Antagonistic Pleiotropy in Human Disease.

Between the 1930s and 1950s, scientists developed key principles of population genetics to try and explain the aging process. Almost a century later, these aging theories, including antagonistic pleiotropy and mutation accumulation, have been experimentally validated in animals. Although the theories have been much harder to test in humans despite research dating back to the 1970s, recent research is closing this evidence gap. Here we examine the strength of evidence for antagonistic pleiotropy in humans, one of the leading evolutionary explanations for the retention of genetic risk variation for non-communicable diseases. We discuss the analytical tools and types of data that are used to test for patterns of antagonistic pleiotropy and provide a primer of evolutionary theory on types of selection as a guide for understanding this mechanism and how it may manifest in other diseases. We find an abundance of non-experimental evidence for antagonistic pleiotropy in many diseases. In some cases, several studies have independently found corroborating evidence for this mechanism in the same or related sets of diseases including cancer and neurodegenerative diseases. Recent studies also suggest antagonistic pleiotropy may be involved in cardiovascular disease and diabetes. There are also compelling examples of disease risk variants that confer fitness benefits ranging from resistance to other diseases or survival in extreme environments. This provides increasingly strong support for the theory that antagonistic pleiotropic variants have enabled improved fitness but have been traded for higher burden of disease later in life. Future research in this field is required to better understand how this mechanism influences contemporary disease and possible consequences for their treatment. [ABSTRACT FROM AUTHOR]

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