Randolph Nesse
Natural selection shapes living systems to such remarkable efficacy and robustness that disease vulnerability is usually and correctly attributed to the limits of natural selection. Mutation, migration, genetic drift, path dependence and the slow pace of evolution are important explanations for disease vulnerability. Some systems are, however, intrinsically vulnerable to failure for other reasons. The role of tradeoffs is well-recognized, but it may have wider applications than is often appreciated. For instance, antagonistic pleiotropy provides benefits early in life that maximize reproduction at the cost of a shorter life span. Systems that regulate defenses such as immune responses and anxiety are expected to generate false alarms because the costs of not responding are far higher than the costs of a false alarm. Some such systems become more responsive after repeated arousal, making them inherently vulnerable to runaway positive feedback, as may be illustrated by panic disorder and cytokine storm. Traits with cliff-edged fitness functions are especially vulnerable to failure. Strong selection on a trait vulnerable to catastrophic failure, such as racehorse bones, is an example. Even in the absence of strong recent selection, such traits are likely to be vulnerable because natural selection shapes them to a mean value that maximizes multigenerational gene transmission despite the associated increase in the proportion of population with low fitness. Pathogen pressure is likely to also shape fitness functions with steep slopes. Higher telomerase activity and numbers of stem cells provide advantageous tissue repair but increases the risk of cancer. Uric acid concentrations give increasing antioxidant benefits until crystals form and cause gout. The high heritability of many diseases is turning out to arise from the tiny effects of many alleles spread across the entire genome. Some are deleterious mutations subject to mutation selection balance, but some may be maintained because they influence the level of a trait with a cliff-edged fitness function. Disorders that can be considered in this light include epilepsy, atrial fibrillation, migraine headaches, and schizophrenia.
