Sex specific X chromosome expression caused by genomic imprinting

The conflict theory of genomic imprinting predicts that imprinted genes are growth enhancing when paternally expressed and growth suppressing when maternally expressed. The expression pattern of autosomal imprinted genes generally fits these predictions. However, the conflict theory cannot easily account for the pattern of X-linked imprinting in humans and mice. This has led us to propose a novel hypothesis that X-linked imprinting has evolved to control sex specific gene expression in early embryos. The hypothesis links paternal X-imprinting (i.e. paternal copy silencing) to random X-inactivation and the retention of Y-linked copies, and links maternal X-imprinting to escape from random X-inactivation and the loss of Y-linked copies.The hypothesis offers a good explanation of the existing data on X-imprinted genes.     

Evolution of mammalian X chromosome-linked imprinting

We analyse the evolution of X chromosome-linked imprinting by modifying our previous model of imprinting of autosomal genes that influence the trade-off between maternal fecundity and offspring viability through alterations in maternal investment (Mills and Moore, 2004). Unlike previous genetic models, we analyse X-linked imprinting in the context of populations at equilibrium for either autosomal or X-linked biallelically expressed alleles at loci that influence the fecundity/viability trade-off. We show that selection under parental conflict over maternal investment in offspring can parsimoniously explain the occurrence of sex-specific gene expression patterns, without a requirement to postulate direct selection for sexual dimorphism mediated through imprinting. We note that sex chromosome imprinting causes a small distortion of the post-weaning sex ratio, providing a possible selection pressure against the evolution of X-linked imprints. We discuss our conclusions in the context of recent reports of imprinting of mouse X-linked Xlr genes.     

Sex-dependent selection differentially shapes genetic variation on and off the guppy Y chromosome

Because selection is often sex-dependent, alleles can have positive effects on fitness in one sex and negative effects in the other, resulting in intralocus sexual conflict. Evolutionary theory predicts that intralocus sexual conflict can drive the evolution of sex limitation, sex-linkage, and sex chromosome differentiation. However, evidence that sex-dependent selection results in sex-linkage is limited. Here, we formally partition the contribution of Y-linked and non-Y-linked quantitative genetic variation in coloration, tail, and body size of male guppies (Poecilia reticulata)-traits previously implicated as sexually antagonistic. We show that these traits are strongly genetically correlated, both on and off the Y chromosome, but that these correlations differ in sign and magnitude between both parts of the genome. As predicted, variation in attractiveness was found to be associated with the Y-linked, rather than with the non-Y-linked component of genetic variation in male ornamentation. These findings show how the evolution of Y-linkage may be able to resolve sexual conflict. More generally, they provide unique insight into how sex-specific selection has the potential to differentially shape the genetic architecture of fitness traits across different parts of the genome.     

An adaptive hypothesis for the evolution of the Y chromosome.

Population geneticists remain unsure of the forces driving the evolution of Y chromosomes. Here we consider the possibility that the degeneration of the Y reflects its inability to evolve adaptively. Because the overwhelming majority of favorable mutations on a nonrecombining proto-Y suffer a zero probability of fixation, the fitness of the Y must lag far behind that of the recombining X. At some point, this disparity will grow so large that selection favors an increase in the expression of (fit) X-linked alleles and a decrease in the expression of (unfit) Y-linked alleles. Our calculations suggest that this process acts far more rapidly than hitchhiking-induced erosion of the Y and at least as rapidly as the fixation of deleterious alleles on the Y by background selection. Most important, this hypothesis can explain the evolution of Y chromosomes in taxa such as Drosophila that have very large population sizes.     

The Evolution of Genomic Imprinting

In some mammalian genes, the paternally and maternally derived alleles are expressed differently: this phenomenon is called genomic imprinting. Here we study the evolution of imprinting using multivariate quantitative genetic models to examine the feasibility of the genetic conflict hypothesis. This hypothesis explains the observed imprinting patterns as an evolutionary outcome of the conflict between the paternal and maternal alleles. We consider the expression of a zygotic gene, which codes for an embryonic growth factor affecting the amount of maternal resources obtained through the placenta. We assume that the gene produces the growth factor in two different amounts depending on its parental origin. We show that genomic imprinting evolves easily if females have some probability of multiple partners. This is in conflict with the observation that not all genes controlling placental development are imprinted and that imprinting in some genes is not conserved between mice and humans. We show however that deleterious mutations in the coding region of the gene create selection against imprinting.     

Perspective: maternal kin groups and the origins of asymmetric genetic systems-genomic imprinting, haplodiploidy, and parthenogenesis

The genetic systems of animals and plants are typically eumendelian. That is, an equal complement of autosomes is inherited from each of two parents, and at each locus, each parent's allele is equally likely to be expressed and equally likely to be transmitted. Genetic systems that violate any of these eumendelian symmetries are termed asymmetric and include parent-specific gene expression (PSGE), haplodiploidy, thelytoky, and related systems. Asymmetric genetic systems typically arise in lineages with close associations between kin (gregarious siblings, brooding, or viviparity). To date, different explanatory frameworks have been proposed to account for each of the different asymmetric genetic systems. Haig's kinship theory of genomic imprinting argues that PSGE arises when kinship asymmetries between interacting kin create conflicts between maternally and paternally derived alleles. Greater maternal than paternal relatedness within groups selects for more "abstemious" expression of maternally derived alleles and more "greedy" expression of paternally derived alleles. Here, I argue that this process may also underlie origins of haplodiploidy and many origins of thelytoky. The tendency for paternal alleles to be more "greedy" in maternal kin groups means that maternal-paternal conflict is not a zero-sum game: the maternal optimum will more closely correspond to the optimum for family groups and demes and for associated entities such as symbionts. Often in these circumstances, partial or complete suppression of paternal gene expression will evolve (haplodiploidy, thelytoky), or other features of the life cycle will evolve to minimize the conflict (monogamy, inbreeding). Maternally transmitted cytoplasmic elements and maternally imprinted nuclear alleles have a shared interest in minimizing agonistic interactions between female siblings and may cooperate to exclude the paternal genome. Eusociality is the most dramatic expression of the conflict-reducing effects of haplodiploidy, but its original and more widespread function may be suppression of intrafamilial cannibalism. In rare circumstances in which paternal gene products gain access to maternal physiology via a placenta, PSGE with greedy paternal gene expression can persist (e.g., in mammals).     

The resolution of sexual antagonism by gene duplication

Disruptive selection between males and females can generate sexual antagonism, where alleles improving fitness in one sex reduce fitness in the other. This type of genetic conflict arises because males and females carry nearly identical sets of genes: opposing selection, followed by genetic mixing during reproduction, generates a population genetic "tug-of-war" that constrains adaptation in either sex. Recent verbal models suggest that gene duplication and sex-specific cooption of paralogs might resolve sexual antagonism and facilitate evolutionary divergence between the sexes. However, this intuitive proximal solution for sexual dimorphism potentially belies a complex interaction between mutation, genetic drift, and positive selection during duplicate fixation and sex-specific paralog differentiation. The interaction of these processes--within the explicit context of duplication and sexual antagonism--has yet to be formally described by population genetics theory. Here, we develop and analyze models of gene duplication and sex-specific differentiation between paralogs. We show that sexual antagonism can favor the fixation and maintenance of gene duplicates, eventually leading to the evolution of sexually dimorphic genetic architectures for male and female traits. The timescale for these evolutionary transitions is sensitive to a suite of genetic and demographic variables, including allelic dominance, recombination, sex linkage, and population size. Interestingly, we find that female-beneficial duplicates preferentially accumulate on the X chromosome, whereas male-beneficial duplicates are biased toward autosomes, independent of the dominance parameters of sexually antagonistic alleles. Although this result differs from previous models of sexual antagonism, it is consistent with several findings from the empirical genomics literature.     

Indirect evidence from DNA sequence diversity for genetic degeneration of the Y-chromosome in dioecious species of the plant Silene: the SlY4/SlX4 and DD44-X/DD44-Y gene pairs

The action of natural selection is expected to reduce the effective population size of a nonrecombining chromosome, and this is thought to be the chief factor leading to genetic degeneration of Y-chromosomes, which cease recombining during their evolution from ordinary chromosomes. Low effective population size of Y chromosomes can be tested by studying DNA sequence diversity of Y-linked genes. In the dioecious plant, Silene latifolia, which has sex chromosomes, one comparison (SlX1 vs. SlY1) indeed finds lower Y diversity compared with the homologous X-linked gene, and one Y-linked gene with no X-linked homologue has lower species-wide diversity than a homologous autosomal copy (SlAp3Y vs. SlAp3A). To test whether this is a general pattern for Y-linked genes, we studied two further recently described X and Y homologous gene pairs in samples from several populations of S. latifolia and S. dioica. Diversity is reduced for both Y-linked genes, compared with their X-linked homologues. Our new data are analysed to show that the low Y effective size cannot be explained by different levels of gene flow for the X vs. the Y chromosomes, either between populations or between these closely related species. Thus, all four Y-linked genes that have now been studied in these plants (the two studied here, and two previously studied genes, have low diversity). This supports other evidence for an ongoing degeneration process in these species.     

The mechanism of the mixed inheritance of chloroplast genes in Pelargonium

Summary The distributions are given of gene frequencies among embryos after G X W and W X G plastid crosses within and between eight Pelargonium cultivars and some of their inbred or hybrid derivatives.Two distinct segregation patterns are recognized. Homozygous type I female parents (Pr₁Pr₁) have a high frequency of progeny with only maternal alleles, are intermediate for biparental and low for paternal offspring. Heterozygous type II female plants (Pr₁Pr₂) have an equally high frequency of maternal and paternal offspring and a generally low biparental frequency. These correspond to L-shaped and U-shaped gene frequency distributions respectively in which the only modes are at 0 per cent (maternal embryos) and 100 per cent (paternal embryos), with no mode corresponding to the population mean and no sign of a Gaussian distribution.The extremely variable plastid gene frequencies are strongly influenced by the maternal nuclear genotype and by the plastid genotype in which the wild-type allele is always more successful than the mutant in strict comparisons.The relative frequencies of maternal and paternal zygotes, and the mean gene frequency among all the zygotes in a cross, are explicable in terms of the input frequencies of genes from the two parents, their degree of mixing, and by some form of selective replication of plastids. This selection is controlled by nuclear and plastid genotypes which may act in the same direction, to increase the frequency of either the maternal or the paternal alleles, or in opposition. But selection alone is inadequate to explain the shapes of the gene frequency distributions. Instead, a model is proposed in which the segregation or replication of plastids appears to have a strong random element, which results in random drift of gene frequencies within a heteroplasmic zygote or embryo.     

The parental origin of the single X chromosome in Turner syndrome: lack of correlation with parental age or clinical phenotype.

We have used X- and Y-linked RFLPs to determine the origin of the single X chromosome in 25 live-born individuals with Turner syndrome. We determined that 18 individuals retained a maternal X (Xm) and that seven retained the paternal X (Xp). No occult mosaicism was detected. We found no differences in either maternal or paternal ages for the two groups. The ratio of maternal X to paternal X is just over 2:1, which is consistent with the expected proportion of meiotic or mitotic products, with equal loss at each step, given the nonviability of 45,Y. Six phenotypic or physiologic characteristics were assessed: (1) birth weight, (2) height percentile at time of testing, (3) presence of a webbed neck, (4) cardiovascular abnormalities, (5) renal abnormalities, and (6) thyroid autoimmunity. There were no significant differences in birth weights or heights between the girls who retained the maternal X or the paternal X. In addition, no differences between the groups could be appreciated in the incidence of the physical, anatomic, or physiologic parameters assessed.     

Expression of size-polymorphic androgen receptor (AR) gene in ovarian endometriosis according to the number of cytosine, adenine, and guanine (CAG) repeats in AR alleles.

An increase in androgen receptor (AR) caused by estrogen is recognized as one of the biological phenomena related to estrogen-induced growth in uterine endometrium. The A/B region of AR gene in X chromosome involves the cytosine, adenine, and guanine (CAG) repeats. Random X chromosome inactivation with AR alleles in individual cells occurs in females. Therefore, approximately either paternal or maternal single dominant polymorphic AR mRNA must be expressed in neoplastic tissue originated from monoclone. This prompted us to determine deviated number of CAG repeats in AR mRNA to understand clonality in ovarian endometriosis. In all cases of heterozygous AR alleles, although paternal and maternal AR mRNAs from normal eutopic uterine endometrium were consistently expressed as AR alleles, either paternal or maternal single dominant AR mRNA expression was found in an individual ovarian endometrioma. Therefore, an individual ovarian endometrioma might be formed from an independent monoclonal ovarian endometriotic endometrial cell after inactivation of either AR allele in X chromosome.     

The analysis of parental origin of alleles may detect susceptibility loci for complex disorders.

The phenomenon of genomic imprinting describes the differential behavior of genes depending on their parental origin, and has been demonstrated in a few rare genetic disorders. In complex diseases, parent-of-origin effects have not been systematically studied, although there may be heuristic value in such an approach. Data from a genome scan performed using 356 affected sibling pair families with type 1 diabetes were examined looking for evidence of excess sharing of either maternal or paternal alleles. At the insulin gene (IDDM2), evidence for excess sharing of alleles transmitted from mothers was detected, which is consistent with transmission disequilibrium results published elsewhere. We also identified additional loci that demonstrate allele sharing predominantly from one parent: IDDM8 shows a paternal origin effect, IDDM10 shows a maternal effect, and a locus on chromosome 16q demonstrates a paternal effect. We have also evaluated these loci for confounding by differences in sex-specific meiotic recombination by performing linkage analysis using sex-specific genetic maps. The analysis of the parental origin of shared alleles from genome scans of complex disorders may provide additional evidence for linkage for known loci, help identify regions containing additional susceptibility loci, and assist the cloning of the genes involved.     

Intralocus sexual conflict and the genetic architecture of sexually dimorphic traits in Prochyliza xanthostoma (Diptera: Piophilidae)

Because homologous traits of males and females are likely to have a common genetic basis, sex-specific selection (often resulting from sexual selection on one sex) may generate an evolutionary tug-of-war known as intralocus sexual conflict, which will constrain the adaptive divergence of the sexes. Theory suggests that intralocus sexual conflict can be mitigated through reduction of the intersexual genetic correlation (rMF), predicting negative covariation between rMF and sexual dimorphism. In addition, recent work showed that selection should favor reduced expression of alleles inherited from the opposite-sex parent (intersexual inheritance) in traits subject to intralocus sexual conflict. For traits under sexual selection in males, this should be manifested either in reduced maternal heritability or, when conflict is severe, in reduced heritability through the opposite-sex parent in offspring of both sexes. However, because we do not know how far these hypothesized evolutionary responses can actually proceed, the importance of intralocus sexual conflict as a long-term constraint on adaptive evolution remains unclear. In this study, we investigated the genetic architecture of sexual and nonsexual morphological traits in Prochyliza xanthostoma. The lowest rMF and greatest dimorphism were exhibited by two sexual traits (head length and antenna length) and, among all traits, the degree of sexual dimorphism was correlated negatively with rMF. Moreover, sexual traits exhibited reduced maternal heritabilities, and the most strongly dimorphic sexual trait (antenna length) was heritable only through the same-sex parent in offspring of both sexes. Our results support theory and suggest that intralocus sexual conflict can be resolved substantially by genomic adaptation. Further work is required to identify the proximate mechanisms underlying these patterns.     

Natural Selection and Y-Linked Polymorphism

Several population genetic models allowing natural selection to act on Y-linked polymorphism are examined. The first incorporates pleiotropic effects of a Y-linked locus, such that viability, segregation distortion, fecundity and sexual selection can all be determined by one locus. It is shown that no set of selection parameters can maintain a stable Y-linked polymorphism. Interaction with the X chromosome is allowed in the next model, with viabilities determined by both X- and Y-linked factors. This model allows four fixation equilibria, two equilibria with X polymorphism and a unique point with both X- and Y-linked polymorphism. Stability analysis shows that the complete polymorphism is never stable. When X- and Y-linked loci influence meiotic drive, it is possible to have all fixation equilibria simultaneously unstable, and yet there is no stable interior equilibrium. Only when viability and meiotic drive are jointly affected by both X- and Y-linked genes can a Y-linked polymorphism be maintained. Unusual dynamics, including stable limit cycles, are generated by this model. Numerical simulations show that only a very small portion of the parameter space admits Y polymorphism, a result that is relevant to the interpretation of levels of Y-DNA sequence variation in natural populations.     

Random X Inactivation and Extensive Mosaicism in Human Placenta Revealed by Analysis of Allele-Specific Gene Expression along the X Chromosome

Imprinted inactivation of the paternal X chromosome in marsupials is the primordial mechanism of dosage compensation for X-linked genes between females and males in Therians. In Eutherian mammals, X chromosome inactivation (XCI) evolved into a random process in cells from the embryo proper, where either the maternal or paternal X can be inactivated. However, species like mouse and bovine maintained imprinted XCI exclusively in extraembryonic tissues. The existence of imprinted XCI in humans remains controversial, with studies based on the analyses of only one or two X-linked genes in different extraembryonic tissues. Here we readdress this issue in human term placenta by performing a robust analysis of allele-specific expression of 22 X-linked genes, including XIST, using 27 SNPs in transcribed regions. We show that XCI is random in human placenta, and that this organ is arranged in relatively large patches of cells with either maternal or paternal inactive X. In addition, this analysis indicated heterogeneous maintenance of gene silencing along the inactive X, which combined with the extensive mosaicism found in placenta, can explain the lack of agreement among previous studies. Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals.     

Ploidally antagonistic selection maintains stable genetic polymorphism

Understanding the maintenance of genetic variation in the face of selection remains a key issue in evolutionary biology. One potential mechanism for the maintenance of genetic variation is opposing selection during the diploid and haploid stages of biphasic life cycles universal among eukaryotic sexual organisms. If haploid and diploid gene expression both occur, selection can act in each phase, potentially in opposing directions. In addition, sex-specific selection during haploid phases is likely simply because male and female gametophytes/gametes tend to have contrasting life histories. We explored the potential for the maintenance of a stable polymorphism under ploidally antagonistic as well as sex-specific selection. Furthermore, we examined the role of the chromosomal location of alleles (autosomal or sex-linked). Our analyses show that the most permissible conditions for the maintenance of polymorphism occur under negative ploidy-by-sex interactions, where stronger selection for an allele in female than male diploids is coupled with weaker selection against the allele in female than male haploids. Such ploidy-by-sex interactions also promote allele frequency differences between the sexes. With constant fitness, ploidally antagonistic selection can maintain stable polymorphisms for autosomal and X-linked genes but not for Y-linked genes. We discuss the implications of our results and outline a number of biological settings where the scenarios modeled may apply.     

Self-imposed silence: parental antagonism and the evolution of X-chromosome inactivation

A model is proposed for the evolution of X-chromosome inactivation (XCI) in which natural selection initially favors the silencing of paternally derived alleles of X-linked demand inhibitors. The compensatory upregulation of maternally derived alleles establishes a requirement for monoallelic expression in females. For this reason, XCI is self-reinforcing once established. However, inactivation of a particular X chromosome is not. Random XCI (rXCI) is favored over paternal XCI because rXCI reduces the costs of functional hemizygosity in females. Once present, rXCI favors the evolution of locus-by-locus imprinting of X-linked loci, which creates an evolutionary dynamic in which different chromosomes compete to remain active.     

Disruption of Imprinting by Mutator Transposon Insertions in the 5′ Proximal Regions of the Zea mays Mez1 Locus

Imprinting is a form of epigenetic gene regulation in which alleles are differentially regulated according to the parent of origin. The Mez1 gene in maize is imprinted such that the maternal allele is expressed in the endosperm while the paternal allele is not expressed. Three novel Mez1 alleles containing Mutator transposon insertions within the promoter were identified. These mez1-mu alleles do not affect vegetative expression levels or result in morphological phenotypes. However, these alleles can disrupt imprinted expression of Mez1. Maternal inheritance of the mez-m1 or mez1-m4 alleles results in activation of the normally silenced paternal allele of Mez1. Paternal inheritance of the mez1-m2 or mez1-m4 alleles can also result in a loss of silencing of the paternal Mez1 allele. The paternal disruption of imprinting by transposon insertions may reflect a requirement for sequence elements involved in targeting silencing of the paternal allele. The maternal disruption of imprinting by transposon insertions within the Mez1 promoter suggests that maternally produced MEZ1 protein may be involved in silencing of the paternal Mez1 allele. The endosperms with impaired imprinting did not exhibit phenotypic consequences associated with bi-allelic Mez1 expression.     

Polyandry, life-history trade-offs and the evolution of imprinting at Mendelian loci

Genomic imprinting causes parental origin-dependent differential expression of a small number of genes in mammalian and angiosperm plant embryos, resulting in non-Mendelian inheritance of phenotypic traits. The "conflict" theory of the evolution of imprinting proposes that reduced genetic relatedness of paternally, relative to maternally, derived alleles in offspring of polygamous females supports parental sex-specific selection at gene loci that influence maternal investment. While the theory's physiological predictions are well supported by observation, the requirement of polyandry in the evolution of imprinting from an ancestral Mendelian state has not been comprehensively analyzed. Here, we use diallelic models to examine the influence of various degrees of polyandry on the evolution of both Mendelian and imprinted autosomal gene loci that influence trade-offs between maternal fecundity and offspring viability. We show that, given a plausible assumption on the physiological relationship between maternal fecundity and offspring viability, low levels of polyandry are sufficient to reinforce exclusively the fixation of "greedy" paternally imprinted alleles that increase offspring viability at the expense of maternal fecundity and "thrifty" maternally imprinted alleles of opposite effect. We also show that, for all levels of polyandry, Mendelian alleles at genetic loci that influence the trade-off between maternal fecundity and offspring viability reach an evolutionary stable state, whereas pairs of reciprocally imprinted alleles do not.     

Estimating sex-specific processes in human populations: Are XY-homologous markers an effective tool?

Homologous markers on the sex-specific regions of the X- and Y-chromosomes are differentially inherited through males and females, and have similar molecular characteristics. They may therefore be useful as a complement to the comparison of mtDNA and Y-chromosomal haplotypes for estimating sex-specific processes shaping human population structure. To test this idea, we analyzed XY-homologous microsatellite diversity in 33 human populations from Africa, Asia and Europe. Interpopulation comparisons suggest that the generally discordant pattern of genetic variation observed for X- and Y-linked markers could be an outcome of sex-specific migration processes (m(females)/m(males) approximately 3) or sex-specific demographic processes (N(females)/N(males) approximately 11) or a combination of both. However, intrapopulation diversity estimated by the X/Y ratio Watterson estimator (theta(H(Y))/theta(H(X))) suggests that the scenarios required to explain the global genetic variation of XY-homologous markers are many and complex, and that the sex-specific processes (effective population size and migration rate) shaping human population structures are likely to be specific to each population under study. XY-homologous markers provide an insight into the genuine complexity of sex-specific processes, and their further exploitation in human population studies seems worthwhile.