Lessons from model organisms: phenotypic robustness and missing heritability in complex disease

Abstract

Genetically tractable model organisms from phages to mice have taught us invaluable lessons about fundamental biological processes and disease-causing mutations. Owing to technological and computational advances, human biology and the causes of human diseases have become accessible as never before. Progress in identifying genetic determinants for human diseases has been most remarkable for Mendelian traits. In contrast, identifying genetic determinants for complex diseases such as diabetes, cancer, and cardiovascular and neurological diseases has remained challenging, despite the fact that these diseases cluster in families. Hundreds of variants associated with complex diseases have been found in genome-wide association studies (GWAS), yet most of these variants explain only a modest amount of the observed heritability, a phenomenon known as "missing heritability." The missing heritability has been attributed to many factors, mainly inadequacies in genotyping and phenotyping. We argue that lessons learned about complex traits in model organisms offer an alternative explanation for missing heritability in humans. In diverse model organisms, phenotypic robustness differs among individuals, and those with decreased robustness show increased penetrance of mutations and express previously cryptic genetic variation. We propose that phenotypic robustness also differs among humans and that individuals with lower robustness will be more responsive to genetic and environmental perturbations and hence susceptible to disease. Phenotypic robustness is a quantitative trait that can be accurately measured in model organisms, but not as yet in humans. We propose feasible approaches to measure robustness in large human populations, proof-of-principle experiments for robustness markers in model organisms, and a new GWAS design that takes differences in robustness into account.

Figure 1. HSP90 inhibition increases homologous recombination in plants.

(A) Transgenic plants carrying reporter constructs that monitor somatic homologous recombination (HR) events were grown with and without HSP90 inhibition. HR restores a functional GUS gene, allowing for detection of somatic HR events. Intra-chromosomal HR events were significantly increased in plants grown with the HSP90 inhibitor geldanamycin for direct and indirect repeat reporter constructs (Poisson regression p = 0.0078). A total of 925 seedlings were analyzed with 381 seedlings for the direct repeat reporter line and 544 for the indirect repeat reporter line. (B) Example of somatic HR event in plant leaf (blue circle around GUS spot) (unpublished data by K. Carlson, A. Nuttle, and C. Queitsch).

Figure 2. Current and suggested GWAS approaches.

(A) Current approach. GWAS identify variants that are overrepresented in cases. Rare variants of large effect (red square, blue star) may escape detection, thereby contributing to missing heritability. Common variants that are overrepresented in cases (small yellow bar, 6 versus 2) do not contribute strongly to disease risk. A cryptic disease-related variant does not show significant overrepresentation in cases (open circle). (B) Suggested approach. Individuals are first analyzed for phenotypic robustness (bold box) and then for variants associated with disease. Rare variants of large effect will be enriched in robust cases, although they may also be present in nonrobust cases. Variants that are overrepresented in all cases (robust, nonrobust) will show higher penetrance in nonrobust individuals (large yellow bars). The formerly cryptic, disease-related variant (open circle) is significantly enriched in nonrobust cases versus nonrobust controls (and robust cases) and can therefore be identified. Together, heritability significantly increases. The formerly cryptic genetic variant and higher penetrance variant can be thought of as “disease-specifiers” as they determine the specific disease phenotype of individuals carrying them. Note symbols represent highly simplified frequencies of specific variant in indicated groups and not individuals carrying certain variants.