Evaluating candidate agents of selective pressure for cystic fibrosis

Abstract

Cystic fibrosis is the most common lethal single-gene mutation in people of European descent, with a carrier frequency upwards of 2%. Based upon molecular research, resistances in the heterozygote to cholera and typhoid fever have been proposed to explain the persistence of the mutation. Using a population genetic model parameterized with historical demographic and epidemiological data, we show that neither cholera nor typhoid fever provided enough historical selective pressure to produce the modern incidence of cystic fibrosis. However, we demonstrate that the European tuberculosis pandemic beginning in the seventeenth century would have provided sufficient historical, geographically appropriate selective pressure under conservative assumptions. Tuberculosis has been underappreciated as a possible selective agent in producing cystic fibrosis but has clinical, molecular and now historical, geographical and epidemiological support. Implications for the future trajectory of cystic fibrosis are discussed. Our result supports the importance of novel investigations into the role of arylsulphatase B deficiency in cystic fibrosis and tuberculosis.

Figure 1

Age-specific probability of death owing to candidate diseases from historical records (Woods & Shelton 1997). Tuberculosis curve represents the peak of the European epidemic during 1600–1900, with 20% of all-cause mortality; the rates we used prior to 1600 were fractions of the same curve. SDC refers to secretory diarrhoea including cholera, and hence includes diarrhoea due to E. coli.

Figure 2

Model realizations of CF incidence over time for candidate diseases, given 100% resistance (ρ=1) to the specified disease. Tuberculosis has been assigned responsibility for a fraction, τ=1.6%, of mortality prior to 1600. All the populations are initiated with 1 in 20 000 CF allele frequencies. Typhoid fever and SDC were initiated 50 000 yrBP. Tuberculosis was given the more restrictive start time of 18 000 yrBP. Under these conditions, tuberculosis resistance produces an observed modern European CF incidence of 1 in 3000 (arrow). The inflection point in the tuberculosis curve is due to the conservative assumption that tuberculosis rates jumped to their historically documented levels in 1600, rather than increasing gradually prior to 1600.

Figure 3

Range of CF incidences given resistance to tuberculosis in the heterozygote. The independent variables are fraction of resistance to tuberculosis in the CF carrier and percent of all deaths owing to tuberculosis prior to the pandemic that began in the 1600s. From 1600 until 1900, 20% of all deaths are ascribed to tuberculosis, as it is consistent with historical records. Light grey regions indicate combinations of parameters that could have produced the observed CF incidence (greater than 1 in 3000) in Europe. Tuberculosis resistance is a sufficient cause of CF across a broad range of parameters. In contrast, neither SDC nor typhoid fever produces sufficient CF incidence in any region of their parameter space, even allowing peak mortality levels extending back indefinitely into the past—their entire graphs are dark grey (not shown).