Questions: Genomic Imprinting and Parent-of-Origin Effects

Question 1

A child is born with a deletion of chromosomal region 15q11-q13 on the paternal chromosome. Which syndrome would you expect, and why?

• A. Prader-Willi syndrome — paternally expressed genes in this region are deleted, and the maternal copies are silenced by imprinting and cannot compensate
• B. Angelman syndrome — UBE3A is paternally expressed, so deleting the paternal copy eliminates the only active allele
• C. Neither syndrome — the intact maternal copy of all genes in this region will fully compensate for the paternal deletion
• D. Beckwith-Wiedemann syndrome — paternal deletions at 15q11 cause overgrowth through loss of growth restraint

Answer: (A)

Prader-Willi syndrome results from loss of paternally expressed genes at 15q11-q13. When the paternal chromosome is deleted, these genes are gone — and the maternal copies of those genes are already silenced by imprinting, so they cannot rescue. Angelman syndrome (option B) is wrong because UBE3A is maternally expressed (it's the maternal copy that's active); loss of the paternal chromosome leaves the maternal UBE3A intact. This is the key insight: for imprinted genes, parent-of-origin determines which copy counts.

Question 2

A patient with Prader-Willi syndrome has two chromosomes 15 — one normal maternal copy and one paternal copy with a deletion. A clinician asks why the intact maternal chromosome cannot compensate for the missing paternal genes. The best explanation is:

• A. The maternal copy of Prader-Willi-associated genes is silenced by imprinting and cannot be expressed regardless of what happens to the paternal copy
• B. The deletion on the paternal chromosome contains a dominant-negative element that actively suppresses maternal gene expression
• C. Maternal versions of these genes encode functionally inferior protein variants that cannot substitute for paternal-origin proteins
• D. The deletion also removes shared regulatory sequences needed to drive expression from either chromosome

Answer: (A)

This is the core principle of genomic imprinting: the 'backup' copy doesn't work because it's been epigenetically silenced based on its parent-of-origin. For the genes that cause Prader-Willi syndrome, the rule is 'only the paternal copy is expressed.' The maternal copies are silenced by methylation at the imprinting control region. Having two copies is irrelevant if the rule is that one is always off — and which one is off is fixed by which parent contributed it.

Question 3

Genomic imprinting is consistent with standard Mendelian inheritance because phenotype depends on which alleles are present, not which parent contributed them.

• T. True
• F. False

Answer: False

Genomic imprinting directly violates this Mendelian expectation. For imprinted genes, parent-of-origin is the critical variable — two children with identical genotypes can have completely different diseases depending on whether the mutant allele came from the mother or father. Prader-Willi and Angelman syndromes both involve the 15q11-q13 region but arise from defects in opposite parental contributions. This is why family pedigrees of imprinting disorders show unusual inheritance patterns that cannot be explained by standard dominance and recessiveness.

Question 4

The parental conflict hypothesis proposes that paternally expressed genes tend to promote fetal resource extraction while maternally expressed genes tend to restrain it — reflecting divergent evolutionary interests between maternal and paternal genomes.

• T. True
• F. False

Answer: True

In species where females can mate with multiple males, a father's genetic interest is maximizing the growth of his current offspring (regardless of cost to the mother's other offspring by different fathers), while the mother's interest is balancing investment across all her offspring. Imf2 (paternally expressed, growth-promoting) and Igf2r (maternally expressed, growth-restraining, sequesters IGF2) exemplify this tug-of-war. The parental conflict hypothesis explains why imprinting evolved as an adaptive system despite its apparent riskiness.

Question 5

Why do Prader-Willi and Angelman syndromes arise from defects in the same chromosomal region, and what does this reveal about the logic of genomic imprinting?

Model answer: Prader-Willi results from loss of paternally expressed genes at 15q11-q13 (paternal deletion, maternal uniparental disomy, or imprinting defects); Angelman results from loss of the maternally expressed gene UBE3A in the same region (maternal deletion or paternal uniparental disomy). Same region, opposite parental origin, completely different clinical syndromes. This demonstrates that for imprinted genes, each parental chromosome contributes a non-interchangeable set of active genes — losing one parental copy is not rescued by doubling the other, because the other is already silenced.

The existence of two such distinct syndromes at the same locus provides compelling clinical evidence that imprinting is real, robust, and consequential. It also explains why uniparental disomy — having two copies from the same parent — causes disease even without any mutation, because you end up with two silenced copies or two active copies of genes that should have exactly one of each.