Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups
Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.
Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-Based on the passage, is the mutated PKD1 allele likely to be eradicated from the gene pool by natural selection?

Question

Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups

Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.

Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-Based on the passage, is the mutated PKD1 allele likely to be eradicated from the gene pool by natural selection?

Quizplus · Accepted Answer

11ecba2d_0f95_7366_a3bf_d938c849993e_MD0008_00 Evolution by means of natural selection occurs via the propagation of genes encoding phenotypes that provide organisms with improved survivability and reproductive capabilities in a given environment. Over time, the genes that are better adapted to the environment are selected for and are more likely to be passed on to the next generation. However, genes that are less suited to the environment or deleterious (ie, causing premature death or disease) are slowly removed from the gene pool because the individuals who possess these unfavorable phenotypes are less likely to survive and reproduce. According to Table 1, the mean age of ADPKD onset is ~58 for patients with PKD1 mutations and ~80 for patients with PKD2 mutations. This finding signifies that the observable characteristics of the disease do not emerge until after child-bearing age. Although ADPKD-causing dominant alleles are deleterious, they are able to remain in the gene pool and escape eradication by natural selection because they can be passed to an affected individual's offspring before the individual's reproductive capabilities are affected. (Choice A) If the relationship between the alleles is one of autosomal dominance (eg, ADPKD), then despite having a heterozygous genotype, the organism displays only the dominant phenotype. Therefore, a dominant allele cannot, by definition, be masked (hidden). (Choice B) The inclusive fitness of an individual is the sum of direct fitness (its own reproduction) and indirect fitness (its cooperative behavior to increase the number of offspring by close relatives). Therefore, inclusive fitness serves as a metric of an individual's total evolutionary success. The PKD1 mutation does not improve survival/reproduction of the affected individual or any of his or her family members. (Choice C) In directional selection, one extreme phenotype is favored over all other phenotypes because of the additional fitness it confers. Consequently, the frequency of the related allele increases dramatically within a population. ADPKD does not improve fitness; therefore, it gains no directional advantage over the wild-type phenotype (ie, healthy kidneys). Educational objective: Deleterious dominant alleles can remain in the gene pool if the organism's fitness remains unaffected, even when the deleterious alleles reduce survival after the reproductive years. Deleterious recessive alleles evade elimination by natural selection through phenotypic masking in heterozygotes.

Passage Autosomal Dominant Polycystic Kidney Disease (ADPKD) Is One of the the Most