs) to 10-30 cM regions (1, 2), but association studies based on linkage disequilibrium (LD) may allow identification of the actual genes represented by QTLs. Only polymorphisms with extremely tight linkage to a locus with phenotypic effects are likely to be significantly associated with the trait in a randomly mating population, providing much finer resolution than genetic mapping. Association methods have been especially important for studying the genetic basis of human diseases, for which controlled genetic experiments are not feasible. However, these methods also have great potential for resolving individual genes responsible for QTLs (3-5).The resolution of association studies in a test sample depends on the structure of LD across the genome. LD, or the correlation between alleles at different sites, is generally dependent on the history of recombination between polymorphisms. However, factors such as genetic drift, selection within populations, and population admixture can also cause LD between markers and traits. [Following common practice (6, 7), we refer to gametic phase disequilibrium as LD whether or not it is caused by linkage.] Because many factors affect LD, its genomic structure in particular crop plants must be empirically determined before association studies can be applied. In maize, for example, divergent selection for adaptive traits such as time of maturation in different regions may have created LD among chromosomal regions containing major genes for these traits.Our goal in this study was to evaluate patterns of LD among 102 maize inbred lines representing the diversity ...

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