Genome-wide analysis reveals a complex pattern of genomic imprinting in mice

Abstract

Parent-of-origin-dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life.

Figure 1. All possible phenotypic patterns of genomic imprinting.

Two principal patterns are possible: parental expression and dominance imprinting. Parental expression has two subtypes describing which allele is being expressed (paternal versus maternal). Dominance imprinting refers to the case where the two homozygotes are the same while the heterozygotes are different from each other. There are two subtypes of dominance imprinting: bipolar and polar. Bipolar dominance refers to the case where one heterozygote is larger than the homozygotes while the other heterozygote is smaller (i.e., one heterozygote shows overdominance while the other shows underdominance). Polar dominance refers to the case where one heterozygote is the same as the two homozygotes while the other heterozygote is not. Polar dominance may show overdominance, where the heterozygote differing from the other three genotypes is larger, or underdominance, where it is smaller. The plots give examples of the expected pattern of phenotypes for the four ordered genotypes when the sign of i is either positive or negative.

Figure 2. Three examples of imprinting patterns found in the genome-wide scan.

Each of the four genotypes is shown with its corresponding average phenotype plus standard error of the mean at the locus. A) Wti1.1 serves as an example for paternal expression for week 9 body weight (g). B) Wti3.2 provides an example of bipolar dominance for week 7 body weight (g), C) Wti5.1 provides an example of polar overdominance for week 10 body weight (g).

Figure 3. Change in imprinting pattern for iQTL Wti5.1 caused by imprinting effects on growth.

For week 4 body weight (g) the locus shows paternal expression (A), but later the locus shows polar overdominance (see Figure 2A for the pattern in week 10). The change in the pattern of imprinting is due to polar overdominance for growth from week 3 to 10 (B), where the LS heterozygote grows more than the other three ordered genotypes. Error bars denote standard errors of the mean.

Figure 4. A pattern of paternal expression associated with partial imprinting.

Locus Wti7.1 shows a pattern of paternal expression for week 6 body weight (g) where the difference between the genotypic values of the heterozygotes (0.81g) is less than half the difference between the homozygotes (1.66g).

Figure 5. A hypothetical model explaining the appearance of bipolar dominance imprinting.

In this model, a QTL with two alleles (1 and 2) is comprised of two genes (A and B), which are in close linkage. Gene A is paternally expressed while B is maternally expressed. Allele 1 has a positive effect on a trait when paternally inherited but a negative effect when maternally inherited while allele 2 shows the opposite pattern. When the same allele is inherited from both the father and the mother the effects cancel out, yielding no difference between the two homozygotes. However, if two different alleles are inherited from the parents then the joint effects of the paternal and maternal copy do not cancel anymore but produce a pattern of bipolar dominance.