Large-scale genome-wide association (GWA) studies have become an important tool in human genomics, mostly focused on disease but also on adaptive variations such as skin colour. The technique is now shown to be similarly useful in plants. Atwell et al. report a GWA study of over a hundred phenotypes in naturally occurring inbred lines of Arabidopsis thaliana. The results range from significant associations, usually for single genes, to more difficult-to-interpret findings that indicate confounding by complex genetics and population structure. The accompanying paper by Todesco et al. demonstrates the ability of this technique to detect major-effect gene loci. Using forward genetics and GWA analyses, they show that variation at a single locus (ACD6) in Arabidopsis underlies phenotypic variation in vegetative growth as well as resistance to infection. The strong enhancement of resistance mediated by one of the alleles at this locus explains its persistence in natural populations throughout the world, despite it drastically reducing new leaf production. Here, large-scale genome-wide association studies were carried out with the naturally occurring inbred lines of Arabidopsis thaliana, which can be genotyped once and phenotyped repeatedly. The results range from significant associations, usually corresponding to single genes, to findings that are more difficult to interpret, because confounding by complex genetics and population structure makes it hard to distinguish true associations from false. Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases1,2, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits3. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.

Large-scale genome-wide association (GWA) studies have become an important tool in human genomics, mostly focused on disease but also on adaptive variations such as skin colour. The technique is now shown to be similarly useful in plants. Atwell et al. report a GWA study of over a hundred phenotypes in naturally occurring inbred lines of Arabidopsis thaliana. The results range from significant associations, usually for single genes, to more difficult-to-interpret findings that indicate confounding by complex genetics and population structure. The accompanying paper by Todesco et al. demonstrates the ability of this technique to detect major-effect gene loci. Using forward genetics and GWA analyses, they show that variation at a single locus (ACD6) in Arabidopsis underlies phenotypic variation in vegetative growth as well as resistance to infection. The strong enhancement of resistance mediated by one of the alleles at this locus explains its persistence in natural populations throughout the world, despite it drastically reducing new leaf production. Here, a combination of forward genetics and genome-wide association analyses has been used to show that variation at a single genetic locus in Arabidopsis thaliana underlies phenotypic variation in vegetative growth as well as resistance to infection. The strong enhancement of resistance mediated by one of the alleles at this locus explains the allele's persistence in natural populations throughout the world, even though it drastically reduces the production of new leaves. Plants can defend themselves against a wide array of enemies, from microbes to large animals, yet there is great variability in the effectiveness of such defences, both within and between species. Some of this variation can be explained by conflicting pressures from pathogens with different modes of attack1. A second explanation comes from an evolutionary ‘tug of war’, in which pathogens adapt to evade detection, until the plant has evolved new recognition capabilities for pathogen invasion2,3,4,5. If selection is, however, sufficiently strong, susceptible hosts should remain rare. That this is not the case is best explained by costs incurred from constitutive defences in a pest-free environment6,7,8,9,10,11. Using a combination of forward genetics and genome-wide association analyses, we demonstrate that allelic diversity at a single locus, ACCELERATED CELL DEATH 6 (ACD6)12,13, underpins marked pleiotropic differences in both vegetative growth and resistance to microbial infection and herbivory among natural Arabidopsis thaliana strains. A hyperactive ACD6 allele, compared to the reference allele, strongly enhances resistance to a broad range of pathogens from different phyla, but at the same time slows the production of new leaves and greatly reduces the biomass of mature leaves. This allele segregates at intermediate frequency both throughout the worldwide range of A. thaliana and within local populations, consistent with this allele providing substantial fitness benefits despite its marked impact on growth.

There is currently tremendous interest in the possibility of using genome-wide association mapping to identify genes responsible for natural variation, particularly for human disease susceptibility. The model plant Arabidopsis thaliana is in many ways an ideal candidate for such studies, because it is a highly selfing hermaphrodite. As a result, the species largely exists as a collection of naturally occurring inbred lines, or accessions, which can be genotyped once and phenotyped repeatedly. Furthermore, linkage disequilibrium in such a species will be much more extensive than in a comparable outcrossing species. We tested the feasibility of genome-wide association mapping in A. thaliana by searching for associations with flowering time and pathogen resistance in a sample of 95 accessions for which genome-wide polymorphism data were available. In spite of an extremely high rate of false positives due to population structure, we were able to identify known major genes for all phenotypes tested, thus demonstrating the potential of genome-wide association mapping in A. thaliana and other species with similar patterns of variation. The rate of false positives differed strongly between traits, with more clinal traits showing the highest rate. However, the false positive rates were always substantial regardless of the trait, highlighting the necessity of an appropriate genomic control in association studies. There is currently tremendous interest in using association mapping to find the genes responsible for natural variation, particularly for human disease. In association mapping, researchers seek to identify regions of the genome where individuals that are phenotypically similar (for example, they all have the same disease) are also unusually closely related. A potentially serious problem is that spurious correlations may arise if the population is structured so that members of a subgroup tend to be much more closely related. Because few genome-wide association studies have been carried out, it is not yet known how important this problem will be in practice. In one of the first genome-wide association studies to date, this paper considers the model plant Arabidopsis thaliana. A very large number of spurious genotype–phenotype correlations are found, especially for traits that vary geographically. For example, plants from northern latitudes flower later; however, in addition to sharing genetic variants that make them flower late, they also tend to share variants across the genome, making it difficult to determine which genes are responsible for flowering. This notwithstanding, several previously known genes were successfully identified in this study, and the researchers are optimistic about the prospects for association mapping in this species.

Leaf trichomes protect plants from attack by insect herbivores and are often induced following damage. Hormonal regulation of this plant induction response has not been previously studied. In a series of experiments, we addressed the effects of artificial damage, jasmonic acid, salicylic acid, and gibberellin on induction of trichomes in Arabidopsis. Artificial damage and jasmonic acid caused significant increases in trichome production of leaves. The jar1-1 mutant exhibited normal trichome induction following treatment with jasmonic acid, suggesting that adenylation of jasmonic acid is not necessary. Salicylic acid had a negative effect on trichome production and consistently reduced the effect of jasmonic acid, suggesting negative cross-talk between the jasmonate and salicylate-dependent defense pathways. Interestingly, the effect of salicylic acid persisted in the nim1-1 mutant, suggesting that the Npr1/Nim1 gene is not downstream of salicylic acid in the negative regulation of trichome production. Last, we found that gibberellin and jasmonic acid had a synergistic effect on the induction of trichomes, suggesting important interactions between these two compounds.