In the past 20 years, there has been a shift from optimism to pessimism. At first, it seemed possible that QTL mapping could identify something like several to tens of loci with alleles of moderate to large effect that could explain quantitative traits and complex diseases. Latterly, it has become clear that the task will be to identify unambiguously hundreds of genes with alleles with small effects affecting any one trait, and success seems more remote. The challenge becomes particularly arduous given context-dependent effects and the prospect of drilling down from QTL region to candidate gene one QTL at a time.
Several recent technical developments offer the hope of overcoming the difficulties, however. Two major obstacles have been the need for a dense panel of molecular markers for high-resolution mapping in the organism of interest, and for a way of genotyping these markers economically and in parallel in tens of thousands of individuals. Nextgeneration sequencing methods make possible the rapid identification of large numbers of polymorphisms in parental strains used in linkage mapping studies, or a sample of individuals from a population targeted for association mapping, and several companies offer custom genotyping designs for massively parallel genotyping. As the cost of sequencing plummets, we can conceive of eventually determining the whole-genome sequence of every individual in a large population, pushing the challenge of genetic dissection of quantitative traits towards accurate and high-throughput phenotyping. In addition, molecular polymorphisms do not directly affect quantitative traits, but do so by altering levels of transcript abundance, amount and activity of proteins, metabolites and other 'intermediate' phenotypes. Incorporating measures of variation in intermediate phenotypes with genetic variation in molecular markers and quantitative phenotypic variation will provide a biological context in which to interpret the phenotype. Finally, quantitative traits do not exist in a vacuum, but are connected to other traits via the pleiotropic effects of functional variants. Projects to develop sequenced genetic reference panels for model organisms as community resources for QTL mapping (for example, the mouse Collaborative Cross consortium, the Drosophila Genetic Reference Panel, and the Arabidopsis 1001 Genomes Project) will make possible large-scale measurement of multiple phenotypes, including intermediate phenotypes, in multiple environments. These resources offer the prospect of elucidating the genetics of the interdependence of multiple phenotypes, and addressing the longstanding question of the genetic basis of genotype-environment interaction.