EVOLUTIONARY MODELS OF QUANTITATIVE DISEASE RISK-FACTORS

Numerous mutations are now known that have significant effects on vari ous phenotypes; many of these mutations are of interest because they i nfluence quantitative risk factors for major diseases. Such diversity raises the question of how much genetic heterogeneity we should expect to find in the effects of alleles, that is, the size of the effects, the number of severe alleles, and their frequency in the population. C an evolutionary models suggest a general pattern? In this article we e xamine what is currently known about several basic aspects of the prob lem. These include the distribution of quantitative effects of new mut ations on a phenotype, the distribution of allelic effects that would be found in a natural population, and the relationship between these e ffects and Darwinian fitness. We discuss these issues in light of vari ous models that have been proposed and the existing relevant data. The n we consider how these points relate to the distribution of genetic e ffects on an important human trait, the cholesterol ratio, an importan t risk factor for coronary heart disease. The complexities of quantita tive traits and inadequacies in the available data prevent definitive models that can directly connect the mutational effects, allelic effec ts, and fitness distributions from being developed, and we consider ho w sample limitations and the nonequilibrium of human populations cause d by our demographic history make rigorous solutions difficult. Howeve r, based on what is currently known, we argue that for human quantitat ive chronic disease risk factors the nearly neutral models of allelic evolution at single loci probably apply reasonably well. In general, a nd although much is still speculative, the data available for such ris k factors are consistent with these expectations and may enable us to predict many aspects of etiologic heterogeneity for human disease.