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Phylogenetic tree of mammalian evolution. Evolutionary time was calculated with TimeTree (Hedges and Kumar 2009; Hedges et al. 2015). Numbers indicate the time point of divergence, million years ago
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Dosage compensation system with X chromosome upregulation and inactivation have evolved to overcome the genetic imbalance between sex chromosomes in both male and female of mammals. Although recent development of chromosome-wide technologies has allowed us to test X upregulation, discrete data processing and analysis methods draw disparate conclusi...
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... In early bovine embryos imprinted XCI was observed at the morula stage (Ferreira et al. 2010) and random XCI occurred between the blastocyst and elongation stages (Bermejo-Alvarez et al. 2011). Although a recent study reported incomplete X dosage compensation in bovine fat, liver, muscle, and pituitary gland (Ka et al. 2016), further studies are needed for bovine early embryos and germ cells. ...
... Moreover, approximately 15% and 3% of non-PAR Xlinked genes in humans and mice, respectively, are known to escape XCI (Berletch et al. 2011). In the bovine, 55 such Xlinked genes (supplementary table S5, Supplementary Material online) were classified as candidates that escape XCI (Ka et al. 2016). To tease out the effects of these biallelically expressed PAR genes and XCI-escaping genes, we plotted X:A ratios in the categories of "all genes," "expressed genes," "genes subjected to XCI (excluding PAR genes and putative XCI-escaping genes)," and "dosage-sensitive genes" (fig. ...
... This could be related to the fact that may genes related to brain functions, such as MAOA, are located on the X chromosome (Zechner et al. 2001). On the contrary, X dosage of other bovine somatic tissues including fat, liver, muscle, and the pituitary gland was previously determined as incompletely compensated (Ka et al. 2016), which is consistent with results in humans, mice, and ours. ...
Dosage compensation of the mammalian X chromosome (X) was proposed by Susumu Ohno as a mechanism wherein the inactivation of one X in females would lead to doubling the expression of the other. This would resolve the dosage imbalance between eutherian females (XX) versus male (XY) and between a single active X versus autosome pairs (A). Expression ratio of X- and A-linked genes has been relatively well studied in humans and mice, despite controversial results over the existence of upregulation of X-linked genes. Here we report the first comprehensive test of Ohno’s hypothesis in bovine preattachment embryos, germline, and somatic tissues. Overall an incomplete dosage compensation (0.5 < X:A < 1) of expressed genes and an excess X dosage compensation (X:A > 1) of ubiquitously expressed “dosage-sensitive” genes were seen. No significant differences in X:A ratios were observed between bovine female and male somatic tissues, further supporting Ohno’s hypothesis. Interestingly, preimplantation embryos manifested a unique pattern of X dosage compensation dynamics. Specifically, X dosage decreased after fertilization, indicating that the sperm brings in an inactive X to the matured oocyte. Subsequently, the activation of the bovine embryonic genome enhanced expression of X-linked genes and increased the X dosage. As a result, an excess compensation was exhibited from the 8-cell stage to the compact morula stage. The X dosage peaked at the 16-cell stage and stabilized after the blastocyst stage. Together, our findings confirm Ohno’s hypothesis of X dosage compensation in the bovine and extend it by showing incomplete and over-compensation for expressed and “dosage-sensitive” genes, respectively.
... 76 Although XCI has been characterized in many species (Goto and Furthermore, we also investigated the effects of different maternal diets on the expression of X-114 linked genes. Our hypothesis was that X chromosome upregulation in the sheep would be partial, 115 similar to that in the bovine as reported by us (Duan et al. 2016) and others (Ka et al. 2016 Sequence adapter and quality trimming were conducted using Sickle v1.33 (Joshi and 152 Fass 2011) with the parameters Q score ≥ 30 and length ≥ 20 (-q30, -l20). RNA-seq reads were 153 checked using FastQC v0.11.3 (Andrews 2010) for quality control. ...
Ohno's hypothesis predicts that the expression of the single X chromosome in males needs compensatory upregulation to balance its dosage with that of the diploid autosomes. Additionally, X chromosome inactivation ensures that quadruple expression of the two X chromosomes is avoided in females. These mechanisms have been actively studied in mice and humans but lag behind in domestic species. Using RNA sequencing data, we analyzed the X chromosome upregulation in sheep fetal tissues from day 135 of gestation under control, over or restricted maternal diets (100%, 140% and 60% of National Research Council Total Digestible Nutrients), and in conceptuses, juvenile, and adult somatic tissues. By computing the mean expression ratio of all X-linked genes to all autosomal genes (X:A), we found that all samples displayed some levels of X chromosome upregulation. The degrees of X upregulation were not significant (P-value = 0.74) between ovine females and males in the same somatic tissues. Brain, however, displayed complete X upregulation. Interestingly, the male and female reproduction-related tissues exhibited divergent X dosage upregulation. Moreover, expression upregulation of the X chromosome in fetal tissues was not affected by maternal diets. Maternal nutrition, however, did change expression levels of several X-linked genes, such as sex determination genes SOX3 and NR0B1 In summary, our results showed that X chromosome upregulation occurred in nearly all sheep somatic tissues analyzed, thus support Ohno's hypothesis in a new species. However, the levels of upregulation differed by different subgroups of genes such as those that are house-keeping and "dosage-sensitive".
... Birchler 2012; Disteche 2012Disteche , 2016Mank 2013;Pessia et al. 2014;Graves 2016), so here we provide only a brief overview. While various X-to-autosome comparisons provided more or less support for Ohno's elusive "X-upregulation" (Xiong et al. 2010;Deng et al. 2011;He et al. 2011;Kharchenko et al. 2011), subsequent comparative analyses contrasting mammalian X-linked loci with autosomal loci in chickens yielded compelling evidence for the general absence of SCDC in eutherian mammals (Julien et al. 2012;Lin et al. 2012;Ka et al. 2016). This finding was further supported by quantitative proteomic analyses as well as expression in haploid versus diploid human parthenogenetic stem cells (Lin et al. 2012;Chen andZhang 2015, 2016). ...
Many animals with genetic sex determination harbor heteromorphic sex chromosomes, where the heterogametic sex has half the gene dose of the homogametic sex. This imbalance, if reflected in the abundance of transcripts or proteins, has the potential to deleteriously disrupt interactions between X-linked and autosomal loci in the heterogametic sex. Classical theory predicts that molecular mechanisms will evolve to provide dosage compensation that recovers expression levels comparable to ancestral expression prior to sex chromosome divergence. Such dosage compensating mechanisms may also, secondarily, result in balanced sex-linked gene expression between males and females. However, numerous recent studies addressing sex chromosome dosage compensation (SCDC) in a diversity of animals have yielded a surprising array of patterns concerning dosage compensation in the heterogametic sex, as well as dosage balance between sexes. These results substantially contradict longstanding theory, catalyzing both novel pe
... In early bovine embryos imprinted XCI was observed at the morula stage (Ferreira et al. 2010) and random XCI occurred between the blastocyst and elongation stages (Bermejo-Alvarez et al. 2011). Although a recent study reported incomplete X dosage compensation in bovine fat, liver, muscle, and pituitary gland (Ka et al. 2016), further studies are needed for bovine early embryos and germ cells. ...
... Moreover, approximately 15% and 3% of non-PAR Xlinked genes in humans and mice, respectively, are known to escape XCI (Berletch et al. 2011). In the bovine, 55 such Xlinked genes (supplementary table S5, Supplementary Material online) were classified as candidates that escape XCI (Ka et al. 2016). To tease out the effects of these biallelically expressed PAR genes and XCI-escaping genes, we plotted X:A ratios in the categories of "all genes," "expressed genes," "genes subjected to XCI (excluding PAR genes and putative XCI-escaping genes)," and "dosage-sensitive genes" (fig. ...
... This could be related to the fact that may genes related to brain functions, such as MAOA, are located on the X chromosome (Zechner et al. 2001). On the contrary, X dosage of other bovine somatic tissues including fat, liver, muscle, and the pituitary gland was previously determined as incompletely compensated (Ka et al. 2016), which is consistent with results in humans, mice, and ours. ...
The maintenance of a proper gene dosage is essential in cellular networks. To resolve the dosage imbalance between eutherian females (XX) and male (XY), X chromosome inactivation (XCI) occurs in females, while X-chromosome dosage compensation up-regulates the active X to balance its expression with that of autosome pairs [Ohno’s hypothesis; Ohno 1967 Sex Chromosomes and Sex-linked Genes (Springer-Verlag), p. 99]. These phenomena have been well studied in humans and mice, despite many controversies over the existence of such up-regulation. Using RNA sequencing data, we determined X chromosome dosage compensation in the bovine by analysing the global expression profiles of germ cells, embryos, and somatic tissues. Eight bovine RNA-seq data sets were obtained in from the Gene Expression Omnibus, covering bovine immature/mature oocytes (GSE59186 and GSE52415), pre-implantation conceptuses (GSE59186, GSE52415, and GSE56513), extra-embryonic tissues (PRJNA229443), and male/female somatic tissues (GSE74076, GSE63509, PRJEB6377, and GSE65125). The RNAseq data were trimmed and non-uniquely (paralogs included) mapped to the bovine reference genome assembly UMD3.1.1 using Hisat2 (version 2.0.5) aligner. The mRNA level of each gene, estimated by transformed transcripts per kilobase million was quantified by IsoEM (version 1.1.5). These RNA-seq data sets represented 4 chromosome scenarios in cells: XXXX:AAAA (diploid immature oocyte with DNA duplication), XX:AA (haploid mature oocyte with DNA duplication), XX:AA and X:AA (gradual changed X status in bovine pre-implantation conceptuses), and X:AA (extra-embryonic tissues and somatic cells in female with one active X or XY male) were analysed for dosage compensation. A total of 959 X-linked genes and 20,316 autosome genes were used to calculate the relative X to autosomal gene (A) expression (RXE): log2 (X expression) - log2 (A expression). The following dosage determinations were made: RXE values ≥ 0: complete dosage compensation (or X: A ratio ≥ 1); RXE values < 0: in-complete dosage compensation; RXE value = -1: no dosage compensation (or X: A ratio = 0.5). Our analyses showed a decreased RXE after fertilization, from -0.33 in matured oocytes to -0.50 at the 2-cell stage, indicating that the sperm that undergo meiotic sex chromosome inactivation (MSCI) bring in inactive X chromosomes to the matured oocytes. Subsequently, the activation of the bovine embryonic genome at the 4- to 8-cell stage increased RXE from -0.54 to -0.05. This was followed by a sharp RXE decline from -0.02 at the 16-cell stage, 0.1 at the 32-cell stage to -0.29 at the compact morula stage, which is known as paternal X inactivation stage in the bovine. Finally, RXE was stabilised from blastocysts -0.19 through the Day 19 conceptuses -0.25 to somatic tissue average -0.21 with a pattern of incomplete X compensation. These findings support X expression up-regulation as proposed by Ohno. No significant RXE differences were observed between bovine female and male somatic tissues, further supporting Ohno’s hypothesis, which predicts a balance in the expression of X-linked genes to that of autosomes. This study confirms Ohno’s hypothesis of X dosage compensation in bovine germ cells, early embryos, and somatic tissues.
... autosomes (Deng et al., 2011;Ka et al., 2016). ...
FoxO transcription factors promote longevity across diverse organisms through upregulation of parallel stress responses. Therefore, understanding how FoxO activity is regulated may provide insights for improving overall vitality in an aging population. Insulin and insulin-like growth factor signaling (IIS) is highly conserved across metazoans and antagonizes FoxO function. Decreasing IIS pathway activity increases lifespan in model organisms and may be conserve in humans. This association between FoxO transcription factors and longevity was first discovered in studies using the free living nematode Caenorhabditis elegans. In C. elegans, the DAF-2/IIS pathway also influences dauer diapause. Dauer is a state of larval developmental diapause that occurs in response to stressful environmental conditions including population stress perceived through elaboration of a complex pheromone mixture. Mutations that reduce DAF-2/IIS pathway activity arrest as dauers in a manner requiring the FoxO transcription factor DAF-16. When AKT activity is reduced, DAF-16/FoxO translocates to the nucleus, where it is inhibited by EAK- 7/TLDC1, a conserved protein of unknown function. eak-7;akt-1 double mutants always arrest as dauers. We designed a forward genetic screen to discover novel regulators of DAF-16/FOXO by mutagenizing eak-7;akt-1 worms and looking for suppressors of eak-7;akt-1 dauer arrest (seak mutants). Whole genome sequencing revealed one seak mutant strain harbored a mutation in set- 4, which encodes a conserved histone H4 lysine 20 (H4K20) methyltransferase. SET-4 is required for dauer arrest in both reduced IIS mutant backgrounds and in response to dauer inducing pheromone. SET-4 promotes dauer arrest only in XX hermaphrodites, not XO males, consistent with existing data that SET-4 participates in dosage compensation of X chromosomes. We found that neuron-specific overexpression of set-4 rescued dauer arrest in set-4 mutants to a similar extent as the native promoter. SET-4 acts together with DAF-16/FoxO in specific sensory neurons to silence expression of the X-linked insulin-like peptide ins-9. Loss of ins-9 rescues the xvii dauer-defective phenotype observed in set-4 mutants in response to pheromone. ins-9 itself is also sensitive to dauer pheromone. Taken together, these data implicate chromatin remodeling as a novel mechanism that regulates FoxO transcription factor activity. Since epigenetic marks like histone methylation are sensitive to environmental interventions, these findings may lead to new therapies for chronic diseases associated with aging.
The development of dimorphic adult sexes is a critical process for most animals, one that is subject to intense selection. Work in vertebrate and insect model species has revealed that sex determination mechanisms vary widely among animal groups. However, this variation is not uniform, with a limited number of conserved factors. Therefore, sex determination offers an excellent context to consider themes and variations in gene network evolution. Here we review the literature describing sex determination in diverse insects. We have screened public genomic sequence databases for orthologs and duplicates of 25 genes involved in insect sex determination, identifying patterns of presence and absence. These genes and a 3.5 reference set of 43 others were used to infer phylogenies and compared to accepted organismal relationships to examine patterns of congruence and divergence. The function of candidate genes for roles in sex determination (virilizer, female-lethal-2-d, transformer-2) and sex chromosome dosage compensation (male specific lethal-1, msl-2, msl-3) were tested using RNA interference in the milkweed bug, Oncopeltus fasciatus. None of these candidate genes exhibited conserved roles in these processes. Amidst this variation we wish to highlight the following themes for the evolution of sex determination: (1) Unique features within taxa influence network evolution. (2) Their position in the network influences a component's evolution. Our analyses also suggest an inverse association of protein sequence conservation with functional conservation.
