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.” (more…)

Growing Complexities in Relating Genotype to Phenotype

Geneticists and evolutionary biologists have for decades embraced the view, no doubt reinforced by terminology such as “silent” (i.e., synonymous) mutations, that for protein-encoding genes, genotype determines phenotype through control of the amino acid sequence of the corresponding polypeptide chain or chains.  In various contexts, the standard assumption has therefore been that only non-synonymous nucleotide substitutions in a gene have an impact on the phenotype and are subject to selection.

In 2007, Kimchy-Sarfaty et al. (Science) described a likely exception to the conventional wisdom (more…)