Use of alternative promoters may hide genetic effects on phenotypic traits

Abstract

Genome-wide association studies have identified a multitude of single-nucleotide polymorphisms (SNPs) associated with a wide spectrum of human phenotypic traits. However, the SNPs identified so far do not explain much of the expected genetic variation and they are poor predictors of the occurrence of disease. I recently advanced the hypothesis that there is person-to-person variation in the use of alternative regulatory elements (for example, gene promoters) and this new source of variation may explain in part the low genetic variation accounted for known genetic variants. In the present report a simple mathematical model is developed to explore the biological consequences of the proposed hypothesis. The model predicts that in presence of person-to-person variation in the use of alternative promoters the observable effects of genetic variants located inside promoters will be smaller than their actual effects. As a consequence, genetic variation because of those observed polymorphisms will be reduced. The present report suggests new paths of research to elucidate the genetic basis of human complex traits. © 2013 The Japan Society of Human Genetics. All rights reserved.