The Prominence and Pertinence of Pleiotropy

Randy Nesse recently reviewed a new book (“The Evolution of Obesity” by Power and Schulkin) on weight regulation [Nature, 2009)].  In the course of the review, Nesse took note of the authors’ evidence that leptin-associated function is highly context-dependent, where context includes tissue, age, general organismal condition, and the concentrations of other molecules that regulate metabolism.  Consequently, Nesse concluded that, “Attributing one function to a hormone is attractive, but often wrong.”

Based on the preceding, it would be reasonable to expect that the gene encoding leptin would exhibit pleiotropy, the property by which mutations of a single gene can influence multiple traits or phenotypes.  Evidence supporting this inference has been obtained in mice, where homozygosity for a nonsense mutation that shortens the leptin gene product and causes deficient signaling through the leptin receptor is associated with phenotypes including increased body weight, decreased fat-free body mass, decreased lung and mammary tumor incidence, increased blood concentrations of insulin and cortisol, and decreased fertility relative to control, leptin-replete mice (Wolff, GL. J Nutr. 1997).

An experience that brought to mind Nesse’s point about hormones frequently having multiple functions was my recent reading of Michael Sandel’s book, “The Case Against Perfection: Ethics in the Age of Genetic Engineering.”  While the central arguments of this slim volume are clearly explicated and generally worthy of consideration, the implicit underlying assumption about the DNA sequences that might be targets for those wishing to genetically engineer “better” phenotypes appears to be that they each have one well-defined role in the body’s economy.  This assumption is highly doubtful in most instances.  While technology may advance to the point where it is feasible to reliably alter the genome of a human embryo, current knowledge would suggest that it will generally be more challenging than some commentators appear to believe to achieve fine control over the phenotype of the resulting human being.

A recent paper by Edwards et al. (BMC Biol., 2009) on the genetic basis of aggressive behavior in drosophila adds further support to the dictum that gene products and genes, when studied with sufficient intensity and in a sufficiently broad range of contexts, will prove to have multiple functional correlates, what might be called the Principle of Pervasive Protein Pleiotropy.  As Edwards et al. state:  “The general picture emerging from the analysis of quantitative effects of de novo mutations that have been induced in a defined isogenic background is that a large fraction of the genome can potentially affect most quantitative traits, including complex behaviors. Consequently, we expect that most genes have pleiotropic effects on multiple traits…Further, different mutations in the same gene can have a different spectrum of pleiotropic effects, and the mutational effects on any one trait can be contingent on genetic background and the environment.” In their review (Am J Psychiatry, 2006) of earlier studies on the genetics of behavior in model organisms (mice, fruit flies, and nematodes), Kendler and Greenspan strongly support these conclusions.

So, in evaluating the claims of those who are espousing particular policies and agendas relating to personalized medicine, bioethics, and other trendy biomedical causes it will be useful to recall these basic realities that apply to many, perhaps most, genes.  As the great evolutionary theorist, Sewall Wright (cited in part by Wolff), stated 75 years ago:

“We are sure, for example, that development is an epigenetic process.  The genes can not [sic] stand in the simple one to one relation to morphological characters of a pre-formationist theory. … Each character is affected by many genes and each gene affects many characters.”

References

Nesse R. Digesting evolution. Nature 2009; 460:461.

Wolff GL. Obesity as a pleiotropic effect of gene action. J Nutr. 1997 Sep;127(9):1897S-1901S.

Sandel MJ. The Case Against Perfection: Ethics in the Age of Genetic Engineering. Belknap Press, Cambridge, MA, 2007.

Edwards AC, Zwarts L, Yamamoto A, Callaerts P, Mackay TF. Mutations in many genes affect aggressive behavior in Drosophila melanogaster. BMC Biol. 2009; Jun 11;7:29.

Kendler KS, Greenspan RJ. The nature of genetic influences on behavior: lessons from “simpler” organisms. Am J Psychiatry 2006 Oct;163(10):1683-94.

Wright S. Physiological and evolutionary theories of dominance. Am. Nat. 1934; 68:25-53.