USMLE Step 1 Quiz: Molecular Genetics And Gene Expression

What this quiz covers

This quiz focuses on Molecular Genetics And Gene Expression, giving you a quick way to practice the rules, question types, and explanations that matter most for USMLE Step 1.

How to use this quiz

Try each quiz question before looking at the correct answer. Use the explanations to review missed ideas, then come back to similar questions until the pattern feels familiar.

Question 1

1. Reduced dosage of X-linked genes escaping inactivation, impairing growth-related transcription (correct answer)
2. Trisomy 21 causing increased APP gene dosage and early Alzheimer disease
3. Methylation defect at 15q11-q13 causing loss of maternal UBE3A expression
4. APC loss causing increased Wnt target gene transcription in colon epithelium
5. RET loss-of-function causing Hirschsprung disease via neural crest migration failure

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on dosage effects in sex chromosome disorders. Gene expression from X-linked genes escaping inactivation, like SHOX, influences skeletal growth when dosage is reduced. In this vignette, the girl's short stature, webbed neck, and 45,X karyotype indicate Turner syndrome, with haploinsufficiency altering growth transcription. The correct answer identifies reduced dosage of escaping genes, impairing skeletal programs. Choice B is incorrect as it describes Down syndrome, unrelated to the cardiac coarctation. Encourage students to interpret karyotypes and monitor for comorbidities. Practice distinguishing aneuploidy phenotypes by molecular mechanisms.

Question 2

1. Gain of function causing ligand-independent receptor tyrosine kinase signaling (correct answer)
2. Loss of function causing reduced cAMP production in endocrine tissues
3. Frameshift causing nonsense-mediated decay and absent receptor expression
4. Splice-site defect causing truncated collagen and brittle bones
5. Dominant negative effect on microtubule polymerization and axonal transport

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on proto-oncogene mutations in hereditary cancer syndromes. Gene expression is influenced by receptor tyrosine kinases like RET, which activate MAPK pathways for cell proliferation when mutated. In this vignette, the patient's pheochromocytoma, thyroid nodule, and RET mutation suggest MEN2, with constitutive signaling. The correct answer describes the gain-of-function effect on tyrosine kinase activity, increasing transcription of growth genes. Choice D is incorrect as it pertains to osteogenesis imperfecta, unrelated to the endocrine tumors here. Encourage students to correlate mutation types with functional impacts and screen for associated cancers. Practice integrating biochemical tests with genetic findings for diagnosis.

Question 3

1. Transcription factor dosage controlling pharyngeal arch gene expression during embryogenesis (correct answer)
2. Genomic imprinting at 15q11-q13 causing loss of paternal gene expression
3. Mismatch repair deficiency causing microsatellite instability
4. Mitochondrial tRNA mutation causing lactic acidosis and stroke-like episodes
5. Trinucleotide repeat expansion in HTT causing striatal neurodegeneration

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on haploinsufficiency in microdeletion syndromes. Gene expression during embryogenesis is controlled by dosage-sensitive transcription factors like TBX1 for pharyngeal development. In this vignette, the boy's heart defects, cleft palate, and 22q11.2 deletion indicate DiGeorge syndrome, reducing TBX1 dosage. The correct answer explains disrupted transcription factor dosage altering developmental genes. Choice E is incorrect as it describes Huntington, unrelated to hypocalcemia. Encourage students to evaluate immune function and use microarray. Practice distinguishing microdeletion phenotypes.

Question 4

1. Mismatch repair leading to microsatellite instability in colon epithelium
2. mTOR pathway restraint that normally limits cell growth under low energy conditions (correct answer)
3. Lysosomal enzyme targeting via mannose-6-phosphate
4. Heme synthesis due to porphobilinogen deaminase deficiency
5. Chloride channel gating in airway epithelium from CFTR dysfunction

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on nutrient-sensing pathways and their role in syndromic disorders. Gene expression is regulated by environmental cues, with pathways like mTOR balancing cell growth in response to energy availability via tumor suppressors. In this vignette, the patient's pneumothoraces, lung cysts, skin papules, and FLCN variant point to Birt-Hogg-Dubé syndrome, disrupting AMPK-mTOR balance. The correct answer highlights the loss of mTOR restraint under low energy, leading to aberrant growth in lungs and kidneys. Choice A is incorrect as it pertains to Lynch syndrome with microsatellite instability, not relevant to the pulmonary and dermatologic features here. Encourage students to map genetic defects to downstream pathways and consider family history for autosomal dominant patterns. Practice differentiating similar syndromes by key clinical and molecular features.

Question 5

1. Proteasomal degradation of $\beta$-catenin that normally limits Wnt target gene transcription (correct answer)
2. Nucleotide excision repair of thymine dimers after UV exposure
3. Spindle microtubule attachment due to defective kinetochore proteins
4. Glycogen breakdown due to myophosphorylase deficiency
5. Mitochondrial oxidative phosphorylation due to mtDNA deletion

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on Wnt signaling in hereditary colorectal cancer. Gene expression in the intestine is controlled by Wnt pathways, where APC degrades β-catenin to prevent proliferation gene transcription. In this vignette, the patient's adenomas, osteomas, and APC mutation suggest familial adenomatous polyposis, with accumulated β-catenin. The correct answer identifies the disrupted β-catenin degradation, leading to increased Wnt target genes. Choice B is incorrect as it relates to xeroderma pigmentosum, not matching the colonic polyps. Encourage students to recognize extracolonic manifestations and recommend surveillance. Practice interpreting colonoscopy results with genetic data.

Question 6

1. Autosomal recessive loss of CFTR chloride channel function
2. Autosomal dominant tumor suppressor loss requiring second-hit in target tissues (correct answer)
3. Trinucleotide repeat expansion with anticipation and toxic gain-of-function
4. Mitochondrial inheritance causing heteroplasmy and maternal transmission
5. Somatic translocation creating a fusion tyrosine kinase

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on inheritance mechanisms in tumor suppressor gene disorders. Gene expression is controlled by histone modifications and cell cycle regulators, with tumor suppressors like menin preventing unchecked proliferation in endocrine cells. In this vignette, the patient's hypercalcemia, pituitary adenoma, and MEN1 variant suggest multiple endocrine neoplasia type 1, requiring biallelic inactivation. The correct answer captures the autosomal dominant loss with second-hit, leading to dysregulated growth gene expression. Choice C is incorrect as it describes repeat expansions in conditions like Huntington disease, not fitting the endocrine tumor pattern. Encourage students to apply Knudson's two-hit hypothesis and evaluate family histories for penetrance. Practice distinguishing endocrine syndromes by molecular and clinical profiles.

Question 7

1. Endothelial SMAD signaling downstream of TGF-$\beta$/BMP required for vascular remodeling (correct answer)
2. Keratinocyte desmosome adhesion due to desmoglein antibodies
3. Phagolysosome formation due to NADPH oxidase deficiency
4. Thymidylate synthase inhibition causing impaired DNA synthesis
5. Voltage-gated sodium channel inactivation in skeletal muscle

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on TGF-β signaling in vascular disorders. Gene expression in endothelium is regulated by TGF-β/BMP via SMADs, with endoglin facilitating receptor complexes for vessel maturation. In this vignette, the woman's telangiectasias, AVMs, and ENG variant indicate hereditary hemorrhagic telangiectasia, impairing SMAD signaling. The correct answer explains the disrupted endothelial SMAD pathway, leading to abnormal vascular transcription. Choice B is incorrect as it describes pemphigus vulgaris, unrelated to the bleeding diathesis. Encourage students to screen for visceral AVMs and review family histories. Practice integrating imaging with molecular diagnostics.

Question 8

1. Loss of function reducing methylated-DNA binding and transcriptional repression in neurons (correct answer)
2. Gain of function increasing ligand-independent receptor tyrosine kinase signaling
3. Dominant negative effect blocking collagen triple-helix assembly
4. Frameshift increasing $\beta$-globin production and causing polycythemia
5. Splice variant increasing CFTR channel opening in airway epithelium

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on epigenetic modifiers in autism-spectrum disorders. Gene expression is modulated by MeCP2, which represses transcription via methylated CpG binding and deacetylase recruitment in neurons. In this vignette, the girl's regression, hand-wringing, and MECP2 variant indicate Rett syndrome, with loss of repression. The correct answer describes loss-of-function reducing binding and repression. Choice B is incorrect as it pertains to MEN2, unrelated to stereotypies. Encourage students to track developmental milestones and discuss therapies. Practice identifying mutation effects on protein function.

Question 9

1. Increased PI3K-AKT signaling leading to enhanced growth and survival gene transcription (correct answer)
2. Reduced Ras-MAPK signaling due to neurofibromin overactivity
3. Decreased Hedgehog signaling due to Smoothened inhibition
4. Reduced SMAD transcription due to decreased active TGF-$\beta$
5. Increased mismatch repair activity causing reduced mutation rate

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on phosphatase regulation in overgrowth syndromes. Gene expression for growth is inhibited by PTEN dephosphorylating PIP3 to limit PI3K-AKT signaling. In this vignette, the boy's macrocephaly, autism, and PTEN variant suggest PTEN hamartoma syndrome, with increased signaling. The correct answer identifies enhanced PI3K-AKT transcription promoting growth. Choice D is incorrect as it describes Marfan, not matching macrocephaly. Encourage students to screen for cancers and review signaling pathways. Practice correlating behavioral features with genetics.

Question 10

1. Loss of E2F repression leading to increased transcription of S-phase entry genes (correct answer)
2. Increased p16 transcription causing G1 arrest and reduced proliferation
3. Reduced HIF-1$\alpha$ stabilization causing impaired angiogenesis
4. Defective homologous recombination due to BRCA2 loss causing breast cancer
5. Increased dystrophin expression improving sarcolemmal stability

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on cell cycle regulators in hereditary cancers. Gene expression for cell cycle progression is repressed by pRb binding E2F, preventing S-phase entry in retinal cells. In this vignette, the child's retinoblastoma and RB1 variant suggest hereditary retinoblastoma, with loss of E2F repression. The correct answer identifies increased transcription of S-phase genes due to absent pRb. Choice D is incorrect as it pertains to BRCA-associated cancers, not matching the ocular tumor. Encourage students to apply two-hit models and discuss enucleation criteria. Practice correlating germline mutations with tumor risks.

Question 11

1. Constitutive Ras-MAPK signaling due to loss of Ras GTPase-activating protein activity (correct answer)
2. Defective collagen type III synthesis causing arterial rupture
3. Reduced SMN protein causing anterior horn degeneration
4. Increased cGMP in photoreceptors due to PDE6 loss
5. Impaired lysosomal $\alpha$-galactosidase A causing globotriaosylceramide storage

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on Ras signaling in neurocutaneous syndromes. Gene expression for cell growth is regulated by Ras GTPases, with neurofibromin enhancing hydrolysis to inactivate Ras-MAPK pathways. In this vignette, the boy's café-au-lait spots, neurofibromas, and NF1 variant indicate neurofibromatosis type 1, with constitutive Ras signaling. The correct answer explains the increased MAPK activity from lost GTPase function, promoting tumor gene expression. Choice B is incorrect as it describes Ehlers-Danlos syndrome, unrelated to the pigmented lesions. Encourage students to use diagnostic criteria and monitor for complications. Practice differentiating neurocutaneous disorders by molecular mechanisms.

Question 12

1. CGG repeat expansion causing promoter hypermethylation and reduced FMR1 transcription (correct answer)
2. Deletion of dystrophin exons causing absent sarcolemmal stability
3. Point mutation in HBB causing hemoglobin S polymerization
4. Maternal uniparental disomy of chromosome 15 causing Angelman syndrome
5. Activating RET mutation causing ligand-independent MAPK signaling

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on repeat expansions and epigenetic silencing. Gene expression can be silenced by promoter hypermethylation from CGG expansions in FMR1, reducing FMRP for synaptic translation control. In this vignette, the boy's intellectual disability, macroorchidism, and FMR1 repeats indicate fragile X syndrome, with transcriptional silencing. The correct answer describes the CGG expansion causing methylation and reduced transcription. Choice B is incorrect as it pertains to Duchenne dystrophy, not matching the behavioral features. Encourage students to recognize X-linked patterns and test for expansions. Practice integrating physical exam with molecular diagnostics.

Question 13

1. Impaired methylated-DNA binding leading to abnormal chromatin repression and neuronal transcription (correct answer)
2. Defective spliceosome assembly causing widespread intron retention in all tissues
3. Increased telomerase activity promoting unlimited replication in fibroblasts
4. Loss of APC causing nuclear $\beta$-catenin accumulation in colon crypts
5. Reduced sphingomyelinase activity causing lysosomal storage in macrophages

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on chromatin regulators in neurodevelopment. Gene expression in neurons is repressed by MeCP2 binding methylated DNA to recruit deacetylases for chromatin compaction. In this vignette, the boy's dystonia, regression, and MECP2 mutation suggest atypical Rett syndrome, impairing repression. The correct answer identifies disrupted methylated-DNA binding, altering neuronal transcription. Choice D is incorrect as it describes FAP, unrelated to basal ganglia issues. Encourage students to recognize de novo mutations and monitor progression. Practice correlating MRI with genetic findings.

Question 14

1. Loss of paternal allele expression at 15q11-q13 due to imprinting defect (correct answer)
2. Constitutive activation of $\beta$-catenin due to APC mutation
3. Reduced SMAD signaling due to fibrillin-1 mutation
4. Increased Ras signaling due to NF1 loss
5. Impaired mismatch repair due to MLH1 loss

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on epigenetic regulation in imprinting disorders. Gene expression at 15q11-q13 is controlled by methylation, silencing one allele to allow paternal expression for growth regulation. In this vignette, the newborn's hypotonia, poor feeding, and loss of paternal imprint suggest Prader-Willi syndrome, disrupting appetite genes. The correct answer explains the loss of paternal expression due to imprinting, leading to phenotypic alterations. Choice B is incorrect as it describes FAP, unrelated to the hypogonadism. Encourage students to analyze methylation patterns and review neonatal presentations. Practice correlating epigenetics with clinical outcomes.

Question 15

1. snRNP assembly required for pre-mRNA splicing in motor neurons (correct answer)
2. DNA methylation of CpG islands silencing one parental allele
3. Microtubule depolymerization preventing mitotic spindle formation
4. Translation initiation via eIF2 phosphorylation during stress response
5. Ras GTPase activation causing increased MAPK transcriptional output

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on RNA processing in neuromuscular disorders. Gene expression requires proper pre-mRNA splicing via snRNPs assembled by SMN protein in motor neurons. In this vignette, the infant's hypotonia, denervation, and SMN1 deletion indicate spinal muscular atrophy, disrupting splicing. The correct answer explains impaired snRNP assembly altering survival genes. Choice B is incorrect as it relates to imprinting, unrelated to EMG findings. Encourage students to use deletion testing and discuss therapies. Practice differentiating motor neuron diseases by molecular defects.

Question 16

1. Decreased SMAD transcription due to reduced TGF-$\beta$ signaling
2. Increased SMAD-mediated transcription from excess active TGF-$\beta$ signaling (correct answer)
3. Increased p53 degradation due to HPV E6 oncoprotein expression
4. Reduced collagen cross-linking from lysyl hydroxylase deficiency
5. Constitutive Ras activation from NF1 loss causing neurofibroma formation

Explanation: This question assesses understanding of molecular genetics and gene expression, focusing on extracellular matrix proteins and cytokine signaling in connective tissue disorders. Gene expression involves regulatory networks where matrix proteins sequester growth factors, influencing pathways like TGF-β for tissue homeostasis. In this vignette, the patient's tall stature, aortic dilation, and FBN1 variant indicate Marfan syndrome, with increased TGF-β signaling due to poor sequestration. The correct answer explains the excess SMAD-mediated transcription weakening connective tissue, matching the skeletal and vascular phenotype. Choice E is incorrect as it describes neurofibromatosis, unrelated to the arachnodactyly and ectopia lentis seen here. Encourage students to link structural protein defects to signaling alterations and review autosomal dominant inheritance. Practice analyzing echocardiogram and genetic results for syndromic diagnoses.

Question 17

1. Inclusion of an intronic sequence into the mature mRNA (correct answer)
2. Decreased transcription initiation of the DMD gene
3. Premature termination of transcription
4. Impaired binding of ribosomes to the mRNA

Explanation: The creation of a new, or 'cryptic,' splice site within an intron can cause the spliceosome to incorrectly process the pre-mRNA. This often leads to the inclusion of a portion of the intron in the mature mRNA. This insertion typically causes a frameshift, leading to a premature stop codon and the production of a truncated, non-functional protein.

Question 18

1. Genomic imprinting (correct answer)
2. X-chromosome inactivation
3. Somatic mosaicism
4. Codominant inheritance

Explanation: Genomic imprinting is an epigenetic phenomenon where genes are expressed in a parent-of-origin-specific manner. This is achieved through DNA methylation and histone modifications established in the germline. In the 15q11-13 region, certain genes are expressed only from the paternal chromosome and others only from the maternal chromosome. A deletion on the maternal chromosome leads to Angelman syndrome (as in this patient), while a paternal deletion causes Prader-Willi syndrome.

Question 19

1. DNA methyltransferase
2. Histone deacetylase (HDAC) (correct answer)
3. RNA polymerase II
4. Topoisomerase I

Explanation: Histone deacetylation removes acetyl groups from lysine residues on histone tails, increasing their positive charge. This enhances the interaction between histones and negatively charged DNA, leading to condensed chromatin (heterochromatin) and transcriptional repression. Inhibiting histone deacetylases (HDACs) preserves histone acetylation, resulting in a relaxed chromatin state (euchromatin) that allows for gene expression.

Question 20

1. Poly-A tail
2. 7-methylguanosine cap (correct answer)
3. Spliceosome recognition sites
4. Shine-Dalgarno sequence

Explanation: In eukaryotes, the 7-methylguanosine cap at the 5' end of mRNA is crucial for the initiation of translation. It is recognized by the eukaryotic initiation factor eIF4E, which is part of a complex that recruits the small ribosomal subunit to the mRNA. Without this cap, ribosome binding and subsequent translation are severely impaired.