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A review of the literature on the anatomy of the lower female genital tract in therian mammals reveals, contrary to the general perception, a large amount of inter-specific variation. Variation in females is anatomically more radical than that in the male genitalia. It includes the absence of whole anatomical units, like the cervix in many Xenarthra, or the absence of the urogenital sinus (UGS), as well as the complete spatial separation of the external clitoral parts from the genital canal (either vagina or UGS). A preliminary phylogenetic analysis shows two patterns. Some morphs are unique to early branching clades, like the absence of the cervix, while others arose multiple times independently, like the flattening out or loss of the UGS, or the extreme elongation of the clitoris. Based on available information, the ancestral eutherian configuration of the external female genitalia included a cervix, a single vaginal segment, a tubular UGS, and an unperforated clitoris close to the entrance of the genital canal. The evidence for either bilobed or unitary glandes clitorides is ambivalent. Despite the wealth of information available, many gaps in knowledge remain and will require a community-wide effort to come to a more robust model of female genital evolutionary patterns. [ABSTRACT FROM AUTHOR]

Mammalian pregnancy evolved in the therian stem lineage, that is, before the common ancestor of marsupials and eutherian (placental) mammals. Ancestral therian pregnancy likely involved a brief phase of attachment between the fetal and maternal tissues followed by parturition—similar to the situation in most marsupials including the opossum. In all eutherians, however, embryo attachment is followed by implantation, allowing for a stable fetal–maternal interface and an extended gestation. Embryo attachment induces an attachment reaction in the uterus that is homologous to an inflammatory response. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory response was transformed into embryo implantation in the eutherian lineage. We performed a comparative uterine transcriptomic and immunohistochemical study of three eutherians, armadillo (Dasypus novemcinctus), hyrax (Procavia capensis), and rabbit (Oryctolagus cuniculus); and one marsupial, opossum (Monodelphis domestica). Our results suggest that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing one of its modules detrimental to pregnancy, namely, neutrophil recruitment by cytokine IL17A. Further, we propose that this suppression was mediated by decidual stromal cells, a novel cell type in eutherian mammals. We tested a prediction of this model in vitro and showed that decidual stromal cells can suppress the production of IL17A from helper T cells. Together, these results provide a mechanistic understanding of early stages in the evolution of eutherian pregnancy. [ABSTRACT FROM AUTHOR]

Evolution of highly invasive placentation in the stem lineage of eutherians and subsequent extension of pregnancy set eutherians apart from other mammals, that is, marsupials with short-lived placentas, and oviparous monotremes. Recent studies suggest that eutherian implantation evolved from marsupial attachment reaction, an inflammatory process induced by the direct contact of fetal placenta with maternal endometrium after the breakdown of the shell coat, and shortly before the onset of parturition. Unique to eutherians, a dramatic downregulation of inflammation after implantation prevents the onset of premature parturition, and is critical for the maintenance of gestation. This downregulation likely involved evolutionary changes on maternal as well as fetal/placental side. Tripartite-motif family-like2 (TRIML2) only exists in eutherian genomes and shows preferential expression in preimplantation embryos, and trophoblast-derived structures, such as chorion and placental disc. Comparative genomic evidence supports that TRIML2 originated from a gene duplication event in the stem lineage of Eutheria that also gave rise to eutherian TRIML1. Compared with TRIML1, TRIML2 lost the catalytic RING domain of E3 ligase. However, only TRIML2 is induced in human choriocarcinoma cell line JEG3 with poly(I:C) treatment to simulate inflammation during viral infection. Its knockdown increases the production of proinflammatory cytokines and reduces trophoblast survival during poly(I:C) stimulation, while its overexpression reduces proinflammatory cytokine production, supporting TRIML2 's role as a regulatory inhibitor of the inflammatory pathways in trophoblasts. TRIML2's potential virus-interacting PRY/SPRY domain shows significant signature of selection, suggesting its contribution to the evolution of eutherian-specific inflammation regulation during placentation. [ABSTRACT FROM AUTHOR]

Despite sophisticated mathematical models, the theory of microevolution is mostly treated as a qualitative rather than a quantitative tool. Numerical measures of selection, constraints, and evolutionary potential are often too loosely connected to theory to provide operational predictions of the response to selection. In this paper, we study the ability of a set of operational measures of evolvability and constraint to predict short‐term selection responses generated by individual‐based simulations. We focus on the effects of selective constraints under which the response in one trait is impeded by stabilizing selection on other traits. The conditional evolvability is a measure of evolutionary potential explicitly developed for this situation. We show that the conditional evolvability successfully predicts rates of evolution in an equilibrium situation, and further that these equilibria are reached with characteristic times that are inversely proportional to the fitness load generated by the constraining characters. Overall, we find that evolvabilities and conditional evolvabilities bracket responses to selection, and that they together can be used to quantify evolutionary potential on time scales where the G‐matrix remains relatively constant. [ABSTRACT FROM AUTHOR]

Transposable element (TE)-derived sequences make up approximately half of most mammalian genomes, and many TEs have been co-opted into gene regulatory elements. However, we lack a comprehensive tissue- and genome-wide understanding of how and when TEs gain regulatory activity in their hosts. We evaluated the prevalence of TE-derived DNA in enhancers and promoters across hundreds of human and mouse cell lines and primary tissues. Promoters are significantly depleted of TEs in all tissues compared with their overall prevalence in the genome (P<0.001); enhancers are also depleted of TEs, though not as strongly as promoters. The degree of enhancer depletion also varies across contexts (1.5-3x), with reproductive and immune cells showing the highest levels of TE regulatory activity in humans. Overall, in spite of the regulatory potential of many TE sequences, they are significantly less active in gene regulation than expected from their prevalence. TE age is predictive of the likelihood of enhancer activity; TEs originating before the divergence of amniotes are 9.2 times more likely to have enhancer activity than TEs that integrated in great apes. Context-specific enhancers are more likely to be TE-derived than enhancers active in multiple tissues, and young TEs are more likely to overlap context-specific enhancers than old TEs (86% vs. 47%). Once TEs obtain enhancer activity in the host, they have similar functional dynamics to one another and non-TE-derived enhancers, likely driven by pleiotropic constraints. However, a few TE families, most notably endogenous retroviruses, have greater regulatory potential. Our observations suggest a model of regulatory co-option in which TE-derived sequences are initially repressed, after which a small fraction obtains context-specific enhancer activity, with further gains subject to pleiotropic constraints. [ABSTRACT FROM AUTHOR]

The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stemlineage of eutherian mammals, ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type "neo-ESF" in contrast to "paleo-ESF" which is homologous to eutherian ESF but is not able to decidualize. In this study, we compare the transcriptomes of ESF from six therian species: Opossum (Monodelphis domestica; paleo-ESF), mink, rat, rabbit, human (all neo-ESF), and cow (secondarily nondecidualizing neo-ESF). We find evidence for strong stabilizing selection on transcriptome composition suggesting that the expression of approximately 5,600 genes is maintained by natural selection. The evolution of neo-ESF from paleo-ESF involved the following gene expression changes: Loss of expression of genes related to inflammation and immune response, lower expression of genes opposing tissue invasion, increased markers for proliferation as well as the recruitment of FOXM1, a key gene transiently expressed during decidualization. Signaling pathways also evolve rapidly and continue to evolve within eutherian lineages. In the bovine lineage, where invasiveness and decidualization were secondarily lost, we see a re-expression of genes found in opossum, most prominently WISP2, and a loss of gene expression related to angiogenesis. The data from this and previous studies support a scenario, where the proinflammatory paleo-ESF was reprogrammed to express anti-inflammatory genes in response to the inflammatory stimulus coming from the implanting conceptus and thus paving the way for extended, trans-cyclic gestation. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. Their distribution throughout the genome raises critical questions--do these elements contribute to broad tissue- and lineage-specific regulation? If so, in what manner, as enhancers, promoters, RNAs? Here, we devise a novel approach to systematically dissect the genome-wide consequences of TE insertion on gene expression, and test the hypothesis that classes of endogenous retrovirus long terminal repeats (LTRs) exert tissuespecific regulation of adjacent genes. Using correlation of expression patterns across 18 tissue types, we reveal the tissue-specific uncoupling of gene expression due to 62 different LTR classes. These patterns are specific to the retroviral insertion, as the same genes in species without the LTRs do not exhibit the same effect. Although the LTRs can be transcribed themselves, the most highly transcribed TEs do not have the largest effects on adjacent regulation of coding genes, suggesting they function predominantly as enhancers. Moreover, the tissue-specific patterns of gene expression that are detected by our method arise froma limited number of genes, rather than as a general consequence of LTR integration. These findings identify basic principles of co-opting LTRs for genome evolution, and support the utility of our method for the analysis of TE, or other specific gene sets, in relation to the rest of the genome. [ABSTRACT FROM AUTHOR]

Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution of phenotypes produced by complex developmental systems can be shaped by past selective environments is poorly understood. Here we investigate the evolution of a network of recurrent nonlinear ontogenetic interactions, such as a gene regulation network, in various selective scenarios. We find that evolved networks of this type can exhibit several phenomena that are familiar in cognitive learning systems. These include formation of a distributed associative memory that can 'store' and 'recall' multiple phenotypes that have been selected in the past, recreate complete adult phenotypic patterns accurately from partial or corrupted embryonic phenotypes, and 'generalize' (by exploiting evolved developmental modules) to produce new combinations of phenotypic features. We show that these surprising behaviors follow from an equivalence between the action of natural selection on phenotypic correlations and associative learning, well-understood in the context of neural networks. This helps to explain how development facilitates the evolution of high-fitness phenotypes and how this ability changes over evolutionary time. [ABSTRACT FROM AUTHOR]

Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis-regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation. [ABSTRACT FROM PUBLISHER]

Directional epistasis describes a situation in which epistasis consistently increases or decreases the effect of allele substitutions, thereby affecting the amount of additive genetic variance available for selection in a given direction. This study applies a recent parameterization of directionality of epistasis to empirical data. Data stems from a QTL mapping study on an intercross between inbred mouse (Mus musculus) strains LG/J and SM/J, originally selected for large and small body mass, respectively. Results show a negative average directionality of epistasis for body-composition traits, predicting a reduction in additive allelic effects and in the response to selection for increased size. Focusing on average modification of additive effect of single loci, we find a more complex picture, whereby the effects of some loci are enhanced consistently across backgrounds, while effects of other loci are decreased, potentially contributing to either enhancement or reduction of allelic effects when selection acts at single loci. We demonstrate and discuss how the interpretation of the overall measurement of directionality depends on the complexity of the genotype-phenotype map. The measure of directionality changes with the power of scale in a predictable way; however, its expected effect with respect to the modification of additive genetic effects remains constant. [ABSTRACT FROM AUTHOR]

Pleiotropy is an aspect of genetic architecture underlying the phenotypic covariance structure. The presence of genetic variation in pleiotropy is necessary for natural selection to shape patterns of covariation between traits. We examined the contribution of differential epistasis to variation in the intertrait relationship and the nature of this variation. Genetic variation in pleiotropy was revealed by mapping quantitative trait loci (QTLs) affecting the allometry of mouse limb and tail length relative to body weight in the mouse-inbred strain LG/J by SM/J intercross. These relationship QTLs ( rQTLs) modify relationships between the traits affected by a common pleiotropic locus. We detected 11 rQTLs, mostly affecting allometry of multiple bones. We further identified epistatic interactions responsible for the observed allometric variation. Forty loci that interact epistatically with the detected rQTLs were identified. We demonstrate how these epistatic interactions differentially affect the body size variance and the covariance of traits with body size. We conclude that epistasis, by differentially affecting both the canalization and mean values of the traits of a pleiotropic domain, causes variation in the covariance structure. Variation in pleiotropy maintains evolvability of the genetic architecture, in particular the evolvability of its modular organization. [ABSTRACT FROM AUTHOR]

With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated—in terms of effect size—with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype–phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype–phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype–phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for .70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype–phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3—the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype–phenotype map has important consequences for gene identification and may shed light on the evolvability of organisms. [ABSTRACT FROM AUTHOR]