Non-conflict theories for the evolution of genomic imprinting

Theories focused on kinship and the genetic conflict it induces are widely considered to be the primary explanations for the evolution of genomic imprinting. However, there have appeared many competing ideas that do not involve kinship/conflict. These ideas are often overlooked because kinship/conflict is entrenched in the literature, especially outside evolutionary biology. Here we provide a critical overview of these non-conflict theories, providing an accessible perspective into this literature. We suggest that some of these alternative hypotheses may, in fact, provide tenable explanations of the evolution of imprinting for at least some loci.     

The evolution of X-linked genomic imprinting

We develop a quantitative genetic model to investigate the evolution of X-imprinting. The model compares two forces that select for X-imprinting: genomic conflict caused by polygamy and sex-specific selection. Genomic conflict can only explain small reductions in maternal X gene expression and cannot explain silencing of the maternal X. In contrast, sex-specific selection can cause extreme differences in gene expression, in either direction (lowered maternal or paternal gene expression), even to the point of gene silencing of either the maternal or paternal copy. These conclusions assume that the Y chromosome lacks genetic activity. The presence of an active Y homologue makes imprinting resemble the autosomal pattern, with active paternal alleles (X- and Y-linked) and silenced maternal alleles. This outcome is likely to be restricted as Y-linked alleles are subject to the accumulation of deleterious mutations. Experimental evidence concerning X-imprinting in mouse and human is interpreted in the light of these predictions and is shown to be far more easily explained by sex-specific selection.     

A maternal-offspring coadaptation theory for the evolution of genomic imprinting

Imprinted genes are expressed either from the maternally or paternally inherited copy only, and they play a key role in regulating complex biological processes, including offspring development and mother–offspring interactions. There are several competing theories attempting to explain the evolutionary origin of this monoallelic pattern of gene expression, but a prevailing view has emerged that holds that genomic imprinting is a consequence of conflict between maternal and paternal gene copies over maternal investment. However, many imprinting patterns and the apparent overabundance of maternally expressed genes remain unexplained and may be incompatible with current theory. Here we demonstrate that sole expression of maternal gene copies is favored by natural selection because it increases the adaptive integration of offspring and maternal genomes, leading to higher offspring fitness. This novel coadaptation theory for the evolution of genomic imprinting is consistent with results of recent studies on epigenetic effects, and it provides a testable hypothesis for the origin of previously unexplained major imprinting patterns across different taxa. In conjunction with existing hypotheses, our results suggest that imprinting may have evolved due to different selective pressures at different loci.     

Selective abortion and the evolution of genomic imprinting

Mothers can determine which genotypes of offspring they will produce through selective abortion or selective implantation. This process can, at some loci, favour matching between maternal and offspring genotype whereas at other loci mismatching may be favoured (e.g. MHC, HLA). Genomic imprinting generally renders gene expression monoallelic and could thus be adaptive at loci where matching or mismatching is beneficial. This hypothesis, however, remains unexplored despite evidence that loci known to play a role in genetic compatibility may be imprinted. We develop a simple model demonstrating that, when matching is beneficial, imprinting with maternal expression is adaptive because the incompatible paternal allele is not detected, protecting offspring from selective abortion. Conversely, when mismatching is beneficial, imprinting with paternal expression is adaptive because the maternal genotype is more able to identify the presence of a foreign allele in offspring. Thus, imprinting may act as a genomic ‘cloaking device’ during critical periods in development when selective abortion is possible.     

The evolution of genomic imprinting via variance minimization: an evolutionary genetic model

A small number of mammalian loci exhibit genomic imprinting, in which only one copy of a gene is expressed while the other is silenced. At some such loci, the maternally inherited allele is inactivated; others show paternal inactivation. Several hypotheses have been put forward to explain how this genetic system could have evolved in the face of the selective advantages of diploidy. In this study, we examine the variance-minimization hypothesis, which proposes that imprinting arose through selection for reduced variation in levels of gene expression. We present an evolutionary genetic model incorporating both this selection pressure and deleterious mutations to elucidate the conditions under which imprinting could evolve. Our analysis implies that additional mechanisms such as genetic drift are required for imprinting to evolve from an initial nonimprinting state. Other predictions of this hypothesis do not appear to fit the available data as well as predictions for two alternative hypotheses, genetic conflict and the ovarian time bomb. On the basis of this evidence, we conclude that the variance-minimization hypothesis appears less adequate to explain the evolution of genomic imprinting.     

Gene interactions in the evolution of genomic imprinting

Numerous evolutionary theories have been developed to explain the epigenetic phenomenon of genomic imprinting. Here, we explore a subset of theories wherein non-additive genetic interactions can favour imprinting. In the simplest genic interaction—the case of underdominance—imprinting can be favoured to hide effectively low-fitness heterozygous genotypes; however, as there is no asymmetry between maternally and paternally inherited alleles in this model, other means of enforcing monoallelic expression may be more plausible evolutionary outcomes than genomic imprinting. By contrast, more successful interaction models of imprinting rely on an asymmetry between the maternally and paternally inherited alleles at a locus that favours the silencing of one allele as a means of coordinating the expression of high-fitness allelic combinations. For example, with interactions between autosomal loci, imprinting functionally preserves high-fitness genotypes that were favoured by selection in the previous generation. In this scenario, once a focal locus becomes imprinted, selection at interacting loci favours a matching imprint. Uniparental transmission generates similar asymmetries for sex chromosomes and cytoplasmic factors interacting with autosomal loci, with selection favouring the expression of either maternal or paternally derived autosomal alleles depending on the pattern of transmission of the uniparentally inherited factor. In a final class of models, asymmetries arise when genes expressed in offspring interact with genes expressed in one of its parents. Under such a scenario, a locus evolves to have imprinted expression in offspring to coordinate the interaction with its parent''s genome. We illustrate these models and explore key links and differences using a unified framework.     

Influence of mom and dad: quantitative genetic models for maternal effects and genomic imprinting

The expression of an imprinted gene is dependent on the sex of the parent it was inherited from, and as a result reciprocal heterozygotes may display different phenotypes. In contrast, maternal genetic terms arise when the phenotype of an offspring is influenced by the phenotype of its mother beyond the direct inheritance of alleles. Both maternal effects and imprinting may contribute to resemblance between offspring of the same mother. We demonstrate that two standard quantitative genetic models for deriving breeding values, population variances and covariances between relatives, are not equivalent when maternal genetic effects and imprinting are acting. Maternal and imprinting effects introduce both sex-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the two approaches. We use a simple example to demonstrate that both imprinting and maternal genetic effects add extra terms to covariances between relatives and that model misspecification may over- or underestimate true covariances or lead to extremely variable parameter estimation. Thus, an understanding of various forms of parental effects is essential in correctly estimating quantitative genetic variance components.     

Do we understand the evolution of genomic imprinting?

The conflict theory is the only hypothesis to have attracted any critical attention for the evolution of genomic imprinting. Although the earliest data appeared supportive, recent systematic analyses have not confirmed the model's predictions. The status of theory remains undecided, however, as post-hoc explanation can be provided as to why these predictions are not borne out.     

A statistical model for dissecting genomic imprinting through genetic mapping

As a result of nonequivalent genetic contribution of maternal and paternal genomes to offsprings, genomic imprinting or called parent-of-origin effect, has been broadly identified in plants, animals and humans. Its role in shaping organism’s development has been unanimously recognized. However, statistical methods for identifying imprinted quantitative trait loci (iQTL) and estimating the imprinted effect have not been well developed. In this article, we propose an efficient statistical procedure for genomewide estimating and testing the effects of significant iQTL underlying the quantitative variation of interested traits. The developed model can be applied to two different genetic cross designs, backcross and F₂ families derived from inbred lines. The proposed procedure is built within the maximum likelihood framework and implemented with the EM algorithm. Extensive simulation studies show that the proposed model is well performed in a variety of situations. To demonstrate the usefulness of the proposed approach, we apply the model to a published data in an F₂ family derived from LG/S and SM/S mouse stains. Two partially maternal imprinting iQTL are identified which regulate the growth of body weight. Our approach provides a testable framework for identifying and estimating iQTL involved in the genetic control of complex traits.     

Intralocus sexual conflict can drive the evolution of genomic imprinting

Genomic imprinting is a phenomenon whereby the expression of an allele differs depending upon its parent of origin. There is an increasing number of examples of this form of epigenetic inheritance across a wide range of taxa, and imprinting errors have also been implicated in several human diseases. Various hypotheses have been put forward to explain the evolution of genomic imprinting, but there is not yet a widely accepted general hypothesis for the variety of imprinting patterns observed. Here a new evolutionary hypothesis, based on intralocus sexual conflict, is proposed. This hypothesis provides a potential explanation for much of the currently available empirical data, and it also makes new predictions about patterns of genomic imprinting that are expected to evolve but that have not, as of yet, been looked for in nature. This theory also provides a potential mechanism for the resolution of intralocus sexual conflict in sexually selected traits and a novel pathway for the evolution of sexual dimorphism.     

Convergent evolution of genomic imprinting in plants and mammals

Parental genomic imprinting is characterized by the expression of a selected panel of genes from one of the two parental alleles. Recent evidence shows that DNA methylation and histone modifications are responsible for this parent-of-origin-dependent expression of imprinted genes. Because similar epigenetic marks have been recruited independently in plants and mammals, the only organisms in which imprinted gene loci have been identified so far, this phenomenon represents a case for convergent evolution. Here we discuss the emerging parallels in imprinting in both taxa. We also describe the significance of imprinting for reproduction and discuss potential models for its evolution.     

Possible genomic imprinting of three human obesity-related genetic loci

To detect potentially imprinted, obesity-related genetic loci, we performed genomewide parent-of-origin linkage analyses under an allele-sharing model for discrete traits and under a family regression model for obesity-related quantitative traits, using a European American sample of 1,297 individuals from 260 families, with 391 microsatellite markers. We also used two smaller, independent samples for replication (a sample of 370 German individuals from 89 families and a sample of 277 African American individuals from 52 families). For discrete-trait analysis, we found evidence for a maternal effect in chromosome region 10p12 across the three samples, with LOD scores of 5.69 (single-point) and 4.52 (multipoint) for the pooled sample. For quantitative-trait analysis, we found the strongest evidence for a maternal effect (single-point LOD of 2.85; multipoint LOD of 4.01 for body mass index [BMI] and 3.69 for waist circumference) in region 12q24 and for a paternal effect (single-point LOD of 4.79; multipoint LOD of 3.72 for BMI) in region 13q32, in the European American sample. The results suggest that parent-of-origin effects, perhaps including genomic imprinting, may play a role in human obesity.     

Host defenses to transposable elements and the evolution of genomic imprinting

Genomic imprinting is the differential expression of maternally and paternally inherited alleles of specific genes. Several organismic level hypotheses have been offered to explain the evolution of genomic imprinting. We argue that evolutionary explanations of the origin of imprinting that focus exclusively on the organismic level are incomplete. We propose that the complex molecular mechanisms that underlie genomic imprinting originally evolved as an adaptive response to the mutagenic potential of transposable elements (TEs). We also present a model of how these mechanisms may have been co-opted by natural selection to evolve molecular features characteristic of genomic imprinting.     

Population models of genomic imprinting. I. Differential viability in the sexes and the analogy with genetic dominance

Many single-locus, two-allele selection models of genomic imprinting have been shown to reduce formally to one-locus Mendelian models with a modified parameter for genetic dominance. One exception is the model where selection at the imprinted locus affects the sexes differently. We present two models of maternal inactivation with differential viability in the sexes, one with complete inactivation, and the other with a partial penetrance for inactivation. We show that, provided dominance relations at the imprintable locus are the same in both sexes, a globally stable polymorphism exists for a range of viabilities that is independent of the penetrance of imprinting. The conditions for a polymorphism are the same as in previous models with differential viability in the sexes but without imprinting and in a model of the paternal X-inactivation system in marsupials. The model with incomplete inactivation is used to illustrate the analogy between imprinting and dominance by comparing equilibrium bifurcation plots for fixed values of dominance and penetrance. We also derive a single expression for the dominance parameter that leaves the frequency and stability of equilibria unchanged for all levels of inactivation. Although an imprinting model with sex differences does not formally reduce to a nonimprinting scheme, close theoretical parallels clearly exist.     

遗传多样性上限假说所揭示的进化历程

作为生物进化的两个主流理论, 中性学说和现代达尔文进化理论相对系统地揭示了进化机理和历程, 但也都有缺陷, 比如对某些重大进化现象如遗传等距离和重叠位点(Overlap sites)的忽视, 对复杂性的视而不见, 对遗传多样性的片面解读, 以及与化石证据相悖等。遗传多样性上限假说(Maximum genetic diversity hypothesis, MGD)通过对遗传等距离现象的重新解读, 给出了复杂性的量化定义和可操作研究手段, 提出了重叠特征和遗传多样性具有上限等结论。它对人猿分类关系和现代人多地区起源的分子解读结论, 与独立的化石证据契合度较高, 重新肯定了中国在人类发展中的关键作用, 点出了流行分子结论的荒谬在于误用了极限距离。该理论同时对复杂性状和复杂疾病的遗传机制研究具有指导意义。文章对多种酵母、鱼类、灵长类的细胞色素c进行序列比对, 独立验证了MGD假说的部分论断, 并解释了重叠位点在遗传距离计算上的重要意义。MGD假说中的上限或最佳平衡概念, 与传统国学和中医阴阳中庸思想对宇宙基本规律的描述是一脉相承的。     

Sexual selection modulates genetic conflicts and patterns of genomic imprinting

Recent years have seen a surge of interest in linking the theories of kin selection and sexual selection. In particular, there is a growing appreciation that kin selection, arising through demographic factors such as sex‐biased dispersal, may modulate sexual conflicts, including in the context of male–female arms races characterized by coevolutionary cycles. However, evolutionary conflicts of interest need not only occur between individuals, but may also occur within individuals, and sex‐specific demography is known to foment such intragenomic conflict in relation to social behavior. Whether and how this logic holds in the context of sexual conflict—and, in particular, in relation to coevolutionary cycles—remains obscure. We develop a kin‐selection model to investigate the interests of different genes involved in sexual and intragenomic conflict, and we show that consideration of these conflicting interests yields novel predictions concerning parent‐of‐origin specific patterns of gene expression and the detrimental effects of different classes of mutation and epimutation at loci underpinning sexually selected phenotypes.     

Evolutionary genomics: molecular evolution at the genomic scale

The Symposium on Evolutionary Genomics was held in Atami, Japan, from 4 to 6 November 2001.     

Mammalian viviparity: a complex niche in the evolution of genomic imprinting

Evolution of mammalian reproductive success has witnessed a strong dependence on maternal resources through placental in utero development. Genomic imprinting, which has an active role in mammalian viviparity, also reveals a biased role for matrilineal DNA in its regulation. The co-existence of three matrilineal generations as one (mother, foetus and post-meiotic oocytes) has provided a maternal niche for transgenerational co-adaptive selection pressures to operate. In utero foetal growth has required increased maternal feeding in advance of foetal energetic demands; the mammary glands are primed for milk production in advance of birth, while the maternal hypothalamus is hormonally primed by the foetal placenta for nest building and post-natal care. Such biological forward planning resulted from maternal–foetal co-adaptation facilitated by co-expression of the same imprinted allele in the developing hypothalamus and placenta. This co-expression is concurrent with the placenta interacting with the adult maternal hypothalamus thereby providing a transgenerational template on which selection pressures may operate ensuring optimal maternalism in this and the next generation. Invasive placentation has further required the maternal immune system to adapt and positively respond to the foetal allotype. Pivotal to these mammalian evolutionary developments, genomic imprinting emerged as a monoallelic gene dosage regulatory mechanism of tightly interconnected gene networks providing developmental genetic stability for in utero development.     

Genetic conflicts,multiple paternity and the evolution of genomic imprinting.

We present nine diallelic models of genetic conflict in which one allele is imprintable and the other is not to examine how genomic imprinting may have evolved. Imprinting is presumed to be either maternal (i.e., the maternally derived gene is inactivated) or paternal. Females are assumed to be either completely monogamous or always bigamous, so that we may see any effect of multiple paternity. In contrast to previous verbal and quantitative genetic models, we find that genetic conflicts need not lead to paternal imprinting of growth inhibitors and maternal imprinting of growth enhancers. Indeed, in some of our models--those with strict monogamy--the dynamics of maternal and paternal imprinting are identical. Multiple paternity is not necessary for the evolution of imprinting, and in our models of maternal imprinting, multiple paternity has no effect at all. Nevertheless, multiple paternity favors the evolution of paternal imprinting of growth inhibitors and hinders that of growth enhancers. Hence, any degree of multiple paternity means that growth inhibitors are more likely to be paternally imprinted, and growth enhancers maternally so. In all of our models, stable polymorphism of imprinting status is possible and mean fitness can decrease over time. Neither of these behaviors have been predicted by previous models.