The complexity of the genotype-phenotype relationship and the limitations of using genetic "markers" at the individual level

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Many associations have recently been discovered between phenotypic variation and genetic loci, causing some to advocate what Robert Sinsheimer has called "a new eugenics" that would treat genetic "defects" in individuals prone to a disease. The first premise of this vision is that genetic association studies reveal the biological cause of the phenotypic variation. Once the responsible genes are known, the second premise is that we should focus upon changing "nature" rather than "nurture" by correcting the "defective" genes. The first premise is flawed because associations between genetic markers and phenotypes can be spurious, as shown by an example. Moreover, it is shown that using non-causative but associated genetic markers one at a time (the normal practice) can lead to incorrect predictions of disease risk for many individuals. Going from association to causation is a non-trivial step scientifically that has rarely been done in much of the human genetic research. Even when a particular locus does contribute to the phenotypic variation of interest, the first premise remains flawed because phenotypes in general arise from complex interactions among genes and between genes and environments as shown for genes associations with coronary artery disease (CAD). The ability of current molecular genetic tools to "fix" defective genotypes is extremely limited, but even if the technological problems could be overcome, the studies on CAD reveal no obvious "defective" gene to fix because the genetic effects are so context dependent (upon both other genes and environmental factors). Contrary to the second premise of the new eugenics, the more we learn about how different genotypes show variable responses to environments, the more important the environment becomes for individual treatment. The paradigm of a "defective gene" may work for classical Mendelian genetic diseases that are due to loss-of-function mutations. However, such mutations affect only a small portion of humanity. When the focus is changed to common disease and behavioral phenotypes, the "defective gene" paradigm is biologically meaningless and often harmful when applied to individuals. Thus, even when genes clearly do influence common phenotypic variation, the premises of the "new eugenics" are biologically indefensible.

Original languageEnglish
Pages (from-to)373-389
Number of pages17
JournalScience in Context
Issue number3-4
StatePublished - 1998
Externally publishedYes

Bibliographical note

Funding Information:
important and fascinating symposium. Finally, I thank two anonymous reviewers for their suggestions for improving an earlier draft of this paper. This work was supported by NIH grant R01 HL39107.

ASJC Scopus subject areas

  • General Social Sciences
  • History and Philosophy of Science


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