The mystery of the mystery of common genetic diseases

Abstract

Common monogenic genetic diseases, ones that have unexpectedly high frequencies in certain populations, have attracted a great number of conflicting evolutionary explanations. This paper will attempt to explain the mystery of why two particularly extensively studied common genetic diseases, Tay Sachs disease and cystic fibrosis, remain evolutionary mysteries despite decades of research. I review the most commonly cited evolutionary processes used to explain common genetic diseases: reproductive compensation, random genetic drift (in the context of founder effect), and especially heterozygote advantage. The latter process has drawn a particularly large amount of attention, having so successfully explained the elevated frequency of sickle cell anemia in malaria-endemic areas. However, the empirical evidence for heterozygote advantage in other common genetic diseases is quite weak. I introduce and illustrate the significance of a hierarchy of genetic disease phenomena found within the genetic disease explanations, which include the phenomena: single mutation variants of a common genetic disease, single genetic diseases, and classes of diseases with related phenotypic effects. I demonstrate that some of the confusion over the explanations of common genetic diseases can be traced back to confusions over which phenomena are being explained. I proceed to briefly evaluate the existing evidence for two common human genetic diseases: Tay Sachs disease and cystic fibrosis. The above considerations will ultimately shed light on why these diseases' evolutionary explanations remain so deeply unresolved after so such a great volume of research.

Ten questions for evolutionary studies of disease vulnerability

“…Analysis of new genetic evidence shows positive selection in Askanazi Jews for ability to metabolize alcohol and lactose, but the frequency of sphingolipid diseases seems better accounted for by bottleneck effects ( Bray et al 2010 ). Another review considers the general difficulties of reaching firm evolutionary conclusions about the evolutionary significance of recessive alleles and the excessive attention associated with hypotheses about heterozygote advantage ( Valles 2010 ). This review also documents the prevalence of confusion arising from failure to specify the exact object of explanation, and it provides a useful taxonomy of evolutionary explanations for alleles that cause disease (see Table 2 ).…”