1 Why does cystic fibrosis (CF) show the prevalence and distribution observed in human populations? A literature review

Abstract

Objective To explain: 1.The prevalence of CF despite sufferers' reduced evolutionary fitness. 2.The higher frequency of carriers in European populations, 1:25 (UK) vs 1:150 (Japan). Methods A literature search from 1960 to 2014 was conducted using the key words CF, CFTR, genetics, epidemiology, and evolution, to identify relevant research. Results The following factors were considered: 1.Genetic mutation. 2.The ‘founder effect'. 3.Heterozygote advantage, conveyed either by reproductive advantage, or immunity to an infectious disease. Three candidate agents emerged: a.Vibrio cholerae. It is geographically incongruent. The original cholera reservoir existed in the Ganges river in India, and was only spread to Europe via trade routes in the 19th century. Cholera did not kill enough people to explain the observed frequency, even if heterozygotes' immunity was 100%. b.Salmonella typhi. c.Mycobacterium tuberculosis (TB). TB was seen as a ‘white plague'. As humans moved North, hunter-gatherers became farmers. Intimate human contact, along with the domestication of cattle, accelerated spread. TB comfortably killed enough people. A heterozygote resistance of just 13% would explain the observed allele frequency. In vitro, fibroblasts of heterozygotes produce an excess of hyaluronic acid, a substance with a known role in defence against TB. Conclusion 1.The most influential factor in causing the high CF prevalence in Caucasians is heterozygote advantage to TB. 2.The ‘founder effect' accounts for the additional amplification of allele frequency in emigrant populations, e.g. Ohio Amish. 3.Mutations continually increase the CF allele pool at a linear rate across all populations.