Role in Disease
The survival of many serious genetic disorders in our long evolutionary history has led researchers to reassess the role of antagonistic pleiotropy in disease. If genetic disorders are defined by the existence of deleterious alleles, then natural selection acting over evolutionary time would result in a lower frequency of mutations than are currently observed. In a recent article, Carter and Nguyen identify several genetic disorders, arguing that far from being a rare phenomenon, antagonistic pleiotropy might be a fundamental mechanism for the survival of these non-optimal alleles.
In one of these studies, 99 individuals with Laron Syndrome (a rare form of Dwarfism) were monitored alongside their non-dwarf kin for a period of ten years. Patients with Laron Syndrome possess one of three genotypes for the growth hormone receptor gene (GHR). Most patients have an A->G splice site mutation in position 180 in exon 6. Some others possess a nonsense mutation (R43X), while the rest are heterozygous for the two mutations. Interestingly, Laron Syndrome patients experienced a lower incidence of cancer mortality and diabetes compared to their non-dwarf kin. This suggests a role for antagonistic pleiotropy, whereby a deleterious mutation is preserved in a population because it still confers some survival benefit.
Another instance of antagonistic pleiotropy is manifested in Huntington's disease, a rare neurodegenerative disorder characterized by a high number of CAG repeats within the Huntingtin gene. The onset of Huntington’s is usually observed post-reproductive age and generally involves involuntary muscle spasms, cognitive difficulties and psychiatric problems. Incidentally, the high number of CAG repeats is associated with increased activity of p53, a tumor suppressing protein that participates in apoptosis. It has been hypothesized that this explains the lower rates of cancer among Huntington’s patients. Huntington’s disease is also correlated with high fecundity.
Sickle cell anemia, Beta-thalassemia, and cystic fibrosis are some other examples of the role antagonistic pleiotropy may play in genetic disorders.
Read more about this topic: Antagonistic Pleiotropy Hypothesis
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