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Plant Physiology 138:567-568 (2005) © 2005 American Society of Plant Biologists Natural Variation in Arabidopsis. How Do We Find the Causal Genes?Department of Molecular Biology, Max Planck Institute for Developmental Biology, D–72076 Tuebingen, Germany (D.W.); Plant Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 (D.W.); and Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089 (M.N.)
According to PubMed, more than one-third of all papers on natural genetic variation in Arabidopsis (Arabidopsis thaliana) have been published since the beginning of 2004, underscoring the rapid growth of this area of Arabidopsis research. Motivations for studying variation found in wild strains range from simply exploiting it in order to find new genes involved in specific aspects of plant physiology or development, to trying to understand the molecular basis of adaptations to the local environment. However, irrespective of our ultimate goal, we first have to solve two more immediate problems. Which are the genes that affect variation in a specific trait? And, what is the nature of the allelic differences?
These are unfortunately difficult questions to answer. The main reason is that although major genetic differences that segregate as Mendelian factors are sometimes found (e.g. Bowman et al., 1993
Because phenotypic effects of individual genes are often small and because of complex interactions between the genes, it is generally not easy to obtain definitive proof for the identification of a QTL or quantitative trait nucleotide. For this reason, the mammalian quantitative genetics community (Members of the Complex Trait Consortium, 2003
Obviously, it will be rare (and rarely necessary) that all of these criteria are fulfilled. In addition, some of the criteria will provide stronger evidence than others. Interestingly, unambiguous fine mapping, which has been achieved in a particularly heroic effort with tomato (Lycopersicon esculentum; Fridman et al., 2000
As difficult as it is to demonstrate that a particular allelic variant is indeed causally related to the phenotype, the rate-limiting step typically remains the initial mapping and identification of the QTL. Several types of whole-genome analyses across a large panel of wild strains have been proposed as shortcuts. One is the direct identification of genes whose expression is correlated with a trait. Another is the identification of sequence variants that correlate with a particular phenotype, so-called linkage disequilibrium (LD) or association mapping. Because LD typically decays rapidly in Arabidopsis (over 25–50 kb; Nordborg et al., 2005
Panels for genome-wide association scans are becoming available through sequencing efforts targeting thousands of regions across the entire genome (Nordborg et al., 2005
However, it is important to remember that LD mapping does not provide direct evidence. A confounding factor in these analyses is that marker-trait associations may not be due to causal relationships (or even linkage), but rather due to an unexpected statistical association between a (unknown) causal gene and other genes. This would be the case, for example, if strains that show a certain phenotype are more likely to be related to each other (genome wide, as opposed to with respect to the causative loci) than expected by chance. This is known as population structure and may occur because strains from the same geographic area, where they may be exposed to similar environments, are also often more related than those that come from geographically distant regions. Genome-wide marker information allows us to gain insight into the severity of this problem. When many more markers than expected are identified as significantly associated with a trait, one can safely assume that many of these associations are not due to causal marker-trait relationships. Statistical methods that help to correct for this problem have been proposed (e.g. Devlin and Roeder, 1999 The true power of association studies lies in the combination with other approaches, especially the analysis of experimental populations. If association studies point to alleles with opposite effects on a trait of interest, one can quickly generate multiple F2 populations from parents that harbor contrasting alleles and determine whether differences in phenotype cosegregate with the locus in question. Even more powerful will be the use of RILs, which are immortalized F2 populations that need to be genotyped only once but can be repeatedly phenotyped (just like natural strains). Some 50 RIL sets have been produced or are currently in production in different laboratories (www.inra.fr/qtlat/NaturalVar/RILSummary.htm), and these will be an invaluable resource not only for conventional QTL mapping but also in combination with association studies. Expression studies can also provide valuable information by further narrowing the list of candidate genes likely to be causally linked to the trait. In summary, we feel that the plant genetic community would do well to adopt a set of standards for what does and what does not constitute acceptable proof that naturally occurring genetic variants cause differences in phenotype. Once we have solved this problem, we can turn to the difficult questions, such as the following. Is an unusual allele simply a deleterious variant that has become fortuitously fixed in the population? Or, does this allele indeed provide a fitness advantage in the local environment?
www.plantphysiol.org/cgi/doi/10.1104/pp.104.900157. * Corresponding author; e-mail weigel{at}weigelworld.org; fax 49–7071–601–1410.
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Hagenblad J, Tang C, Molitor J, Werner J, Zhao K, Zheng H, Marjoram P, Weigel D, Nordborg M (2004) Haplotype structure and phenotypic associations in the chromosomal regions surrounding two Arabidopsis thaliana flowering time loci. Genetics 168: 1627–1638 Hästbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E (1992) Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet 2: 204–211[CrossRef][Web of Science][Medline]
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Johanson U, West J, Lister C, Michaels S, Amasino R, Dean C (2000) Molecular analysis of FRIGIDA, a major determinant of natural variation in Arabidopsis flowering time. Science 290: 344–347 Members of the Complex Trait Consortium (2003) The nature and identification of quantitative trait loci: a community's view. Nat Rev Genet 4: 911–916[Web of Science][Medline] Nordborg M, Hu T, Ishino Y, Toomajian C, Jhaveri J, Bakker E, Calabrese GJ, Goyal RP, Jakobsson M, Jhaveri J, et al (2005) The genomic pattern of polymorphism in Arabidopsis thaliana. PLoS Biol 3: e196[CrossRef][Medline] Pritchard JK, Stephens M, Rosenberg NA, Donnelly P (2000) Association mapping in structured populations. Am J Hum Genet 67: 170–181[CrossRef][Web of Science][Medline] This article has been cited by other articles:
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