Imprinted genes can have oppositional effects on adult behavior in mice.
Mammalian genomes show the marks of a genetic tug-of-war between mothers and fathers. These imprinted genes are marked by epigenetic modifications, which means the expression of an imprinted allele depends on whether it was inherited from the mother or the father. A new report in GENETICS expands our understanding of this phenomenon by describing a pair of imprinted genes with opposing effects on adult mouse behavior.
Seeking the evolutionary underpinnings of imprinting has fueled a number of theories and debates. One explanation is based on the conflicting evolutionary pressures on alleles with different parental origins. This theory of intragenomic conflict suggests that the function of imprinting is to control the expression of genes that have opposite effects on maternal and paternal fitness. For example, a paternally inherited allele might favor the growth of offspring as large as possible, but a gene inherited from the mother might instead favor conserving maternal resources for future offspring. Supporting this idea, a number of examples have been found where pairs of genes with antagonistic effects on embryonic growth and early development have inverse patterns of imprinting (i.e. one is expressed only from the paternal allele and the other only from the maternal allele).
In the mouse central nervous system, only the maternal copy of Nesp55 is expressed, while only the paternal copy of Grb10 is expressed. The authors of the GENETICS study previously found that mice lacking maternal Nesp55 make more impulsive choices, but the role of Grb10 was unknown. Given that the two genes have similar expression patterns, the authors hypothesized that they might play related roles.
To address this question, the authors used the same experimental setup they had used for their previous study of Nesp55. They tested mice lacking paternal Grb10 and their wild-type littermates with two different measures of impulsivity. First, they tested impulsive choice by using a delayed reinforcement test, in which mice have to choose between a small reward immediately or a larger reward after a wait. Then, they measured impulsive action by using a stop-signal reaction time test, where mice had to learn to stop a prepotent action in order to get a reward. Although “impulsive choice” and “impulsive action” are deceptively similar terms, they refer to discrete behaviors.
In their previous study, the authors found that mice lacking maternal Nesp55 make more impulsive choices, i.e. they show a preference for a small but quick reward. In this study, mice lacking paternal Grb10 showed the exact opposite phenotype; they made significantly fewer impulsive choices. The behavioral effect was quite specific; all the mice studied showed no change in impulsive action. This suggests that these two genes have opposing effects on this particular aspect of mouse behavior—and this behavior could be subject to conflicting selection pressures, in line with the theory of intragenomic conflict.
This is the first report of imprinted genes acting in opposition in adult behavior, and it suggests that the genomic tug-of-war between parental alleles could have effects that extend into adulthood—far beyond those observed in utero and in early development. The authors suggest that such imprinted genes may even play roles in human disorders that involve impulsivity, like addiction.
Impulsive Choice in Mice Lacking Paternal Expression of Grb10 Suggests Intragenomic Conflict in Behavior
Claire L. Dent, Trevor Humby, Katie Lewis, Andrew Ward, Reiner Fischer-Colbrie, Lawrence S. Wilkinson, Jon F. Wilkins, Anthony R. Isles
GENETICS May 1, 2018 vol. 209 no. 1 233-239; DOI: 10.1534/genetics.118.300898