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. For certain genes, individuals express only the copy of the gene they inherit from either their mother (“maternally expressed” genes) or their father (“paternally expressed” genes). This “parent-of-origin–dependent” pattern of gene expression is known as genomic imprinting and has been shown to play an important role in modulating a variety of traits ranging from developmental processes to cognitive abilities and associated disorders. While various molecular techniques have allowed for the identification of many imprinted genes, very little is known about the contribution of imprinting to variation seen among individuals in continuously varying traits such as body size. Here we address this issue by using a genome-wide analysis aimed at finding regions of the genome that show an effect of imprinting on body weight and growth in mice. We identified ten loci that displayed complex and diverse patterns of effect, including four loci with effects similar to the unusual callipyge mutation found in sheep and three that displayed a new phenotypic pattern that we refer to as bipolar dominance. Surprisingly, most imprinting effects were strongest during the post-weaning period, and many showed shifts in the pattern of imprinting over ontogenetic time.