Molecular heterosis: a review.

Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counterintuitive to the expectation that if the 1 allele of a two-allele polymorphism is associated with a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to 50% of all gene associations. A number of examples are reviewed, including those for the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor. Several examples are given in which the heterosis is gender-specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U-shaped response curve in which either to little or too much gene expression is deleterious, with optimal gene expression occurring in 12 heterozygotes. The second proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score, while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele-based linkage techniques usually miss heterotic associations. Because up to 50% of association studies show a heterosis effect, this can significantly diminish the power of family-based linkage and association studies. Copyright 2000 Academic Press.