Association Mapping: Critical Considerations Shift from Genotyping to Experimental Design

Abstract

The goal of many plant scientists' research is to explain natural phenotypic variation in terms of simple changes in DNA sequence. Traditionally, linkage mapping has been the most commonly employed method to reach this goal: experimental crosses are made to generate a family with known relatedness, and attempts are made to identify cosegregation of genetic markers and phenotypes within this family. In vertebrate systems, association mapping (also known as linkage disequilibrium mapping) is increasingly being adopted as the mapping method of choice. Association mapping involves searching for genotype-phenotype correlations in unrelated individuals and often is more rapid and cost-effective than traditional linkage mapping. We emphasize here that linkage and association mapping are complementary approaches and are more similar than is often assumed. Unlike in vertebrates, where controlled crosses can be expensive or impossible (e.g., in humans), the plant scientific community can exploit the advantages of both controlled crosses and association mapping to increase statistical power and mapping resolution. While the time and money required for the collection of genotype data were critical considerations in the past, the increasing availability of inexpensive DNA sequencing and genotyping methods should prompt researchers to shift their attention to experimental design. This review provides thoughts on finding the optimal experimental mix of association mapping using unrelated individuals and controlled crosses to identify the genes underlying phenotypic variation. GENETIC MAPPING: IT'S ALL ABOUT RECOMBINATIONThe aim of many genetic mapping studies is to identify quantitative trait loci (QTL) that are responsible for phenotypic variation. Although often viewed as fundamentally different, linkage and association mapping share a common strategy that exploits recombination's ability to break up the genome into fragments that can be correlated with phenotypic variation. The key difference between the two methods is the control the experimenter has over recombination. On the one hand, linkage mapping is a highly controlled experiment: individuals are crossed to generate a mapping population in which relatedness is known. In plants, these are generally biparental crosses, while in humans these populations may be extended pedigrees. The experimenter thereby creates a closed system and uses a small number of genetic markers to infer the locations of the relatively few recombination breakpoints. With genotype data from across the genome, the experimenter can then determine if a chromosomal fragment between two specific breakpoints is associated with a phenotype. Association mapping, on the other hand, is not a controlled experiment, but rather a natural experiment. Genotype and phenotype data are collected from a population in which relatedness is not controlled by the experimenter, and correlations between genetic markers and phenotypes are sought within this population. This open system design provides higher mapping resol...

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