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Review
. 2006 Nov 24;2(11):e147.
doi: 10.1371/journal.pgen.0020147.

Genomic imprinting in mammals: emerging themes and established theories

Andrew J Wood  1 , Rebecca J Oakey
Affiliations
Review

Genomic imprinting in mammals: emerging themes and established theories

Andrew J Wood et al. PLoS Genet. .

Abstract

The epigenetic events that occur during the development of the mammalian embryo are essential for correct gene expression and cell-lineage determination. Imprinted genes are expressed from only one parental allele due to differential epigenetic marks that are established during gametogenesis. Several theories have been proposed to explain the role that genomic imprinting has played over the course of mammalian evolution, but at present it is not clear if a single hypothesis can fully account for the diversity of roles that imprinted genes play. In this review, we discuss efforts to define the extent of imprinting in the mouse genome, and suggest that different imprinted loci may have been wrought by distinct evolutionary forces. We focus on a group of small imprinted domains, which consist of paternally expressed genes embedded within introns of multiexonic transcripts, to discuss the evolution of imprinting at these loci.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Imprinting on Mouse Chromosome 7
Maternally expressed genes are shown in red, paternally expressed in blue. Individual clusters are controlled by oocyte-derived (red) or sperm-derived (blue) methylation marks.
Figure 2
Figure 2. Regulatory Models at Imprinted Loci
Blue boxes represent paternally expressed alleles, red boxes maternally expressed alleles, black boxes silenced alleles, and grey boxes nonimprinted genes. Arrows on boxes indicate transcriptional orientation. (A) The enhancer–blocker model (also known as the boundary model) is well studied at the Igf2/H19 locus and consists of an ICR located between a pair of reciprocally expressed genes that controls access to shared enhancer elements [38,116]. On the paternal allele, the differentially methylated domain (DMD) acquires methylation (black circles) during spermatogenesis, which leads to repression of the H19 promoter [117]. The hypomethylated maternal DMD acts as an insulator element, mediated through binding sites for the methylation-sensitive boundary factor CTCF (shaded ellipse). When CTCF is bound, Igf2 promoter access to the enhancers (E) distal to H19 is blocked. (B) At the Igf2r locus on Chromosome 17, the paternally expressed, noncoding RNA Air acts to induce bidirectional cis-mediated silencing (black curved lines) on neighbouring protein-coding genes (maternally expressed Igf2r, Slc22a3, and Slc22a2) [50]. The grey ellipses are the intronic imprint control elements that are maternally methylated (black circles) and contain the promoter of the Air RNA. (C) At microimprinted domains, oocyte-derived methylation in the promoter region of a protein-coding gene is likely to be the primary epigenetic mark leading to monoallelic silencing. With the exception of the U2af1-rs1 locus, the multiexonic genes within which the paternally expressed transcripts are embedded, escape imprinting (Table 1). The paternally expressed Nap1l5 is situated within intron 22 of Herc3, which is expressed from both alleles.
Figure 3
Figure 3. Overview of the Evolution of Imprinted Loci
Blue represents paternal or paternally derived alleles, red represents maternal or maternally derived alleles, and yellow represents transposed sequence. Black lollipops represent methylated CpGs, and the light blue dome represents a trans-acting factor. An asterisk denotes a gene duplicate. (A) Random molecular events or mutations in the germ-cell lineage generate alleles that undergo differential methylation when passing through the male and female germ line, which can confer either (B) negative or (C) positive fitness. While most of these alleles would be expected to confer negative fitness (B), a small proportion are maintained (C). Possible reasons for the spread of these alleles (C) are discussed further in the text and in Figure 4, which are by no means intended to be exhaustive. F1, first filial generation.
Figure 4
Figure 4. Possible Gene Dosage Scenarios before and after the Acquisition of Imprinting
For the two duplication scenarios (A and B), imprinting of the duplicated locus is presumed to arise while functional redundancy exists with the original copy. For simplicity, each example refers to a paternally expressed imprinted gene. Grey ovals represent autosomes, hatched ovals represent the X chromosome, red represents maternally derived chromosomes and alleles, and blue represents paternally derived chromosomes and alleles. (A) A nonimprinted autosomal gene undergoes duplication (i), resulting in a 2-fold (2:4) increase in active gene copy number. Imprinting (ii) reduces this increase to 1.5-fold (2:3). An example is the Mkrn3 gene on mouse Chromosome 7 [118]. (B) A gene subject to X-inactivation undergoes trans-duplication, resulting in a 3-fold (1:3) increase in active gene copy number. Imprinting reduces this increase to 2-fold (1:2). An example is the U2af1-rs1 locus [58]. (C) A nonimprinted autosomal gene acquires imprinting without undergoing a recent duplication, resulting in a 50% decrease in active gene copy number (2:1). This is likely to be the most common scenario, an example being the Igf2 locus [95].
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