Molecular Genetics

Molecular Genetics US Medical PG Question 1: A researcher is investigating compounds that modulate the cell cycle as possible chemotherapeutic agents against peripheral T-cell lymphoma. The researcher discovers a group of natural compounds with inhibitory activity against histone deacetylases, a class of enzymes that remove acetyl groups from the lysine residues of histones. A histone deacetylase inhibitor most likely causes which of the following?

• A. Prevention of DNA strand reannealing
• B. Increased heterochromatin formation
• C. Suppression of gene transcription
• D. Relaxation of DNA coiling (Correct Answer)
• E. Tighter coiling of DNA

Molecular Genetics Explanation: ***Relaxation of DNA coiling*** - Histone deacetylase (HDAC) inhibitors block the removal of **acetyl groups** from **histones**, leading to increased histone acetylation. - Increased acetylation **reduces the positive charge** of histones, loosening their grip on the negatively charged DNA and causing **relaxation of DNA coiling**. *Prevention of DNA strand reannealing* - This process is primarily influenced by factors affecting **hydrogen bonding** between DNA strands, such as **temperature** or **DNA denaturing agents**, not directly by histone acetylation. - DNA reannealing is the reformation of a **double helix** from single strands, a different mechanism than chromatin structure. *Increased heterochromatin formation* - **Heterochromatin** is characterized by **tightly coiled DNA** and is associated with **deacetylated histones** and gene silencing. - Increased acetylation, as caused by HDAC inhibitors, would lead to less heterochromatin and more **euchromatin**. *Suppression of gene transcription* - **Relaxation of DNA coiling** makes the DNA more accessible to transcription factors and RNA polymerase, thereby generally **promoting gene transcription**, not suppressing it. - **HDAC inhibitors** primarily promote gene expression by increasing the accessibility of DNA to the transcriptional machinery. *Tighter coiling of DNA* - **Deacetylation of histones** leads to stronger interaction between histones and DNA, resulting in **tighter coiling** and chromatin condensation. - HDAC inhibitors, by preventing deacetylation, promote the opposite effect: **DNA uncoiling** and relaxation.

Molecular Genetics US Medical PG Question 2: A 25-year-old man with a genetic disorder presents for genetic counseling because he is concerned about the risk that any children he has will have the same disease as himself. Specifically, since childhood he has had difficulty breathing requiring bronchodilators, inhaled corticosteroids, and chest physiotherapy. He has also had diarrhea and malabsorption requiring enzyme replacement therapy. If his wife comes from a population where 1 in 10,000 people are affected by this same disorder, which of the following best represents the likelihood a child would be affected as well?

• A. 0.01%
• B. 2%
• C. 0.5%
• D. 1% (Correct Answer)
• E. 50%

Molecular Genetics Explanation: ***Correct Option: 1%*** - The patient's symptoms (difficulty breathing requiring bronchodilators, inhaled corticosteroids, and chest physiotherapy; diarrhea and malabsorption requiring enzyme replacement therapy) are classic for **cystic fibrosis (CF)**, an **autosomal recessive disorder**. - For an autosomal recessive disorder with a prevalence of 1 in 10,000 in the general population, **q² = 1/10,000**, so **q = 1/100 = 0.01**. The carrier frequency **(2pq)** is approximately **2q = 2 × (1/100) = 1/50 = 0.02**. - The affected man is **homozygous recessive (aa)** and will always pass on the recessive allele. His wife has a **1/50 chance of being a carrier (Aa)**. If she is a carrier, she has a **1/2 chance of passing on the recessive allele**. - Therefore, the probability of an affected child = **(Probability wife is a carrier) × (Probability wife passes recessive allele) = 1/50 × 1/2 = 1/100 = 1%**. *Incorrect Option: 0.01%* - This percentage is too low and does not correctly account for the carrier frequency in the population and the probability of transmission from a carrier mother. *Incorrect Option: 2%* - This represents approximately the carrier frequency (1/50 ≈ 2%), but does not account for the additional 1/2 probability that a carrier mother would pass on the recessive allele. *Incorrect Option: 0.5%* - This value would be correct if the carrier frequency were 1/100 instead of 1/50, which does not match the given population prevalence. *Incorrect Option: 50%* - **50%** would be the risk if both parents were carriers of an autosomal recessive disorder (1/4 chance = 25% for affected, but if we know one parent passes the allele, conditional probability changes). More accurately, 50% would apply if the disorder were **autosomal dominant** with one affected parent, which is not the case here.

Molecular Genetics US Medical PG Question 3: A 71-year-old man with colorectal cancer comes to the physician for follow-up examination after undergoing a sigmoid colectomy. The physician recommends adjuvant chemotherapy with an agent that results in single-stranded DNA breaks. This chemotherapeutic agent most likely has an effect on which of the following enzymes?

• A. DNA polymerase III
• B. Topoisomerase I (Correct Answer)
• C. Helicase
• D. Telomerase
• E. Topoisomerase II

Molecular Genetics Explanation: ***Topoisomerase I*** - **Topoisomerase I** creates **single-stranded DNA (ssDNA) breaks** to relieve torsional stress during DNA replication and transcription. - Many chemotherapeutic agents, such as camptothecin and its derivatives (e.g., irinotecan, topotecan), target topoisomerase I, leading to DNA damage and apoptosis in cancer cells. *DNA polymerase III* - **DNA polymerase III** is primarily involved in bacterial DNA replication, synthesizing new DNA strands in a 5' to 3' direction. - While essential for bacterial survival, it is not the target of chemotherapeutic agents that induce single-stranded DNA breaks in human cells. *Helicase* - **Helicase** is responsible for unwinding the DNA double helix during replication and transcription, separating the two strands. - While its function is critical for DNA processes, it does not directly create DNA breaks as its primary mechanism of action. *Telomerase* - **Telomerase** is an enzyme that maintains telomere length at the ends of chromosomes, particularly active in cancer cells. - Inhibitors of telomerase aim to shorten telomeres, leading to cellular senescence or apoptosis, but they do not primarily cause single-stranded DNA breaks. *Topoisomerase II* - **Topoisomerase II** creates **double-stranded DNA (dsDNA) breaks** to untangle and decatenate DNA. - Though also a target for chemotherapy (e.g., etoposide, doxorubicin), its mechanism involves double-stranded breaks, not single-stranded breaks as specified in the question.

Molecular Genetics US Medical PG Question 4: An investigator is studying the biology of human sperm cells. She isolates spermatogonia obtained on a testicular biopsy from a group of healthy male volunteers. She finds that the DNA of spermatogonia obtained from these men show a large number of TTAGGG sequence repeats. This finding can best be explained by increased activity of an enzyme with which of the following functions?

• A. Ligation of Okazaki fragments
• B. Proofreading of synthesized daughter strands
• C. RNA-dependent synthesis of DNA (Correct Answer)
• D. Production of short RNA sequences
• E. Hemimethylation of DNA strand

Molecular Genetics Explanation: ***RNA-dependent synthesis of DNA*** - The TTAGGG sequence repeats are **telomeric sequences**, which are maintained by **telomerase**, an enzyme that synthesizes DNA from an RNA template. - **Spermatogonia** are germline stem cells that express high levels of telomerase to maintain telomere length across generations. *Ligation of Okazaki fragments* - This function is carried out by **DNA ligase**, which joins discontinuous DNA fragments during replication on the lagging strand. - This process is essential for general DNA replication but is not specific to the formation or maintenance of telomeric repeats. *Proofreading of synthesized daughter strands* - This is a function of **DNA polymerase exonuclease activity**, which corrects errors during DNA replication. - While important for genetic fidelity, it does not explain the presence or increase of specific TTAGGG repeat sequences at telomeres. *Production of short RNA sequences* - This function is performed by **primase**, which synthesizes RNA primers necessary to initiate DNA synthesis during replication. - These RNA primers are later removed and replaced with DNA, and this process is not directly responsible for generating or extending telomeric repeats. *Hemimethylation of DNA strand* - Hemimethylation occurs during **DNA replication** when new DNA strands are unmethylated while parental strands are methylated. - This phenomenon is involved in DNA repair and gene regulation but is unrelated to the synthesis or regulation of telomeric sequences.

Molecular Genetics US Medical PG Question 5: A 30-year-old man presents to his primary care physician for a routine check-up. During the appointment, he remarks that he has started noticing some thinning and hair loss without other symptoms. The physician reassures him that he is likely experiencing male-pattern baldness and explains that the condition is largely inherited. Specifically he notes that there are multiple genes that are responsible for the condition so it is difficult to predict the timing and development of hair loss. What genetic principle is being illustrated by this scenario?

• A. Uniparental disomy
• B. Polygenic inheritance (Correct Answer)
• C. Pleiotropy
• D. Anticipation
• E. Heteroplasmy

Molecular Genetics Explanation: ***Polygenic inheritance*** - This scenario describes male-pattern baldness as being influenced by **multiple genes**, which is the definition of polygenic inheritance. - The difficulty in predicting the timing and development of hair loss further supports polygenic inheritance, as the combined effect of several genes and environmental factors can lead to a **continuous variation** in phenotypic expression. *Uniparental disomy* - This refers to the inheritance of **two copies of a chromosome** or part of a chromosome from **one parent** and no copies from the other parent. - It is typically associated with specific genetic disorders like Prader-Willi or Angelman syndromes and does not explain the general inheritance pattern of male-pattern baldness. *Pleiotropy* - **Pleiotropy** occurs when a **single gene** affects **multiple seemingly unrelated phenotypic traits**. - This principle is incorrect because the scenario explicitly states that male-pattern baldness is influenced by "multiple genes," not a single gene affecting multiple traits. *Anticipation* - **Anticipation** is a phenomenon where the symptoms of a genetic disorder become more severe or appear earlier with each successive generation. - This phenomenon is observed in conditions like Huntington's disease or myotonic dystrophy and is not the genetic principle described for male-pattern baldness. *Heteroplasmy* - **Heteroplasmy** refers to the presence of **more than one type of mitochondrial DNA** (mtDNA) within a single cell or individual. - This principle is exclusive to mitochondrial inheritance and is not relevant to the inheritance pattern of male-pattern baldness, which is generally considered to be affected by nuclear genes.

Molecular Genetics Flashcard 1 of 5

Question: If mutations at different loci can produce a similar phenotype, a disease has _____

Answer: locus heterogeneity

Molecular Genetics Flashcard 2 of 5

Question: Generally, the 3' end of DNA or RNA is a _____ group

Answer: hydroxyl

Molecular Genetics Flashcard 3 of 5

Question: _____ proteins prevent DNA strands from reannealing during replication

Answer: Single-stranded binding

Molecular Genetics Flashcard 4 of 5

Question: If a disease has an X-linked dominant inheritance pattern, there is NO _____ transmission

Answer: male-to-male

Molecular Genetics Flashcard 5 of 5

Question: What form of chromatin is highly condensed? _____

Answer: Heterochromatin