Genomic Imprinting

Genomic imprinting is an epigenetic phenomenon in which a subset of genes is expressed from only one of the two parental alleles according to its parent of origin. Some imprinted genes are expressed only from the maternally inherited copy and others only from the paternally inherited copy. The imprint is set as a DNA-methylation mark in the germline, survives early-embryonic reprogramming, and is then read throughout the individual's life.

Definition

Genomic imprinting is the epigenetic marking of certain genes in the germline such that they are expressed from only the maternally or only the paternally inherited allele in the offspring.

Scope

The topic covers the definition and biological logic of imprinting, the establishment of parent-specific methylation marks in the germline, imprinting control regions and the clusters of genes they govern, the maintenance of imprints through development, and the evolutionary interpretation of why imprinting exists. Specific human conditions are treated in the imprinting-disorders topic.

Core questions

• What does it mean for a gene to be imprinted?
• How are parent-specific imprints established in eggs and sperm?
• How are imprints maintained while the rest of the genome is reprogrammed in the embryo?
• Why has imprinting evolved if it sacrifices the safety of having two working alleles?

Key concepts

• Parent-of-origin-specific expression
• Germline establishment of imprints
• Differentially methylated regions (imprinting control regions)
• Imprinted gene clusters
• Maintenance through embryonic reprogramming
• Maternally versus paternally expressed genes

Key theories

Parental-conflict (kinship) theory

Imprinting is interpreted as the product of an evolutionary conflict between maternally and paternally inherited alleles over the transfer of resources to offspring, predicting that paternally expressed genes tend to enhance and maternally expressed genes tend to limit growth.

Mechanisms

Imprints are differential epigenetic marks, principally DNA methylation, established at imprinting control regions during gametogenesis: certain sequences are methylated in the female germline and others in the male germline. After fertilisation, when most of the genome is demethylated and re-methylated, these imprinting control regions are protected so that the parental marks persist. The methylation status of an imprinting control region then governs allele-specific expression of nearby genes, often by controlling insulator function or noncoding-RNA transcription across an imprinted cluster, so that one parental allele is expressed and the other silenced. The mouse Igf2 gene provided an early demonstration that an autosomal gene can be expressed in a parent-of-origin-dependent manner.

Clinical relevance

Because an imprinted gene is functionally present in only one active copy, a mutation, deletion, or epigenetic change affecting that copy is not buffered by the other allele, so imprinting makes certain loci uniquely vulnerable and gives rise to parent-of-origin-dependent disease. The topic explains why the parental origin of a genetic change can determine whether and how disease appears; it is descriptive and is not a basis for individual diagnosis or treatment.

Epidemiology

Imprinted genes are a small fraction of the genome, estimated in the low hundreds, and are concentrated in clusters. They have outsized importance in growth, placental function, and brain development relative to their number.

History

Nuclear-transplantation experiments in the 1980s showed that the maternal and paternal genomes are not interchangeable, establishing the existence of imprinting. The molecular era began around 1991 when the mouse Igf2 gene was shown to be expressed only from the paternal allele, and subsequent work mapped imprinted clusters, identified imprinting control regions, and connected imprinting to DNA methylation and noncoding RNA. The evolutionary parental-conflict theory provided an influential framework for why imprinting exists.

Key figures

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

Seminal works

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

Frequently asked questions

How is genomic imprinting different from a mutation?

Imprinting does not change the DNA sequence; it is an epigenetic mark, mostly DNA methylation, that silences one parental copy of a gene. The same gene can therefore be active or silent depending only on which parent it was inherited from.

Are imprints permanent?

Within an individual the imprint is stable, but in the germline the old imprints are erased and reset according to the sex of the person, so a gene's imprint can switch when it is passed to the next generation.