Eric Lander and David Botstein on Mapping Quantitative Traits

The rediscovery of Mendel’s work in the early 20th century sparked heated debate about the inheritance of continuously variable “size” traits (e.g., East 1916). But, although evidence accumulated in support of Mendelian models of quantitative trait inheritance, for most of the century it was rare for geneticists to be able to link such traits to specific Mendelian factors. The principles of mapping quantitative traits to qualitative characters had been well understood since Sax (1923) established the linkage of seed size to pigmentation in beans. What was missing was a systematic method to identify the specific factors underlying quantitative traits, to estimate their effects, and to characterize their interactions.

The foundation for change began with a proposal to develop genome-wide maps of restriction fragment length polymorphism (RFLP) markers in humans (Botstein et al. 1980). In principle, RFLP markers fell close enough together that the whole genome could be efficiently scanned for linkage to a trait of interest. But it was the landmark article of Lander and Botstein (1989) that brought together the power of model organism crosses with genome-wide RFLP maps and provided a systematic strategy for mapping the long sought factors or quantitative trait loci (QTL). The key innovation—known as interval mapping—is a statistical algorithm to use all of the information available in the genome-wide markers. This increased the power and precision of mapping in comparison to older methods that evaluated linkage one marker at a time. By bridging the gaps between markers, the log-likelihood profiles obtained from interval mapping provided the first genome-wide view of the QTL landscape.

Lander and Botstein (1989) is rich with ideas and open questions that fueled methodological research, including the problem of multiple testing in genome-wide searches (Churchill and Doerge 1994). Lander and Botstein (1989) also addressed practical questions of study design that inspired and empowered hundreds of applications of their method in agricultural, biomedical, and basic research in the decades that followed.

Researchers were soon faced with new questions and challenges, however. QTL were numerous and the effort of isolating the causal genes and variants often proved to be daunting. Studies of blood pressure in the laboratory rat, for example, identified QTL on almost every chromosome (Rapp 2000). QTL could encompass multiple tightly linked variants; they were often dependent on genetic background or environmental contexts; their effects could be small or large, pleiotropic, additive, or epistatic. In an early and innovative application, Damerval and colleagues (1994) applied QTL mapping to the quantitative expression of proteins (Damerval et al. 1994). QTL mapping of molecular phenotypes has since revealed elaborate networks of genetic regulation. Application of Lander and Botstein’s method for isolating Mendelian factors has revealed the true magnitude of quantitative genetic complexity, confirming an expectation set forth a century ago by the first geneticists.