Cystic Fibrosis Questions

These questions address the J. R. Soc. Interface article entitled “Evaluating candidate agents of selective pressure for cystic fibrosis” by Poolman and Galvani, 2007. Be sure to explain your answers.

1. Is cystic fibrosis a qualitative or quantitative trait?

The introduction asserts that about 2% of the population are carriers of the CF allele. Using H-W, tell me the frequency of the mutant alleles in the population (q), as well as the frequency of the wild type allele (p).

• Cystic fibrosis is a qualitative trait, meaning that trait or allele is either present or absent. In the case of cystic fibrosis, the recessive allele must be present for a person to have the disease.
• 2%=0.02 are carriers of CF allele
• q² = 0.02

            √0.02 = 0.14142

1-0.14142 = 0.85858 = p

q frequency (mutant allele) = 0.14142

p frequency (wild type allele) = 0.85858

• Check: p² + 2pq + q² = 1

(0.85858)² + 2(0.85858)(0.14142) + (0.14142)² = 1

0.73716 + 0.24284 + 0.02 = 1

1 = 1

2. What evidence do the authors have that tuberculosis was sufficient to act as a selective agent for CF heterozygotes?

• “The correct selective agent must be plausible according to three lines of evidence: molecular, clinical; and historical-geographical” (Poolman and Galvani 2006).

• 1. “Resistance to tuberculosis in CF patients was recently postulated to arise from diminished activity of the enzyme arylsulphatase B” (Tobacman 2003).

“Thus, dysfunction of arylsulphatase activity in CF is postulated to protect against tuberculosis by depriving the bacteria of a necessary nutrient” (Tobacman 2003).

• 2. Clinical evidence: “There is also clinical evidence of an association between CF and resistance to tuberculosis. A lower tuberculosis mortality rate has been observed among heterozygotes versus controls” (Crawfurd 1972).
• 3. The low incidence of tuberculosis in CF patients has been noted by a number of investigators (Poolman and Galvani 2006)
• “Thus, tuberculosis is supported by both molecular and clinical evidence” (Poolman and Galvani 2006)
• 4. As the researchers model relates CF to tuberculosis, “it predicts that the incidence of CF will fall in regions of the world where tuberculosis is well controlled at a rate of approximately 0.1% per year” (Poolman and Galvani 2006).

3. If, in a population like that of early 17th-century Europe, heterosis were acting on the CF alleles, what might you expect to happen to these alleles over the long term? In a region with no selective pressure conferred by tuberculosis, what would happen to the recessive CF alleles? (Think fitness tables...)

• Heterosis is the tendency of heterozygotes to show qualities superior those of both parents. This is also known as heterozygote superiority (Freeman and Herron 2014).

• If heterosis were acting on CF alleles, it would be expected that both the CF alleles and wild-type alleles would eventually reach an equilibrium.
• If there is no selective pressure conferred by tuberculosis, it is assumed that selection is still acting on the CF alleles. In that case, the recessive CF allele will go towards extinction (but not reach it). In addition, the wild-type dominant allele will go towards and eventually reach fixation.

4. Could founder effect have generated the levels of CF we see today? Why or why not?

• The founder effect is a sampling error in the origin of a small population due to sampling error, only a small fraction of genetic variation in the parent population will be present in the small number of individuals in the founder population (Freeman and Herron 2014). "The founder effect has been proposed to explain the high incidence of CF" (Klinger 1983).
• In this study, the founder effect was modeled as a putative [assuming to have existed] bottleneck population consisting solely of heterozygotes (Poolman and Galvani 2007). "In such a population, CF incidence begins at 1 in 4 births and decays below the observed European incidence in 1800 years" (Poolman and Galvani 2007). Therefore, their model demonstrates that a founder effect could not have proceded the current existing levels of cystic fibrosis, as there has been no such dramatic bottleneck for the entire European population within the past 1800 years.

5. Note: for mathematical modeling of the population, the authors used Freeman and Herron (2004) as their source. What significance does this source have to you?

• This source is our current evolution textbook. We are utilizing the fifth edition in class, but the researchers of this paper used an edition published in 2004 by the same authors.

Works Cited

Crawfurd, M.A., 1972 A genetic study, including evidence for heterosis, of cystic fibrosis of the pancreas. In 168^th Meeting of the Genetical Society of Great Britain, pp. 126. University of Leeds.

Freeman, S. & Herron, J. C., 2004 Evolutionary analysis. Upper Saddle River, NJ: Pearson Prentice Hall.

Freeman, S. & Herron, J. C., 2014 Evolutionary analysis. 5^th ed. Upper Saddle River, NJ: Pearson Prentice Hall.

Klinger, K. W. 1983, Cystic fibrosis in the Ohio Amish: gene frequency and founder effect. Hum. Genet. 65, 94-98. (doi:10.1007/s004390050407)

Poolman, E. M., & Galvani, A. P., 2007. Evaluating candidate agents of selective pressure for cystic fibrosis. Journal of The Royal Society Interface, 4(12), 91-98.

Tobacman, J.K., 2003. Does deficiency of arylsulfatase B have a role in cystic fibrosis? Chest 123, 2130-2139. (doi:10.1378/chest.123.6.2130)