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An investigator is evaluating specific gene mutations that are hypothesized to increase the risk for developing breast cancer Women who are shown to be positive for specific variations in the BRCA-1 and BRCA-2 gene sequence are further screened for sequence variations in other associated genes. The gene sequence 5'-TTCATCATCATCATCATCATCATCATCC-3'. identified from exon 1 of the androgen receptor (AR) gene. is found to have a high degree of heterogeneity between individuals with breast cancer An increased
length of this sequence is reportedly associated with increased incidence of breast cancer in BRCA-1 mutation carriers. During which phase of the cell cycle are these variations most likely generated?

The correct answer is S phase. The sequence described is a polyglutamine repeat consisting of six repetitions of CAT. These repeats. also known as microsatellite repeats, are distributed throughout the genome: variation in their length is referred to as microsatellite instability, which occurs when DNA replication errors occur during the S-phase.

A student investigates DNA replication. During in-vivo analysis of this process. she discovers an enzyme that will synthesize a short strand of RNA that is complementary to the leading strand of DNA and contains a free 3'-OH end. Which of the following enzymes has the student most likely discovered?
DNA ligase, Polymerase I, Polymerase III, Primase, or Topoisomerase?

The correct answer is Primase. The primer molecule required by DNA polymerase is a short strand of RNA (4-10 bases) complementary to the template strand of the DNA molecule. The primer is synthesized by a specific RNA polymerase known as primase. The growing end of the RNA primer is a free 3'-OH group. The primase does not itself require a primer for initiation of nucleotide synthesis.

A 47-year-old HIV-positive woman comes to the physician for a follow-up examination. Antiretroviral therapy was started 8 years ago. Laboratory studies show a steadily decreasing CD4 count. Physical examination shows generalized lymphadenopathy and a diagnosis of cervical dysplasia is made Which of the following is the best test to determine this patient's viral load before making any changes to her treatment plan?

To assess viral load during HIV infection, reverse transcnptase polymerase chain reaction (RT-PCR) must
be performed Since HIV is an RNA virus. RT-PCR is needed to determine the amount of viral RNA in the body. whereas DNA PCR would be used to detect the proviral DNA (the viral genome inserted in the host cell's chromosomes).

A 53-year-old man is brought to the physician by his wife because of strange movements and behavioral changes over the past 2 months His wife says that he has become socially withdrawn. inattentive. apathetic. aggressive, and irritable. Physical examination shows irregular. sudden. jerky movements of both legs and arms. Expansion of which of the following sequences is most likely associated with this patient's symptoms?

This patient is suffering from Huntington disease, which is an autosomal dominant degenerative brain disorder that typically occurs in the fourth or fifth decade. Chorea. behavioral changes. and dementia are the main features. The movements may begin as subtle fidgeting and progress to large. sudden, irregular choreiform movements- There is no treatment for the disease: however. haloperidol, benzodiazepines. and phenothiazines may be helpful The disease involves expansion of a polyglutamine repeat region. encoded by a CAG repeat . For the USMLE. know the following high-yield diseases with trinucleotide repeat expansion:
Huntington disease CAG repeats in the 5' coding region
Fragile X syndrome CGG in the 5' untranslated region
Myotonic dystrophy CTG in the 3' untranslated region

Cloning of a new eukaryotic gene was followed by insertion and ligation of the gene in an expression vector. The protein translated from this gene was then studied on a western blot, and probed with 32 P-DNA. yielding a positive result These findings eliminate which of the following substances as a candidate for the likely gene product?

The stem suggests that the protein isolated is a DNA-binding protein, since the probing was done with a DNA probe and not an antibody Protein kinase A is an enzyme that phosphorylates other proteins rather than interacting with DNA, and therefore would give a negative result with a DNA probe Protein kinase A is a cAMP-dependent kinase

A 30-year-old female presents for a health maintenance exam Review of history reveals that she has a very strong family history of
endometrial. ovarian, and colon cancers. Colonoscopy is performed for cancer screening and demonstrates 30 polyps in the colonS Chromosomal analysis shows a specific mutation in a gene involved with repair of DNA mutations Which of the following DNA repair mechanisms is deficient in this patient?

Patients with hereditary nonpolyposis colorectal cancer (HNPCC. or Lynch syndrome) develop colorectal polyps over their lifetime, and the probability of malignant transformation in these patients is greatly increased. Patients with HNPCC also show an increased incidence of brain. endometrial. gastric, and thyroid cancers Patients with HNPCC type I have been found to display microsatellite instability and to be deficient in the mismatch repair protein MSH2. Mismatch repair in eukaryotes recognizes the helical distortions commonly resulting from errors during DNA replication Mismatch proteins recognize mismatched base pairs (e.g. A-C or G-T) remaining even after DNA polymerase proofreading (3' to 5' exonuclease activity) has occurred during replication. Mismatch proteins also recognize distortions due to insertion or deletion of bases into or from the newly synthesized strand during replication. Insertion/deletion loops occur most frequently when DNA polymerase is replicating frequent short nucleotide repeats, such as those found in microsatellite DNA A deficiency of the mismatch protein MSH2 decreases the repair of mismatches and insertion/deletion loops, leading to both microsatellite DNA instability and an increased frequency of mutations in rapidly dividing cells. Increased mutation frequency in colorectal epithelial cells increases the probability of accumulation of multiple oncogene and tumor suppressor mutations necessary to result in colorectal cancer

An 8-year-old boy is brought to a dermatology clinic by his parents. They note that his skin is extremely sensitive to sunlight, and his chart indicates that he has had multiple melanomas removed over his lifetime. The defective protein in this patient leads to an impairment in repair involving which of the following types of nucleotides?

This patient most likely has xeroderma pigmentosum. an autosomal recessive trait This disease is
characterized by an extreme sensitivity to sunlight, skin changes, and a predisposition to malignancy. The disease results from a defective excision repair mechanism for UV-damaged DNA. which leads to thymine dimers These dimers are formed when the thymine bases of adjacent thymidine nucleotides form hydrogen bonds with each other rather than with their complementary bases on the opposite DNA strand

A laboratory worker accidentally inhales an unknown quantity of anthrax spores. Since the mortality rate for untreated inhalational anthrax infection is approximately 95%. prophylaxis is begun immediately The recommended treatmentlprophylaxis regimen includes ciprot1oxacin Which of the following describes the mechanism of action for the enzyme inhibited by ciprofloxacin?

All prokaryotic and eukaryotic topoisomerases can relax DNA to remove supercoils. but DNA gyrase is the only topoisomerase able to introduce negative supercoils into the DNA. This DNA gyrase is inhibited by ciprofloxacin. which is the first-line agent for anthrax prophylaxis In DNA with a right-handed helix, negative supercoils wrap the DNA helix over itself to the right. which compensates for and stabilizes a partially underwound helix. A slightly underwound DNA helix more easily binds proteins needed to initiate replication and transcription of DNk DNA gyrase uses ATP hydrolysis to introduce negative supercoils at all times into bacterial DNA to facilitate these processes.

A scientist is researching a familial condition with an increased predisposition for developing cancer Examination of the DNA in somatic cells from the affected family members reveals a large number of mutations such as that shown diagrammatically above. The mutation leads to a "kink" in the DNA template. resulting in errors during replication. Which of the following is most likely associated with the genetic disease resulting from this mutation?

The diagram demonstrates the structure of a thymine dimer, which results when UV radiation causes a covalent linkage between two adjacent thymine nucleotides on the same strand. Inability to repair this defect, also known as nucleotide excision repair, results in xeroderma pigmentosa. which is characterized by extreme UV sensitivity, excessive freckling, multiple skin cancers, and corneal ulcerations. It is transmitted with an autosomal recessive pattern of inheritance.

An investigator wants to determine the gene sequence for an area of the HFE gene that contains a mutation associated with hemochromatosis Using a primer that binds to a 3' flanking region on the coding strand to initiate replication of the HFE gene. and radiolabeled dideoxynucleotides to terminate synthesis, he obtains the results shown on the sequencing gel below:
Which of the following is the sequence of the HFE gene in this region?

The sequencing gel, when read from bottom (shortest) to top (longest). gives the sequence of the primer extension (choice D) . and hence the sequence of the strand is complementary to the coding strand being sequenced. The coding strand being sequenced will be complementary and anti-parallel to the primer extension. Note that an efficient strategy would be to identify the first nucleotide of the primer extension (a T on the gel) and deduce that the last nucleotide in the coding strand would be an A. Among the possible answers, only choice B ends with an A.

A patient who has never had chickenpox wants to visit her sister, whose daughter currently has the disease. In order to determine if she has antibodies to the varicella zoster virus, which of the following tests could be performed?

An enzyme-linked immunosorbent assay (ELISA) would be used to determine antibody levels to a particular virus. Viral protein is bound to a microtiter plate and the patient's serum serially diluted across the plate. If specific antibodies for the virus are present. they bind to the virus. The amount of bound antibody is quantitated. using an enzyme-coupled reaction that produces a visible pigment in proportion to the amount of bound antibody. A similar test is used to determine exposure to HIV. Test Type Major Use
ELISA Detect serum antibodies against a specific antigenic protein (screening)
Southern Blot Identify restriction-length polymorphisms (RFLP) for DNA fingerprinting
Identify specific mutations that can lead to disease
Gene-mapping studies
Northern Blot Measure gene expression levels
Detect alternative mRNA splicing
Western Blot Detect serum antibodies against a specific antigenic protein
(confirmatory)
Southwestem Blot Identify DNA-binding proteins (example: transcription factors)
Dot Blot Quick assay to detect presence of specific DNA sequence

A 48-year-old man has been recently diagnosed with colon cancer His maternal uncle died at the age of 50 from colorectal carcinoma Further studies show no evidence of familial polyposis but genetic testing shows a mutation in his MLHI gene. Which of the following is most likely associated with this mutation?

This man most likely has hereditary nonpolyposis colon cancer Microsatellite instability is characteristic of individuals with loss-of-function mutations in the mismatch repair genes (hMLHI, hMSH2 ) These are associated with hereditary nonpolyposis colorectal cancer (HNPCC). hereditary endometrial cancer, and microsatellite instability in the tumor cells. Areas of DNA with dinucleotide repeats (an example of microsatellites) are often associated with strand slippage during DNA replication, allowing change in the number of repeats on the newly synthesized strand (microsatellite inStability). The mismatch repair enzymes normally correct this replication error.

In a eukaryotic gene. one of the introns is mutated at the 3' end as shown:
Normal: 5'.. TTTCCCACCCTTAG 3'
Mutant: 5'TrTCCCACCCTTCG 3'

Which of the following processes is this mutation most likely to affect?

The 3' end of a eukaryotic intron contains a splice acceptor site, with an invariant AG just before the end of the intron This sequence is highly conserved, as it is essential for correctly recognizing and splicing out the intervening sequences. or introns. from the nascent RNA transcript prior to transport out of the nucleus At the 5' end of the intron is an equally important GT (GU in RNA) sequence that is also necessary for splicing (splice donor site).

A 20-year-old wheelchair-bound man with a past medical history of ataxia-telangiectasia presents for fatigue and shortness of breath. Chest x-ray shows a large mediastinal mass He undergoes an extensive non-invasive evaluation prior to surgical removal Pathology reports that this is a non-Hodgkin lymphoma Which of the following is the most likely reason that this patient has developed a lymphoreticular malignancy?

Ataxia telangiectasia consists of telangiectasias of the skin and eyes. variable immunodeficiency, and progressive ataxia Most patients are wheelchair bound by adolescence. The ataxia-telangiectasia mutation (ATM) occurs at 11 q22-23:
the coding gene for a DNA-dependent protein kinase localized mainly to the nucleus. Its function has to do with mitogenic signal - transduction. meiotic recombination. and cell cycle control With the mutation, cells have increased sensitivity to ionizing radiation, have defective DNA repair. and frequent chromosomal abnormalities. There is a high incidence of malignancy, especially lymphoreticular malignancies (Hodgkin and non-Hodgkin lymphomas and leukemias). The gene is a tumor suppressor gene. and the mutation has inactivated it.

A 29-year-old woman presents for genetic testing with her child and husband. Blood samples are taken from the woman, the child, and the woman's husband Microsatellite repeat sequences are amplified by polymerase chain reaction (PCR). The amplified products are then separated by SDS polyacrylamide gel electrophoresis (PAGE) as shown:
Which of the following genetic tests has most likely been performed in this scenario?

Microsatellite testing detects genetic ailierences Detween inaividuais aue to uiiierent ien9tns 01 microsatellite repeats Microsatellites are repeated units of typically 2-4 bp. and the length of the entire repeat is generally less than 150 bp This class, often referred to as simple tandem repeats (STR5), is most typically amplified by polymerase chain reaction (PCR) for paternity testing. which, in the case shown in the figure. suggests possible paternity Microsatellite testing cannot detect single base-pair mutations

The mutation for Wilson disease is located in the short 5' UTR region of the ATP7B gene. Another associated gene (X) was discovered on the opposite non-coding strand of the ATP7B gene The translation start codon of the ATP7B gene is located near the end of the first exon of gene X. The mutation in the ATP7B gene most likely will be complementary to which of the following?

Wilson disease is caused by the failure of copper to enter the circulation in the form of ceruloplasmin. the protein bound form. This leads to the accumulation of copper in the liver, brain, and cornea. Findings include asterixis, basal ganglia degeneration producing parkinsonian symptoms. and corneal deposits (also known as Kayser-Fleischer rings). Evidence suggests that mutations in the 5' untranslated region (UTR) of the Wilson disease gene (ATP7B) are involved. Since gene X is located on the opposite strand of ATP7B. its sequence will run in the opposite direction. The question describes the start codon for the ATP7B gene as being located near the end of the first exon of gene X (see the image below). Based on that location, it would be expected that the 5' UTR of the ATP7B gene would be located immediately upstream of its translation start codon, or immediately downstream of the first exon of gene X. The location of the mutation of the ATP7B gene (found in the 5' UTR) is then expected to correspond to the first intron ofgeneX.

Approximately 10% of patients with familial amyotrophic lateral sclerosis (ALS) have an autosomal dominant mutation in the copper/zinc superoxide dismutate gene SOD1 One therapy under investigation for treatment of this disease is a hammerhead ribozyme Which of
the following best describes the mechanism by which a hammerhead ribozyme would be expected to treat ALS?

Hammerhead ribozymes. first discovered in plant viroids. catalyze the sequence-specific cleavage of RNA phosphodiester bonds due to the secondary structure they formS Synthetic RNA5 containing sequences complementary to the mutant SOD1 mRNA and sequences necessary to form the hammerhead catalytic structure are being studied as a possible therapy for ALS.

A researcher isolates total RNA from cultured cells and subjects the sample to polyacrylamide gel electrophoresis (PAGE). In the gel depicted above, which band corresponds to the RNA species that forms a covalent linkage to amino acids via a CCA trinucieotide located at its 3 end?

In electrophoresis, the smallest bands migrate to the positive end of the electric field, which is at the bottom of the gel tRNA5 are the smallest species of RNA. thus they migrate the farthest when subjected to eIectrophoresis
The largest molecules are in the messenger (mRNA) and heterogeneous nuclear RNA (hnRNA) classes. Most ribosomal RNA (rRNA) is synthesized from a 45S precursor, which is cleaved into 5.8 and 28S rRNAs A 5S rRNA is synthesized separately

A patient presents with retinoblastoma. He has a single tumor in one eye- What test could be used to determine whether this is a heritable or sporadic tumor?

Forty percent of retinoblastomas are heritable: the child inherits one mutant allele through the germline and a somatic mutation in the other allele occurs, resulting in the loss of function of that gene. This leads to tumor development, often with multiple tumors in both eyes. Penetrance. however, is not complete. since the second mutation is a chance event. Sixty percent of retinoblastomas are sporadic: both alleles are inactivated by somatic mutation. Because this is a rare event, tumors usually are in only one eye and present at a later age. To detect a mutation in the Rb gene and differentiate between heritable and sporadic cases of retinoblastoma, PCR is the most appropriate technique of the choices given. Using the appropriate primers, a deletion can be detected as a change in size of the DNA - band amplified. In heritable cases, one chromosome will show the altered length from the deletion or the translocation in any cell in the body. In sporadic retinoblastoma. samples isolated from anywhere other than the tumor should have two normal alleles.

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