Genetic Risk Assessment for Single Gene Disorders

Flashcards covering key Mendelian principles, dihybrid crosses, probability rules, Hardy-Weinberg equilibrium, and clinical genetics risk assessments for single gene disorders like Sickle Cell Disease and Cystic Fibrosis.

Who first described the basic principles of formal genetics?

Johan "Gregor" Mendel (1822-1884).

What is meant by Mendelian inheritance?

An inheritance pattern in which the inheritance of a single mutant allele results in a specific phenotype.

What seven garden pea traits did Gregor Mendel study in his experiments?

Seed shape (round or wrinkled), seed color (yellow or green), pod shape (inflated or constricted), pod color (yellow or green), flower color (purple or white), flower position (axial or terminal), and plant height (tall or dwarf).

What does Mendel's Principle of Segregation state?

It states that sexually reproducing organisms possess genes that occur in pairs, and only one gene of each pair is transmitted to the offspring (the alleles segregate).

What 19th-century theory of inheritance was disproved by Mendel's Principle of Segregation?

The "blending" theory of inheritance.

What does Mendel's Principle of Independent Assortment state?

It states that genes at different loci are transmitted independently of each other.

In what scenario does the Principle of Independent Assortment NOT always hold true?

When genes are located close to each other on the same chromosome.

How are dominant and recessive traits defined in terms of genotype?

Dominant traits are observed in both homozygous dominant ($AA$) and heterozygous ($Aa$) states, whereas recessive traits are observed only in the homozygous recessive ($aa$) state.

What are four human physical traits that follow dominant Mendelian inheritance according to the lecture?

Mid-digital hair, tongue rolling, widow's peak, and free earlobes.

What is a dihybrid cross?

A genetic cross involving two individuals who are both heterozygous for two different genes/traits (e.g., $AaDd \times AaDd$).

What phenotypic ratio is produced in the offspring of a dihybrid cross between two double heterozygotes ($AaDd \times AaDd$)?

A $9:3:3:1$ phenotypic ratio.

How many unique genotypes are possible from a dihybrid cross of two double heterozygotes ($AaDd \times AaDd$)?

$9$ possible genotypes ($1\text{ AADD}$, $1\text{ aadd}$, $2\text{ AADd}$, $2\text{ aaDd}$, $2\text{ Aadd}$, $2\text{ AaDD}$, $4\text{ AaDd}$, $1\text{ AAdd}$, $1\text{ aaDD}$).

If a couple are both carriers for cystic fibrosis and sickle cell disease, what is the probability that they will have a child with EITHER cystic fibrosis OR sickle cell disease, but NOT BOTH?

$37.5\%$ (or $\frac{6}{16}$). This is calculated from the $\mathbf{9:3:3:1}$ dihybrid ratio by adding the two single-disease affected probabilities: $\frac{3+3}{16} = \frac{6}{16} = 0.375$.

What is a phenotype, and what factors determine it?

A phenotype is the physically or clinically observed characteristic of an organism, resulting from the interaction between its genotype and its environment (both internal/genetic and external).

How does Phenylketonuria (PKU) demonstrate environmental interaction with phenotype?

The clinical phenotypic manifestation of PKU (a genetic disorder) can be altered or prevented by modifying the individual's external dietary environment.

What is the Multiplication Rule (AND rule) in probability?

If two events are independent of each other, the probability of obtaining both outcomes is equal to the product of their individual probabilities ($P(A \text{ and } B) = P(A) \times P(B)$).

What is the Addition Rule (OR rule) in probability?

The probability of obtaining either one outcome or another mutually exclusive outcome is found by adding their individual probabilities together ($P(A \text{ or } B) = P(A) + P(B)$).

What basic rule should always be applied first when conducting a genetic risk assessment?

Always begin with the most likely situation and consider the most common reason for inheritance first.

What four population requirements must be satisfied for the Hardy-Weinberg principle to apply?

1. Large population size; 2. No natural selection for or against any genotype; 3. Random mating (panmixia) with respect to the genotype of interest; 4. Negligible rate of new mutations.

What are the Hardy-Weinberg equations for allele frequencies and genotype frequencies?

Allele frequencies: $p + q = 1.0$; Genotype frequencies: $p^2 + 2pq + q^2 = 1.0$, where $p$ is the dominant allele frequency, $q$ is the recessive allele frequency, $p^2$ is homozygous dominant, $2pq$ is heterozygous carrier, and $q^2$ is homozygous recessive.

Given a birth prevalence of Sickle Cell Disease of $1$ in $600$ ($q^2 = \frac{1}{600}$) in African Americans, what is the calculated carrier frequency ($2pq$)?

Approximately $0.08$ (or $\sim 1$ in every $12$ African Americans), calculated using $q = \sqrt{\frac{1}{600}} \approx 0.04$, $p = 1 - 0.04 = 0.96$, and $2pq = 2 \times 0.96 \times 0.04 = 0.0768 \approx 0.08$.

What gene is mutated in Cystic Fibrosis, and what is its normal function?

The $CFTR$ gene, which encodes an ATP-binding cassette (ABC) transporter that acts as a cAMP-regulated, low-conductance chloride ion channel.

What functional categories describe the five major CFTR mutation classes?

Class I: Protein production mutations (no functional protein created); Class II: Protein processing mutations (protein misfolds); Class III: Gating mutations (channel gate does not open properly); Class IV: Conduction mutations (faulty channel function); Class V: Insufficient protein mutations.

What body systems are affected by Cystic Fibrosis as a multisystem disease?

Lungs and pancreas (recurrent infections, pancreatic exocrine insufficiency leading to malnutrition), gastrointestinal system (constipation, ileus), and male genitourinary system (lack of vas deferens development leading to infertility).

Given a Cystic Fibrosis birth prevalence of $1$ in $2,500$ ($q^2 = \frac{1}{2,500}$) in European populations, what is the calculated carrier frequency ($2pq$)?

Approximately $0.04$ (or $\sim 1$ in every $25$ Europeans), calculated as $q = \sqrt{\frac{1}{2,500}} = 0.02$, $p = 1 - 0.02 = 0.98$, and $2pq = 2 \times 0.98 \times 0.02 = 0.0392 \approx 0.04$.

What is the probability that a European couple of unknown genotypes will have a child affected by Cystic Fibrosis?

$0.0004$ or $0.04\%$ (which equals $\frac{1}{2,500}$), calculated as $\frac{1}{25} \times \frac{1}{25} \times \frac{1}{4} = \frac{1}{2,500}$.

What is the probability that a man known to be a carrier of Cystic Fibrosis and his wife of European descent and unknown genotype will have a child with Cystic Fibrosis?

$0.01$ or $1\%$ (which equals $\frac{1}{100}$), calculated as $1 \times \frac{1}{25} \times \frac{1}{4} = \frac{1}{100}$.

What is the probability that a healthy sibling of an individual with severe Cystic Fibrosis is a carrier of the disease (assuming healthy parents)?

$\frac{2}{3}$ (or $\sim 66.7\%$), because both healthy parents are carriers ($Aa$), and among the three possible non-affected offspring genotypes ($AA$, $Aa$, $Aa$), two are carriers.