CGC Molecular Genetics & Mechanisms of Inheritance 2 — Questions and Answers
Question 1: A splicing mutation that activates a cryptic splice site would most likely result in which of the following?
- A protein with a single amino acid substitution
- An mRNA with an additional segment of intronic sequence or deletion of exonic sequence (Correct answer)
- Complete absence of any mRNA transcript
- Expansion of a trinucleotide repeat within the coding sequence
Correct answer: An mRNA with an additional segment of intronic sequence or deletion of exonic sequence
Cryptic splice site activation causes the spliceosome to use an alternative splice site, incorporating intronic sequence into the mRNA or skipping part of an exon, altering the protein.
Question 2: Uniparental disomy (UPD) can cause disease even in the absence of a traditional mutation. Which mechanism most commonly explains pathogenicity of UPD?
- Both copies of a chromosome carry a heterozygous mutation
- Disruption of imprinted gene dosage when both copies derive from one parent (Correct answer)
- Mitotic recombination producing loss of heterozygosity
- Replication error causing copy number variation
Correct answer: Disruption of imprinted gene dosage when both copies derive from one parent
UPD causes disease primarily by disrupting imprinted loci—when both copies come from one parent, imprinted genes that should be expressed from only the maternal or paternal allele are either doubly silenced or doubly expressed.
Question 3: Loss of heterozygosity (LOH) in tumor cells most often represents which event according to Knudson's two-hit hypothesis?
- Activation of an oncogene on the wild-type allele
- Somatic inactivation of the remaining wild-type tumor suppressor allele (Correct answer)
- Germline mutation in a DNA repair gene
- Epigenetic silencing of an oncogene
Correct answer: Somatic inactivation of the remaining wild-type tumor suppressor allele
In hereditary cancer syndromes, the first hit is the inherited germline mutation; LOH in tumor tissue represents somatic inactivation (the second hit) of the remaining wild-type allele of the tumor suppressor gene.
Question 4: Which of the following correctly distinguishes an oncogene from a tumor suppressor gene regarding mechanism of cancer causation?
- Oncogenes require loss of both alleles; tumor suppressors require gain of function in one allele
- Oncogenes cause cancer by gain-of-function mutations acting dominantly; tumor suppressors cause cancer when both alleles are inactivated (recessive) (Correct answer)
- Oncogenes are only activated by chromosomal translocations; tumor suppressors are only inactivated by point mutations
- Oncogenes and tumor suppressors are functionally identical but differ in chromosomal location
Correct answer: Oncogenes cause cancer by gain-of-function mutations acting dominantly; tumor suppressors cause cancer when both alleles are inactivated (recessive)
Oncogenes act dominantly—a single gain-of-function mutation drives uncontrolled cell growth—whereas tumor suppressor genes act recessively, requiring biallelic inactivation to lose growth control.
Question 5: X-inactivation (lyonization) in females results in which of the following outcomes relevant to X-linked carrier females?
- Equal expression of both X chromosomes in all cells throughout life
- Random inactivation of one X per cell that becomes fixed clonally, potentially leading to skewed X-inactivation in some tissues (Correct answer)
- Preferential inactivation of the paternally derived X chromosome in all somatic cells
- Complete inactivation of both X chromosomes leaving no X gene expression
Correct answer: Random inactivation of one X per cell that becomes fixed clonally, potentially leading to skewed X-inactivation in some tissues
X-inactivation is random per cell but fixed clonally; extreme skewing toward inactivating the normal X can cause manifesting carrier females to express X-linked recessive conditions.
Question 6: A copy number variant (CNV) is best defined as:
- A single nucleotide change that alters a codon's amino acid
- A structural variation involving a segment of DNA ≥1 kb that differs in copy number between individuals (Correct answer)
- A trinucleotide repeat expansion beyond the normal range
- An epigenetic modification that alters gene expression without changing sequence
Correct answer: A structural variation involving a segment of DNA ≥1 kb that differs in copy number between individuals
CNVs are structural genomic variants ≥1 kb involving deletions, duplications, or other rearrangements that result in variation in the number of copies of that segment compared to a reference genome.
Question 7: Which inheritance pattern is characterized by mitochondrial DNA mutations transmitting exclusively through the maternal line with all offspring of an affected mother being at risk?
- Autosomal dominant inheritance
- X-linked dominant inheritance
- Mitochondrial (maternal) inheritance (Correct answer)
- Autosomal recessive inheritance
Correct answer: Mitochondrial (maternal) inheritance
Mitochondrial DNA is maternally inherited because virtually all mitochondria in the zygote derive from the egg; therefore, an affected mother transmits the mutation to all her children, but an affected father does not transmit it.
CGC Molecular Genetics & Mechanisms of Inheritance 2
A splicing mutation that activates a cryptic splice site would most likely result in which of the following?