Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases1,2, advances in genotyping and sequencing technology have made genome-wide association (GWA) studies 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 selfing model plant, known to harbor 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 with 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 from false associations. However, a priori candidates are significantly overrepresented among these associations as well, making many of them excellent candidates for follow-up experiments by the Arabidopsis community. Our study clearly demonstrates the feasibility of GWA studies in A. thaliana, and suggests that the approach will be appropriate for many other organisms.

Cadmium (Cd) tolerance seems to be a constitutive species-level trait in Arabidopsis halleri sp. halleri. Therefore, an interspecific cross was made between A. halleri and its closest nontolerant interfertile relative, Arabidopsis lyrata sp. petraea, and a firstgeneration backcross population (BC1) was used to map quantitative trait loci (QTL) for Cd tolerance. Three QTL were identified, which explained 43%, 24%, and 16% of the phenotypic variation in the mapping population. Heavy metal transporting ATPases4 (HMA4), encoding a predicted heavy metal ATPase, colocalized with the peak of the major QTL Cdtol-1 and was consequently further studied. HMA4 transcripts levels were higher in the roots and the shoots of A. halleri than in A. lyrata sp. petraea. Pollutants such as heavy metals can occur at very high concentrations in the soil as a consequence of either ancient natural processes or recent human activities such as mining, industrial, and agricultural practices. Although heavy metals are very toxic at high concentrations, some metal-tolerant plant species have developed the ability to grow and reproduce on soils highly polluted by heavy metals (Macnair, 1987). Among those metal-tolerant plants, some possess a remarkable physiological trait called hyperaccumulation that enables them to tolerate and accumulate high heavy metal concentrations in their shoots (about 100 times those occurring in nonaccumulator plants growing in the same substrates). Metal hyperaccumulators are consequently a particularly valuable resource to study the genetic basis of metal homeostasis.Arabidopsis halleri is an emerging model species for the molecular elucidation of metal tolerance and hyperaccumulation (Becher et al., 2004;Weber et al., 2004;Craciun et al., 2006;Filatov et al., 2006). This species belongs to the family Brassicaceae and shares about 94% DNA sequence identity within coding regions with the non-metal-tolerant plant species Arabidopsis (Arabidopsis thaliana; Becher et al., 2004). A. halleri constitutively tolerates zinc (Zn;Pauwels et al., 2006) and so far all the identified accessions are able to tolerate cadmium (Cd) and to hyperaccumulate Zn (Macnair et al., 1999). Hyperaccumulation of Cd was

The species Arabidopsis halleri, an emerging model for the study of heavy metal tolerance and accumulation in plants, has evolved a high level of constitutive zinc tolerance. Mapping of quantitative trait loci (QTL) was used to investigate the genetic architecture of zinc tolerance in this species. A firstgeneration backcross progeny of A. halleri ssp. halleri from a highly contaminated industrial site and its nontolerant relative A. lyrata ssp. petraea was produced and used for QTL mapping of zinc tolerance. A genetic map covering most of the A. halleri genome was constructed using 85 markers. Among these markers, 65 were anchored in A. thaliana and revealed high synteny with other Arabidopsis genomes. Three QTL of comparable magnitude on three different linkage groups were identified. At all QTL positions zinc tolerance was enhanced by A. halleri alleles, indicating directional selection for higher zinc tolerance in this species. The two-LOD support intervals associated with these QTL cover 24, 4, and 13 cM. The importance of each of these three regions is emphasized by their colocalization with HMA4, MTP1-A, and MTP1-B, respectively, three genes well known to be involved in metal homeostasis and tolerance in plants.M ETAL tolerance in plants has been considered ''an example of more powerful evolution in action than industrial melanism in moths' ' (Antonovics et al. 1971). Therefore it has been the focus of many evolutionary studies, in which it was argued that metal tolerance could evolve rapidly following exposure to heavy metal stress (Wu et al. 1975;Al-Hiyali et al. 1988). Some heavy metals, like zinc and copper, are oligo-nutrients and thus essential in small quantities for normal plant development. To avoid metal toxicity, all plants have evolved basic tolerance mechanisms. Binding by proteins or nonprotein thiol peptides in the cytoplasm and subsequent sequestration in the vacuole are the major component processes in the cellular heavy metal detoxification (Clemens 2001;Krämer 2005). However, at so-called metalliferous sites, heavy metals can occur at highly elevated concentrations in the soil, either through ancient natural processes, as in nickel-rich serpentine soils, or through recent human activities, as in zinc-and cadmium-rich calamine soils surrounding smelters. The total metal content of contaminated sites, depending on the metal, can be up to 10-to 1000-fold higher than that of uncontaminated sites (Bert et al. 2002). At these extreme concentrations, both essential and nonessential heavy metals become toxic (Clemens 2001;Hall 2002) and only a small number of plant species have evolved tolerance to such concentrations. These species have been classified as either absolute (strict or eu-) or facultative (pseudo-) metallophytes, according to their occurrence either on contaminated sites only or on both metalliferous and nonmetalliferous soils (Lambinon and Auquier 1964).The genetic basis of adaptive quantitative traits is still the matter of strong debates among evolutionists. Current que...