a. Immunoblot analysis reveals the boy is not affected with fragile X syndrome but one brother is.

b. Northern blot analysis reveals the boy is affected with fragile X syndrome and that his mother is a carrier.

c. Southern blot analysis reveals the boy is affected with fragile X syndrome as is one brother.

d. Western blot analysis reveals that the boy and his siblings do not have fragile X syndrome.

e. Southern blot analysis depicts normal results for this family.

177. A 2-year-old Scottish-American girl presents with deeply pigmented and scarred skin and her growth is delayed. Her dermatologist obtains a skin biopsy, suspecting the xeroderma pigmentosum group of diseases (MIM*278730); these have decreased ability to repair thymine-thymine dimers in DNA that are caused by ultraviolet light (sunlight exposure). Which of the following strategies would best measure unscheduled DNA synthesis (DNA repair) in the patient’s skin fibroblasts?

a. Cell synchrony, then incubation with labeled iodine in G phase to complex with newly created hydroxyl groups in deoxyribose residues

b. Incubation with labeled purines to replace newly synthesized bases on the outside of the DNA duplex

c. Cell synchrony, then incubation with labeled deoxyribonucleotides in G phase to measure extension of single DNA strands in the 3′ to 5′ direction

d. Incubation with labeled deoxyribonucleotide triphosphates to measure extension of both strands in the 5′ to 3′ direction

e. Incubation with labeled deoxyribonucleotide triphosphates to measure extension of both strands in the 3′ to 5′ direction

178. A 55-year-old Caucasian male becomes exhausted after jogging 2 miles despite a prior schedule of jogging 30 miles per week. Evaluation discloses severe anemia with elevated white blood cell count, and bone marrow examination suggests a diagnosis of chronic myeloid leukemia (MIM*608232). Which of the following results would be most diagnostic of chromosome 22 deletion that can be seen in this leukemia?

a. Increased incorporation of labeled acetate into histones of chromatin regions on chromosome 22

b. Altered DNA restriction patterns of chromosome 22 regions with methylation-sensitive endonucleases

c. Altered pattern of small RNAs along leukemic chromatin

d. Altered DNA sequence for at least one chromosome 22 locus

e. Decreased transcription from loci on chromosome 22

179. A 20-year-old Caucasian male with sensorineural deafness has a mother, grandmother, and other maternal relatives who are also affected. He has been counseled that his family’s pattern fits autosomal dominant inheritance (eg, MIM*124900 among >10 types), conferring a 50% risk for his offspring to be deaf with each pregnancy. His family has been involved with the deaf community and has resisted gene testing, but he and his wife are interested in preconception/prenatal diagnosis options. Which of the following statements accurately conveys DNA testing options for the man and his wife, focusing particularly on restriction fragment length polymorphism (RFLP) analysis?

a. The man and his wife could have RFLP analysis and determine fetal outcome by which paternal RFLP allele was inherited.

b. Survey of RFLPs for an allele cotransmitted with deafness in the man and his affected family members could provide a marker for deafness in his offspring.

c. Finding an RFLP-encoded protein could distinguish mutated and normal genes for deafness.

d. Survey of the man’s DNA for mutations outside of the putative deafness gene would reveal a restriction site that reflected an amino acid coding change.

e. Restriction of the man’s DNA would produce fragments of the same size but with differences in charge.

180. It is well known that DNA polymerases synthesize DNA only in the 5′ to 3′ direction. Yet, at the replication fork, both strands of parental DNA are being replicated with the synthesis of new DNA. An experiment examines incorporation of radio-labeled nucleotide triphosphates in unsynchronized cells and finds a small amount of incorporated label in DNA fragments of small size. Which of the following statements explains why the experiment is compatible with new DNA from both strands being added in the 5′ to 3′ direction?

a. A different DNA polymerase replicates the complementary DNA strand as a series of small fragments.

b. A 3′ to 5′ DNA polymerase is active in cells with high rates of DNA replication.

c. DNA synthesis on complementary strand produces small 5′ to 3′ fragments that are continuously ligated together.

d. DNA replication switch strands every 100 nucleotides, a detail not resolved by microscopy.

e. DNA synthesis on the complementary strand does not use RNA primers.

181. A newborn boy has a cleft lip and palate with severe limb defects. The hands emerge directly from the shoulders (phocomelia means literally “flipper” limb) and the legs consist of the roots of the thighs only. A medical student searches the Online Mendelian Inheritance in Man database and suggests the diagnosis of Roberts syndrome (MIM*268300), an autosomal recessive disorder associated with altered chromatin condensation. The attending postulates that the chromatin change may impair DNA replication, and discusses why mammalian genomes are 100 times the size of bacterial genomes, yet are replicated in just a few minutes. Which of the following best explains this fact?

a. Eukaryotic DNA polymerases are extraordinarily fast compared with prokaryotic polymerases.

b. The higher temperature of mammalian cells allows for an exponentially higher replication rate.

c. Hundreds of replication forks work simultaneously on each piece of mammalian genomic DNA.

d. Histones and microRNAs complexed with bacterial DNA speed up the rate of DNA replication.

e. The presence of histones in mammalian chromatin speeds up the rate of DNA replication.

182. A 24-year-old African-American female requests pregnancy counseling because of learning differences and her family history; her DNA analysis for fragile X syndrome, an X-linked recessive disorder, is shown in the figure below. The test examines amplification of a 3 bp (triplet) CGG repeat adjacent to the fragile X mental retardation-1 (FMR-1) gene (MIM*309550) on the X chromosome by determining DNA fragment size after restriction cleavage and electrophoresis (Southern blot). Her analysis (lane 5) is shown after that of her father (lane 1), normal sister (lane 2), and her brothers with mental disability (lanes 3 and 4). Her mother also had mild mental disability. The bands of higher molecular weight (slower mobility by electrophoresis) derive from fragile X gene fragments that contain higher number of CGG repeats. A discrete upper band is seen in the patient’s mother (lane 2), a more diffuse upper band in the patient (lane 5), and very diffuse, slowly moving bands in the patient’s disabled brothers (lanes 3 and 4). Which of the following would be the best interpretation of the results?

a. The patient has one fragile X gene with expanded triplet repeats and a 50% risk for a son with fragile X syndrome.

b. The patient has one fragile X gene with expanded triplet repeats and a 25% risk for a son with fragile X syndrome.

c. The patient has a restriction fragment length polymorphism within her fragile X genes with no increased risk for a child with fragile X syndrome.

d. The patient has one fragile X gene with expanded repeats that will produce a string of abnormal amino acids in fragile X protein; she has a 25% risk for a son with fragile X syndrome.

e. The patient has one fragile X gene with expanded triplet repeats and a 100% risk for a son with fragile X syndrome.

183. A 2-year-old child presents with poor weight gain, sparse hair, unusual face with sunken eyes, and skin that reddens markedly in sunlight. A diagnosis of Cockayne syndrome (MIM*216400) is considered and studies of DNA synthesis are undertaken. In vitro assay of labeled thymidine incorporation reveals decreased levels of DNA synthesis compared to controls, but normal-sized labeled DNA fragments. The addition of protein extract from normal cells gently heated to inactivate DNA polymerase restores DNA synthesis in Cockayne cells to normal. Which of the following enzymes used in DNA replication is most likely to be defective in Cockayne syndrome?

a. DNA-directed DNA polymerase

b. Unwinding proteins

c. DNA polymerase I

d. DNA-directed RNA polymerase

e. DNA ligase

184. A 20-year-old African-American male consults a physician because his father and a paternal aunt developed colon cancer in their mid-20s. Neither relative had multiple colonic polyps, so a diagnosis of hereditary nonpolyposis colon cancer (HNPCC-MIM*114500) is considered. The man’s physician discusses testing for HNPCC, knowing that affected patients have genes with microsatellite instability, many gene regions containing abnormal, small loops of unpaired DNA. These DNA loops are the result of a mutation affecting which of the following?

a. Mismatch repair

b. Chain-break repair

c. Base excision repair

d. Depurination repair

e. Nucleotide excision repair

185. A recombinant viral DNA containing a 300 bp human gene sequence is replicated in vitro using media containing bromodeoxyuridine triphosphate, completely saturating the DNA with bromodeoxyuridine residues. The bromo-substituted viral DNA is then switched to media with regular deoxyuridine triphosphate and allowed to undergo two rounds of DNA replication. The human DNA fragment is then cleaved by restriction enzyme digestion and subjected to ultracentrifugation in cesium chloride under conditions that will separate bromo-substituted DNA duplexes, hybrid bromo-substituted/normal duplexes, and normal duplexes. Which of the results depicted in the figure below (with their interpretations) should be obtained?

a. One DNA band of low density, meaning all DNA duplexes have two strands with normal uridine

b. One DNA band of intermediate density, meaning all DNA duplexes have one strand with uridine, one with bromouridine

c. One DNA band of high density, meaning all DNA duplexes have two strands with bromouridine

d. One DNA band of high density and one of intermediate density, indicating the corresponding types of DNA duplexes

e. One DNA band of intermediate density and one of low density, indicating the corresponding types of DNA duplexes

186. A 3-year-old boy offspring of first-cousin parents has a falloff in growth despite normal food intake. The child also has skin that is more darkly pigmented than his parents, and his skin also becomes bright red after sunlight exposure and leaves scars after healing. A skin biopsy is obtained and the cultured fibroblasts tested for xeroderma pigmentosum (XP-MIM*278700). The laboratory reports positive testing with assignment to complementation group A. Which of the following is the most likely information in this report?

a. The patient’s fibroblasts had low amounts of thymine dimers after ultraviolet light exposure, which were increased by fusion with other XP cell lines except those in complementation group A.

b. The patient’s fibroblasts had low exogenous nucleotide-excision repair that could not be restored by fusion with any XP cell lines.

c. The patient’s fibroblasts had low levels of RNA polymerase that were restored by fusion with XP cell lines except those from complementation group A.

d. The patient’s fibroblast had low exogenous nucleotide-excision repair that was restored to normal levels by fusion with all XP cell lines except those in complementation group A.

e. The fibroblast had high amounts of thymine dimers after x-ray exposure, which were increased by fusion with all XP cell lines.

187. A 21-year-old female has a history of frequent pneumonias and is hospitalized with fever, severe cough, low blood pressure, and bruises on her lower limbs that are interpreted as hemorrhage (purpura). Streptococcus pneumoniae is cultured from her bloodstream and she improves after antibiotic therapy. She undergoes testing to evaluate white cell responsiveness to bacterial endotoxins that can be altered in the presence of mutated toll-like receptors (TLRs-MIM*603030). White cells from the patient and a control are isolated (buffy coat after centrifugation of heparinized blood) and incubated with endotoxin in the presence of tritiated thymidine to measure stimulation of DNA synthesis. DNA is isolated from the leucocyte samples and size-fractionated, yielding a high-molecular-weight fraction with slight differences and low-molecular-weight fractions with dramatically greater incorporation of tritiated thymidine in the control versus the patient. This result is interpreted as showing the patient has decreased leucocyte response to endotoxin, which is best explained by which of the following?

a. The high-molecular-weight fraction is mostly indicative of DNA repair, while smaller DNA fragments reflect new and discontinuous DNA replication on both DNA strands.

b. The high-molecular-weight fraction arises from 3′ to 5′ DNA replication, while the smaller DNA fragments arise from 5′ to 3′ replication that reflects new DNA synthesis.

c. The high-molecular-weight fraction reflects continuous DNA replication on the leading (Watson) strand; this strand then serves as a template for new and discontinuous DNA synthesis on the lag (Crick) strand.

d. The low-molecular-weight fraction is a direct measure of DNA replication rather than repair, reflecting discontinuous 5′ to 3′ synthesis of DNA fragments on the lag strand using primase, RNA primers, and ligase.

e. The low-molecular-weight fraction is a direct measure of DNA replication rather than repair, reflecting newly synthesized Okazaki fragments directed by both DNA strands.

188. A 6-month-old Caucasian boy has been followed since birth because of extreme growth failure. His birth weight was 4 lb after a term 40-week uncomplicated pregnancy. Measures of tritiated thymidine incorporation by his stimulated white blood cells show a marked decrease compared to controls. Which of the following is the most likely interpretation of these results?

a. Homozygous nonsense mutation in the gene synthesizing the RNA primer used in DNA replication

b. Homozygous nonsense mutation in DNA polymerase

c. Homozygous mutation in helicase (rep protein) that continuously unwinds duplex DNA at the replication fork during synthesis

d. Homozygous mutation in an exonuclease used in excision repair

e. Homozygous mutation in DNA ligase that repeatedly joins the ends of DNA along the growing strand

189. A 19-year-old female experiences recurrent respiratory infection and night sweats after becoming pregnant, attributing these symptoms to pregnancy until she notes a weight loss rather than expected weight gain. Obstetric evaluation reveals a positive test for tuberculosis and then a low white blood cell count. She admits to multiple sexual partners in the past, and an HIV antibody test is positive. Her doctor places her on a regimen of antituberculous drugs and recommends azidothymidine (AZT) therapy against her AIDS (MIM*609432) because it reduces maternal-to-child AIDS transmission by 30%. Which of the following describes the mechanism of action of AZT?

a. It inhibits viral protein synthesis.

b. It inhibits RNA synthesis.

c. It inhibits viral DNA polymerase.

d. It stimulates DNA provirus production.

e. It inhibits viral reverse transcriptase.

190. Nucleic acids extracted from normal and prostate cancer (MIM*176807) tissue are labeled with differently colored fluorescent probes and compared for their degree of hybridization to an array of DNA segments on a glass slide (DNA chip, technique known as comparative genomic hybridization—CGH—or microarray analysis). The DNA segments are chosen to represent the entire genome, and a segment from chromosome 2 gives a much stronger hybridization signal with the cancer tissue. This DNA segment is then used as a probe to characterize the nucleic acid that is more abundant in prostate cancer tissue. This nucleic acid is stable in acid, degraded by base, and migrates as a 30-base pair species in high or low salt by polyacrylamide gel electrophoresis. Which of the following statements best describes the nucleic acid that is more abundant in prostate cancer?

a. A 60 bp, double-stranded DNA fragment from chromosome 2

b. A 30 bp, single-stranded DNA fragment from chromosome 2

c. A 60 bp, double-stranded RNA fragment encoded by a gene on chromosome 2

d. A 30 bp, single-stranded RNA encoded by a gene on chromosome 2

e. A 30 bp, single-stranded RNA with a high degree of secondary structure, most likely a transfer RNA encoded by chromosome 2

191. Which of the following is the correct sequence of events in gene repair mechanisms in patients without a mutated repair process?

a. Nicking, excision, replacement, sealing, and recognition

b. Nicking, recognition, excision, sealing, and replacement

c. Nicking, sealing, recognition, excision, and replacement

d. Recognition, nicking, excision, replacement, and sealing

e. Sealing, recognition, nicking, excision, and replacement

192. Which of the following indicates the correct sequence of chromosome constituents, going from smaller to larger?

a. Chromatin fibril, nucleosome, histone octamer, and chromosome loop

b. Nucleosome, chromatin fibril, chromosome loop, and histone octamer

c. Chromatin fibril, histone octamer, nucleosome, and chromosome loop

d. Nucleosome, histone octamer, chromosome loop, and chromosome fibril

e. Histone octamer, nucleosome, chromatin fibril, and chromosome loop

193. A 2-year-old Caucasian girl presents with a 2-week history of fatigue, pallor, and recent chest pain localized to her sternum. Her physical examination is remarkable for general irritability, tenderness over her sternum, and a lemon-yellow hue to her skin. Blood counts show anemia with a hemoglobin of 5 g/dL (normal >12) and extreme leucocytosis (white blood cell count 130,000 cells/cubic millimeter with normal <12,000). A diagnosis of acute lymphocytic leukemia (MIM*187040) is made after further bone marrow studies, mandating a therapy protocol that includes radiation therapy of the central nervous system to destroy leukemic lymphoblasts. Which of the following describes the rationale for radiation therapy of certain cancers?

a. Cross-linking of DNA in rapidly growing cancer cells

b. Demethylation of DNA to prevent progression of precancerous cells

c. Cleavage of DNA double strands necessary for transcription in G phase

d. Disruption of DNA-RNA transcription complexes necessary for G phase

e. Disruption of purine rings in DNA crucial for S phase and rapidly growing cells

194. A major obstacle to gene therapy involves the difficulty of homologous gene replacement. Which of the following strategies best addresses this issue?

a. A recombinant vector contains complementary DNA sequences that will facilitate site-specific recombination.

b. A recombinant vector expresses antisense nucleotides that will hybridize with the targeted mRNA.

c. A recombinant vector replaces inessential viral genes with a functional human gene.

d. A recombinant vector transfects patient cells, which are returned to the patient.

e. A recombinant vector contains DNA sequences that target its expressed protein to lysosomes.

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