Question

A form of dwarfism known as Ellis-van Creveld syndrome was first discovered in the late 1930 s, when Richard Ellis and Simon van Creveld shared a train compartment on the way to a pediatrics meeting. In the course of conversation, they discovered that they each had a patient with this syndrome. They published a description of the syndrome in \(1940 .\) Affected individuals have a short-limbed form of dwarfism and often have defects of the lips and teeth, and polydactyly (extra fingers). The largest pedigree for the condition was reported in an Old Order Amish population in eastern Pennsylvania by Victor McKusick and his colleagues \((1964) .\) In that community, about 5 per 1000 births are affected, and in the population of \(8000,\) the observed frequency is 2 per \(1000 .\) All affected individuals have unaffected parents, and all affected cases can trace their ancestry to Samuel King and his wife, who arrived in the area in \(1774 .\) It is known that neither King nor his wife was affected with the disorder. There are no cases of the disorder in other Amish communities, such as those in Ohio or Indiana. (a) From the information provided, derive the most likely mode of inheritance of this disorder. Using the Hardy-Weinberg law, calculate the frequency of the mutant allele in the population and the frequency of heterozygotes, assuming Hardy-Weinberg conditions. (b) What is the most likely explanation for the high frequency of the disorder in the Pennsylvania Amish community and its absence in other Amish communities?

Short answer

Answer: Ellis-van Creveld syndrome is inherited in an autosomal recessive manner. The high frequency of the disorder in the Pennsylvania Amish community can be attributed to genetic drift and founder effect as the community is relatively isolated and has a small population, increasing the likelihood of mating between individuals carrying the same rare mutant allele.

Step-by-step solution

(a) Determine the mode of inheritance of Ellis-van Creveld syndrome

The affected individuals have unaffected parents since all affected cases can trace their ancestry to Samuel King and his wife who were both not affected. This information suggests that the syndrome is inherited in an autosomal recessive manner as the parents are carriers, but do not display the disorder themselves. So let's assume that the disorder follows the autosomal recessive pattern of inheritance.

Calculate the frequency of the mutant allele (q) and the frequency of heterozygotes (2pq)

Let p represent the frequency of the dominant allele (unaffected) and q represent the frequency of the recessive allele (mutant). From Hardy-Weinberg law, we have p^2 + 2pq + q^2 = 1 where p^2 represents the frequency of homozygous dominant individuals, 2pq represents the frequency of heterozygotes, and q^2 represents the frequency of homozygous recessive individuals. Given the frequency of affected individuals in the population: q^2 = 2/1000 = 0.002 Now, we can find the frequency of the mutant allele (q) by taking the square root of q^2: q = sqrt(0.002) ≈ 0.0447 Since p + q = 1, we can find the frequency of the dominant allele (p) by subtracting q from 1: p = 1 - q ≈ 1 - 0.0447 ≈ 0.9553 Now, we can find the frequency of heterozygotes (2pq) using the values of p and q: 2pq = 2 * 0.9553 * 0.0447 ≈ 0.0854 Thus, the frequency of the mutant allele (q) in the population is 0.0447, and the frequency of heterozygotes (2pq) is 0.0854.

(b) Explain the high frequency of the disorder in the Pennsylvania Amish community

The high frequency of the Ellis-van Creveld syndrome in the Pennsylvania Amish community can be attributed to genetic drift and founder effect. The Amish population in eastern Pennsylvania is a relatively isolated and small group, which increases the likelihood of mating between individuals who carry the same rare mutant allele. The high frequency of this disorder in this particular community but not in other Amish communities in Ohio or Indiana could be due to the fact that the common ancestors of this community, Samuel King and his wife, were carriers of the mutant allele for this syndrome. The concentration of this rare allele might've been passed through generations in this Pennsylvania community but was not present in other Amish communities, as they don't share ancestry with the carriers of this allele.

Key concepts

Autosomal Recessive Inheritance

Ellis-van Creveld syndrome, as derived from the case study, is inherited in an autosomal recessive manner. This means that the disorder manifests only when an individual inherits two copies of the mutant allele, one from each parent. In this particular scenario, affected individuals have parents who demonstrate no symptoms of the disorder themselves, suggesting the parents are carriers of the recessive allele.

In autosomal recessive inheritance:

• Both parents must carry a copy of the faulty gene to have an affected child.
• Affected individuals inherit two recessive alleles (one from each parent).
• Carrier parents often do not exhibit any symptoms.

By understanding these attributes, one can predict the likelihood of the condition appearing in future generations of a family. This mode of inheritance underlies many other genetic disorders aside from Ellis-van Creveld syndrome, highlighting the importance of genetic counseling for families at risk.

Hardy-Weinberg Principle

The Hardy-Weinberg principle is a foundational concept in genetics that provides a mathematical framework for studying genetic variation in populations. It describes how the frequencies of alleles and genotypes remain constant from generation to generation in the absence of evolutionary influences. This principle allows scientists to predict how genetic variations will distribute in a hypothetical population at equilibrium.

The equation used is: \[ p^2 + 2pq + q^2 = 1 \]
Here:

• \( p^2 \) is the frequency of homozygous dominant individuals.
• \( 2pq \) is the frequency of heterozygotes.
• \( q^2 \) is the frequency of homozygous recessive individuals.

In the context of Ellis-van Creveld syndrome, the frequency of affected individuals (\( q^2 \)) helps in estimating the prevalence of the mutant allele. In the given population, knowing \( q^2 = 0.0020 \) aids in calculating the values of \( p \) and \( q \), and thus, the frequency of carriers (\( 2pq \)).

Genetic Drift

Genetic drift is a mechanism of evolution that refers to random fluctuations in the frequencies of alleles in a small population. These fluctuations can lead to significant changes over time, especially in isolated or small communities like the Amish. As a result, certain rare traits, such as those causing Ellis-van Creveld syndrome, can become more common in these groups due to these random changes.

Key points include:

• Acts strongly in small populations, where random events can significantly alter allele frequencies.
• Can lead to the loss of alleles or fixation of alleles over generations.
• Does not necessarily produce advantageous adaptations but can shape the genetic structure of a population over time.

In isolated communities such as the Pennsylvania Amish, genetic drift can have a pronounced impact, contributing to the elevated frequency of certain genetic disorders.

Founder Effect

The founder effect occurs when a new population is established by a small number of individuals, carrying only a fraction of the genetic variation present in the original population. This often results in a higher representation of certain alleles, which might be rare in the larger original population. For the Pennsylvania Amish, the founder effect is a significant factor behind the relatively high incidence of Ellis-van Creveld syndrome.

This effect is exemplified when:

• A small group of people, such as Samuel King and his wife, form a new, isolated community.
• This new population's genetic diversity is limited to that of the founders.
• Rare genetic traits can become common if present in the founders.

Thus, the syndrome's prevalence in the Pennsylvania Amish can somewhat be traced back to the genetic characteristics brought by its original founders, demonstrating the powerful impact of the founder effect on genetic disorders.