Evolution of genomic imprinting as a coordinator of coadapted gene expression Jason B. Wolf1 Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom Edited by Marcus W. Feldman, Stanford University, Stanford, CA, and accepted by the Editorial Board February 12, 2013 (received for review April 3, 2012) Genomic imprinting is an epigenetic phenomenon in which the (21). Second, imprinted genes appear to modulate a limited expression of a gene copy inherited from the mother differs from number of types of traits, with most genes having effects on growth that of the copy inherited from the father. Many imprinted genes (especially in relation to the demand for maternal provisioning, appear to be highly interconnected through interactions mediated often via the placenta) and/or behaviors (17, 22), with behavioral by proteins, RNA, and DNA. These kinds of interactions often favor effects being largely associated with parental and social behaviors the evolution of genetic coadaptation, where beneficially inter- (13, 23–27). Many of the theories for the evolution of genomic acting alleles evolve to become coinherited. Here I demonstrate imprinting arise from or are strongly tied to this apparently limited theoretically that the presence of gene interactions that favor range of phenotypes influenced by most imprinted genes. For coadaptation can also favor the evolution of genomic imprinting. example, the fact that many imprinted genes appear to influence Selection favors genomic imprinting because it coordinates the prenatal growth and placental traits has been seen as support for coexpression of positively interacting alleles at different loci. Evo- a role of conflict (28, 29) or coadaptation in the origins of im- lution is expected to proceed through a scenario where selection printing (6), as has the role of imprinted genes in social behavior builds associations between beneficial combinations of alleles (e.g., refs. 25, 26) (although it is important to keep in mind that and, if one locus evolves to become imprinted, it leads to selection there are also many cases that do not clearly fit theoretical pre- for its interacting partners to match its pattern of imprinting. This dictions, e.g., ref. 30). Consequently, existing theories are gener- process should favor the evolution of physical linkage between ally consistent with the observation that there is a limited range of interacting genes and therefore may help explain why imprinted traits affected by imprinting (which is not surprising because they genes tend to be found in clusters. The model suggests that, have been motivated to explain these phenotypic effects). How- whereas some genes are expected to evolve their imprinting status ever, existing theories generally do not explain or involve the fi because selection directly favors a speci c pattern of parent-of- clustered nature of imprinted genes (31), although genetic conflict origin-dependent expression, other genes may evolve imprinting has been seen as a potential explanation for the clustering and as a coevolutionary response to match the expression pattern of interfering effects of RNAs at the callipyge locus (32). their interacting partners. As a result, some genes will show phe- Thefactthatimprintedgenesaffectalimitednumberoftrait notypic effects consistent with the predictions of models for the types provides ample opportunities for interactions between fl EVOLUTION evolution of genomic imprinting (e.g., con ict models), but other imprinted genes. Indeed, imprinted genes appear to be highly in- genes may not, having simply evolved imprinting to follow the teractive; for example, a meta-analysis of microarray data (33) has lead of their interacting partners. identified an imprinted gene network (IGN) [also referred to as the Zac1–regulated IGN, where Zac1 is a zinc finger protein that reg- epistasis | recombination ulates apoptosis and cell cycle arrest (34)], where a set of coregu- lated imprinted genes appears to play an important role in enomic imprinting is an epigenetic phenomenon in which modulating embryonic growth. Likewise, a systems study of the Gthe expression of a gene depends on its parent of origin (1). human “interactome” suggests that imprinted genes are tightly Since its discovery, there has been a great deal of interest in un- connected through interactions in the protein interaction network, derstanding the evolutionary processes that could favor such a composing a functionally important “module” of the human peculiar pattern of monoallelic gene expression. Consequently, interactome that is particularly intolerant of errors (35). Fur- there is a diversity of potential explanations for the evolution thermore, noncoding RNAs appear to provide opportunities origins of imprinted expression, with most of the currently favored for interactions between loci within imprinted gene clusters “ ” theories relying on some asymmetry that generates selection (16), as do direct regulatory interactions within and between favoring silencing of either the paternally or the maternally inheri- chromosomes, which show a strong overrepresentation of imprin- ted alleles (2, 3). Such conditions favoring genomic imprinting ted domains (36). For example, locally acting trans interactions fl can arise most notably from con ict between the maternal and involving RNA are responsible for the callipyge phenomenon in paternal genomes over maternal investment (4, 5), but can also sheep (37). Interactions between imprinted genes located in dif- arise from selection favoring coadaptation of gene expression in ferent chromosomes have also been reported (38, 39). mothers (or potentially fathers) and their offspring (6), patterns Imprinted genes are often coregulated (19) and tend to show of asymmetrical inheritance (7, 8), selection for parental similarity coordinated expression, which provides a strong opportunity for (9) or histocompatibility (10), and sexually antagonistic selection selection to favor genetic coadaptation, where combinations of (11). These theories have generated valuable hypotheses about the beneficially interacting alleles (i.e., alleles that “work well” functions of imprinted genes, which can provide important insights into the nature of their phenotypic effects, including the role of imprinted genes in various pathologies (e.g., refs. 12, 13). Author contributions: J.B.W. designed research, performed research, and wrote Although imprinted genes are members of many different gene the paper. families (14, 15), produce a diversity of proteins and noncoding The author declares no conflict of interest. RNAs (16), and have effects on an assortment of biochemical This article is a PNAS Direct Submission. M.W.F. is a guest editor invited by the Editorial pathways (17), they tend to share two conspicuous patterns. Board. First, imprinted genes tend to have a clustered distribution in 1E-mail: [email protected]. mammalian (15, 18, 19) and plant genomes (20), with the mam- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. malian clustering appearing to be conserved in vertebrate evolution 1073/pnas.1205686110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1205686110 PNAS | March 26, 2013 | vol. 110 | no. 13 | 5085–5090 Downloaded by guest on September 24, 2021 together) are coinherited (40). That is, given the temporal and imprinting at the B locus has the value iB(D)y1 and is labeled IB. spatial coupling of imprinted gene expression there is ample op- I use this four-locus system to examine the conditions under portunity for imprinted gene products to interact in their effects which the imprinting alleles at the C and D loci are favored to on fitness, which could lead to genetic coadaptation. For example, understand how epistatic interactions between a pair of loci in- the IGN includes at least 16 imprinted genes that tend to be fluence the evolution of imprinting at those loci. coexpressed and show coordinated changes in response to dif- Selection in this model arises from the assumption that the A ferentiation (41), mutation (e.g., knockout of H19 leads to up- and B loci interact to affect fitness. I use the “classic” model of regulation of several members of the IGN, ref. 42), and in vitro additive-by-additive interactions (45, 46), which is a simple model manipulation (e.g., in vitro fertilization disrupts patterns of meth- of two-locus fitness effects that favors coadaptation, where certain ylation at specific sites within the H19-Igf2 (insulin-like growth allelic combinations at the interacting loci are favored and other factor 2) locus, and these disruptions appear to be compensated for combinations are disfavored. This form of interaction is particu- through the IGN, ref. 43). A subset of 11 of the genes in the IGN larly useful in examining the evolutionary dynamics of imprinting has also been identified as a coexpressed group that shows co- because it does not include any dominance effects. The presence ordinated down-regulation across multiple tissues through time of dominance effects can favor or disfavor the evolution of ge- (34). The fact that imprinted gene clusters are often coregulated nomic imprinting solely because monoallelic expression removes by imprinting control elements (44) also suggests the need for the opportunity for dominance effects to be expressed in heter- coordinated expression. This clustered distribution may also ozygotes (i.e., removes the physiological basis for dominance). reflect an evolutionary history where natural