As population structure can result in spurious associations, it has constrained the use of association studies in human and plant genetics. Association mapping, however, holds great promise if true signals of functional association can be separated from the vast number of false signals generated by population structure. We have developed a unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers. We applied this new approach to two samples: a family-based sample of 14 human families, for quantitative gene expression dissection, and a sample of 277 diverse maize inbred lines with complex familial relationships and population structure, for quantitative trait dissection. Our method demonstrates improved control of both type I and type II error rates over other methods. As this new method crosses the boundary between family-based and structured association samples, it provides a powerful complement to currently available methods for association mapping.

Ten thousand years ago human societies around the globe began to transition from hunting and gathering to agriculture. By 4000 years ago, ancient peoples had completed the domestication of all major crop species upon which human survival is dependent, including rice, wheat, and maize. Recent research has begun to reveal the genes responsible for this agricultural revolution. The list of genes to date tentatively suggests that diverse plant developmental pathways were the targets of Neolithic "genetic tinkering," and we are now closer to understanding how plant development was redirected to meet the needs of a hungry world.

There exists extraordinary morphological and genetic diversity among the maize landraces that have been developed by preColumbian cultivators. To explain this high level of diversity in maize, several authors have proposed that maize landraces were the products of multiple independent domestications from their wild relative (teosinte). We present phylogenetic analyses based on 264 individual plants, each genotyped at 99 microsatellites, that challenge the multiple-origins hypothesis. Instead, our results indicate that all maize arose from a single domestication in southern Mexico about 9,000 years ago. Our analyses also indicate that the oldest surviving maize types are those of the Mexican highlands with maize spreading from this region over the Americas along two major paths. Our phylogenetic work is consistent with a model based on the archaeological record suggesting that maize diversified in the highlands of Mexico before spreading to the lowlands. We also found only modest evidence for postdomestication gene flow from teosinte into maize.

The domestication of crop plants has often involved an increase in apical dominance (the concentration of resources in the main stem of the plant and a corresponding suppression of axillary branches). A striking example of this phenomenon is seen in maize (Zea mays spp. mays), which exhibits a profound increase in apical dominance compared with its probable wild ancestor, teosinte (Zea mays ssp. parviglumis). Previous research has identified the teosinte branched1 (tb1) gene as a major contributor to this evolutionary change in maize. We have cloned tb1 by transposon tagging and show here that it encodes a protein with homology to the cycloidea gene of snapdragon. The pattern of tb1 expression and the morphology of tb1 mutant plants suggest that tb1 acts both to repress the growth of axillary organs and to enable the formation of female inflorescences. The maize allele of tb1 is expressed at twice the level of the teosinte allele, suggesting that gene regulatory changes underlie the evolutionary divergence of maize from teosinte.

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 ...