Application of molecular techniques to the study of human physiological variation

Physiological differences between human populatios, manifest as apparent adaptation to extreme environments, as differences in patterna of growth and development, and as differences in prevalence of common disease, are a mofer subject area of human biology. The approach of the geneticist interested in understanding these difference has been largely that of the proverbial drunk looking for has lost keys. We have characterized those genes whose products are easily assayed from peripheral blood and sought post hoc statistical evidence for a relationship between gene frequencies and physiological variables. With few exceptions, this approach has failed to provide convincing evidence of the role of genes in determining physiological differences between populations. This is not unexpected since the genes which our knowledge of physiology would predict to be important in determining physiological homeostasis. Recent advances in molecular biology (particularly in the ability to isolate and clone specific genes and to use these as probes to detect genomic variation-polymorphism-associated with these genes in human populations) and advances in our ability to resolve and visualize genetic variation in protein products provide the tools for a direct evaluation of the role of specific gene in determining physiological differences between populations. I will review the "candidate genes" available for the study of several physiological systems and present preliminary data from my laboratory related to genetic determinants of lipid metabolism.