Parent-of-Origin Effects on Gene Expression

A parent-of-origin effect occurs when the phenotypic consequence of a genetic locus depends on whether the allele was inherited from the mother or the father. These effects are the observable result of genomic imprinting: because an imprinted gene is expressed from only one parental allele, the same change can have very different consequences depending on which parent transmitted it.

Definition

A parent-of-origin effect is a difference in gene expression or phenotype that depends on whether a given allele or chromosomal region was inherited from the mother or the father, arising because imprinted genes are expressed from only one parental allele.

Scope

The topic explains what parent-of-origin effects are, how they follow from monoallelic imprinted expression, the inheritance patterns they create in pedigrees, and the mechanisms by which the parental origin of a locus is read. It frames the phenomenon conceptually; the specific clinical syndromes are covered in the imprinting-disorders topic.

Core questions

• What makes the effect of an allele depend on the parent it came from?
• How do parent-of-origin effects appear in family inheritance patterns?
• Why can the same deletion cause different disorders on the maternal versus paternal chromosome?
• How is the parental origin of a region recognised at the molecular level?

Key concepts

• Monoallelic, parent-dependent expression
• Maternally versus paternally expressed alleles
• Inheritance patterns that depend on transmitting parent
• Reciprocal phenotypes from one genomic region
• Uniparental disomy as a source of parent-of-origin imbalance
• Germline resetting of imprints between generations

Key theories

Parental-conflict (kinship) theory

The evolutionary tug-of-war between maternally and paternally inherited alleles over offspring resource use predicts opposing growth effects of the two parental genomes and provides a framework for many parent-of-origin phenomena.

Mechanisms

Parent-of-origin effects are the phenotypic readout of imprinting. Because an imprinted gene is silenced on one parental allele and active on the other, the functional copy comes from a specific parent; a mutation or loss affecting the active parental copy is unmasked, whereas the same lesion on the silent copy may have little effect. The parental origin is encoded by germline-set differentially methylated regions that mark the maternal and paternal alleles differently and are maintained through development. When both copies of an imprinted region come from one parent, as in uniparental disomy, the normal balance of maternally and paternally expressed genes is disturbed, producing a parent-of-origin phenotype even without any sequence mutation. In pedigrees, this manifests as conditions that appear only when transmitted by mothers or only when transmitted by fathers.

Clinical relevance

Parent-of-origin effects explain why the transmitting parent can determine whether a child is affected and why deletions of the same chromosomal region can cause different syndromes depending on parental origin. The topic supports reasoning about inheritance in genetic counselling contexts at a conceptual level; it is descriptive and is not a basis for individual diagnosis or treatment.

History

Parent-of-origin effects were recognised once nuclear-transplantation and pronuclear-transfer experiments in the 1980s showed that the maternal and paternal genomes contribute non-equivalently to development. The 1991 demonstration that the mouse Igf2 gene is expressed only from the paternal allele provided a concrete molecular basis, and the parental-conflict theory offered an evolutionary explanation for the opposing effects of the two parental genomes.

Key figures

• David Haig
• Wolf Reik
• Anne Ferguson-Smith
• Azim Surani

Seminal works

• dechiara-1991
• reik-walter-2001
• peters-2014

Frequently asked questions

Why does it matter which parent an allele comes from?

For imprinted genes, only one parental copy is active. If the active copy is the one inherited from a particular parent, then a change to that copy will show its effect, while the same change on the silent copy may not, so the parent of origin determines the outcome.

Can a parent-of-origin effect occur without any mutation?

Yes. If a child inherits both copies of an imprinted region from one parent (uniparental disomy), the normal balance of active maternal and paternal genes is disrupted, which can cause a parent-of-origin phenotype even though the DNA sequence is normal.