Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases
- Subject Areas
- Evolutionary Studies, Genetics, Medical Genetics, Public Health
- Natural selection, Mendelian, Complex disease, mutational robustness, Penetrance, Pleiotropism, genetic architecture, age at onset
- © 2013 Baysal
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Cite this article
- 2013. Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases. PeerJ PrePrints 1:e42v1 https://doi.org/10.7287/peerj.preprints.42v1
Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset).
Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases.
Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases.
Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.
WHO ICD10 International Classification of Diseases
Expanded review of selected common diseases for nonsyndromic Mendelian susceptibility genes
A hypothetical model for mutational robustness in early versus late onset complex diseases
The genetic architecture of late onset common diseases (upper panel) has fewer protective variants (depicted by columns and springs) when compared to early onset common diseases (lower panel). (A random individual is illustrated in the first diagram of each panel.) An abundance of protective variants in early onset common diseases enables buffering of the deleterious coding mutations. In this model, the development of disease (depicted by the tilting of the gene-environment interface platform) is assumed to be primarily driven by environmental factors (depicted by triangles) that accumulate gradually over a lifetime for late onset common diseases, but more rapidly for early onset ones. The types of protective variants (i.e., coding, regulatory) are described in the upper panel. The width of a protective variant is proportional to the relative risk conferred by its loss. Rare variants that alter conserved ancestral genes are assumed to confer the highest relative risk. Protective alleles in early onset common diseases that are enriched by natural selection are assumed to be primarily non-ancestral regulatory variants (depicted by springs). Mutational robustness is constrained in syndromic common disease predisposition genes (depicted by long columns) compared to the non-syndromic genes.