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1.
Proc Biol Sci ; 287(1932): 20201633, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32781951

RESUMO

Females and males may face different selection pressures. Accordingly, alleles that confer a benefit for one sex often incur a cost for the other. Classic evolutionary theory holds that the X chromosome, whose sex-biased transmission sees it spending more time in females, should value females more than males, whereas autosomes, whose transmission is unbiased, should value both sexes equally. However, recent mathematical and empirical studies indicate that male-beneficial alleles may be more favoured by the X chromosome than by autosomes. Here we develop a gene's-eye-view approach that reconciles the classic view with these recent discordant results, by separating a gene's valuation of female versus male fitness from its ability to induce fitness effects in either sex. We use this framework to generate new comparative predictions for sexually antagonistic evolution in relation to dosage compensation, sex-specific mortality and assortative mating, revealing how molecular mechanisms, ecology and demography drive variation in masculinization versus feminization across the genome.


Assuntos
Seleção Genética , Caracteres Sexuais , Alelos , Animais , Evolução Biológica , Compensação de Dosagem (Genética) , Feminino , Masculino , Reprodução , Sexo , Cromossomo X
2.
Nat Protoc ; 15(8): 2645-2667, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32681149

RESUMO

The preferred sex of livestock differs among breeders; for example, dairy farmers prefer female calves for the production of milk, whereas cattle meat producers often prefer males. Sexing of laboratory animals is also beneficial in some research fields, including reproductive biology and metabolic studies. Most sexing methods separate X sperm and Y sperm with a cell sorter. Here, we describe a system in which treatment with the TLR7/8 ligand (R848) separates X sperm from Y sperm. Because this protocol does not require any special equipment or professional skills, it can be easily applied in laboratories where in vitro fertilization (IVF) is performed. The sperm are treated with 0.03 µM R848 in 1 mL of modified human tubal fluid (mHTF) medium (mouse sperm) or 3 mL of mHTF medium (bull sperm) for 60 min, and then the upper layer (400 µL in mouse sperm or 1 mL in bull sperm) and the precipitate are separately collected. After each sample is washed by centrifugation, the sperm are suspended in ligand-free IVF medium and can then be used for IVF. More than 90% of the embryos made with upper-layer sperm are XY in both mice and cattle, and >80% of the embryos made with precipitated sperm are XX in both species. Separation of X sperm and Y sperm for IVF can be completed within 2 h.


Assuntos
Pré-Seleção do Sexo/métodos , Espermatozoides/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Cromossomo X/metabolismo , Cromossomo Y/metabolismo , Animais , Bovinos , Feminino , Masculino , Camundongos
5.
Proc Natl Acad Sci U S A ; 117(21): 11459-11470, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32385148

RESUMO

Genomic regions preferentially associate with regions of similar transcriptional activity, partitioning genomes into active and inactive compartments within the nucleus. Here we explore mechanisms controlling genome compartment organization in Caenorhabditis elegans and investigate roles for compartments in regulating gene expression. Distal arms of C. elegans chromosomes, which are enriched for heterochromatic histone modifications H3K9me1/me2/me3, interact with each other both in cis and in trans, while interacting less frequently with central regions, leading to genome compartmentalization. Arms are anchored to the nuclear periphery via the nuclear envelope protein CEC-4, which binds to H3K9me. By performing genome-wide chromosome conformation capture experiments (Hi-C), we showed that eliminating H3K9me1/me2/me3 through mutations in the methyltransferase genes met-2 and set-25 significantly impaired formation of inactive Arm and active Center compartments. cec-4 mutations also impaired compartmentalization, but to a lesser extent. We found that H3K9me promotes compartmentalization through two distinct mechanisms: Perinuclear anchoring of chromosome arms via CEC-4 to promote their cis association, and an anchoring-independent mechanism that compacts individual chromosome arms. In both met-2 set-25 and cec-4 mutants, no dramatic changes in gene expression were found for genes that switched compartments or for genes that remained in their original compartment, suggesting that compartment strength does not dictate gene-expression levels. Furthermore, H3K9me, but not perinuclear anchoring, also contributes to formation of another prominent feature of chromosome organization, megabase-scale topologically associating domains on X established by the dosage compensation condensin complex. Our results demonstrate that H3K9me plays crucial roles in regulating genome organization at multiple levels.


Assuntos
Caenorhabditis elegans/genética , Cromossomos/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/genética , Regulação da Expressão Gênica , Genoma , Heterocromatina/genética , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Lisina/genética , Metilação , Mutação , Cromossomo X/genética , Cromossomo X/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(20): 10927-10934, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32366643

RESUMO

Lions are one of the world's most iconic megafauna, yet little is known about their temporal and spatial demographic history and population differentiation. We analyzed a genomic dataset of 20 specimens: two ca. 30,000-y-old cave lions (Panthera leo spelaea), 12 historic lions (Panthera leo leo/Panthera leo melanochaita) that lived between the 15th and 20th centuries outside the current geographic distribution of lions, and 6 present-day lions from Africa and India. We found that cave and modern lions shared an ancestor ca. 500,000 y ago and that the 2 lineages likely did not hybridize following their divergence. Within modern lions, we found 2 main lineages that diverged ca. 70,000 y ago, with clear evidence of subsequent gene flow. Our data also reveal a nearly complete absence of genetic diversity within Indian lions, probably due to well-documented extremely low effective population sizes in the recent past. Our results contribute toward the understanding of the evolutionary history of lions and complement conservation efforts to protect the diversity of this vulnerable species.


Assuntos
Evolução Molecular , Leões/genética , Leões/fisiologia , África , Animais , Fluxo Gênico , Variação Genética , Genômica , Geografia , Índia , Leões/classificação , Masculino , Filogenia , Cromossomo X
8.
PLoS Genet ; 16(3): e1008676, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214314

RESUMO

A set of sex chromosomes is required for gametogenesis in both males and females, as represented by sex chromosome disorders causing agametic phenotypes. Although studies using model animals have investigated the functional requirement of sex chromosomes, involvement of these chromosomes in gametogenesis remains elusive. Here, we elicit a germ cell-intrinsic effect of sex chromosomes on oogenesis, using a novel culture system in which oocytes were induced from embryonic stem cells (ESCs) harboring XX, XO or XY. In the culture system, oogenesis using XO and XY ESCs was severely disturbed, with XY ESCs being more strongly affected. The culture system revealed multiple defects in the oogenesis of XO and XY ESCs, such as delayed meiotic entry and progression, and mispairing of the homologous chromosomes. Interestingly, Eif2s3y, a Y-linked gene that promotes proliferation of spermatogonia, had an inhibitory effect on oogenesis. This led us to the concept that male and female gametogenesis appear to be in mutual conflict at an early stage. This study provides a deeper understanding of oogenesis under a sex-reversal condition.


Assuntos
Células Germinativas/metabolismo , Oócitos/metabolismo , Cromossomo X , Cromossomo Y , Animais , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/metabolismo , Feminino , Células Germinativas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Endogâmicos , Oócitos/citologia , Oócitos/ultraestrutura , Oogênese
9.
PLoS Genet ; 16(3): e1008647, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168334

RESUMO

Synthetic sex distorters have recently been developed in the malaria mosquito, relying on endonucleases that target the X-chromosome during spermatogenesis. Although inspired by naturally-occurring traits, it has remained unclear how they function and, given their potential for genetic control, how portable this strategy is across species. We established Drosophila models for two distinct mechanisms for CRISPR/Cas9 sex-ratio distortion-"X-shredding" and "X-poisoning"-and dissected their target-site requirements and repair dynamics. X-shredding resulted in sex distortion when Cas9 endonuclease activity occurred during the meiotic stages of spermatogenesis but not when Cas9 was expressed from the stem cell stages onwards. Our results suggest that X-shredding is counteracted by the NHEJ DNA repair pathway and can operate on a single repeat cluster of non-essential sequences, although the targeting of a number of such repeats had no effect on the sex ratio. X-poisoning by contrast, i.e. targeting putative haplolethal genes on the X chromosome, induced a high bias towards males (>92%) when we directed Cas9 cleavage to the X-linked ribosomal target gene RpS6. In the case of X-poisoning sex distortion was coupled to a loss in reproductive output, although a dominant-negative effect appeared to drive the mechanism of female lethality. These model systems will guide the study and the application of sex distorters to medically or agriculturally important insect target species.


Assuntos
Edição de Genes/métodos , Processos de Determinação Sexual/genética , Pré-Seleção do Sexo/métodos , Animais , Sistemas CRISPR-Cas/genética , Reparo do DNA por Junção de Extremidades/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Endonucleases/genética , Feminino , Masculino , Modelos Animais , Controle Biológico de Vetores/métodos , Razão de Masculinidade , Espermatogênese/genética , Cromossomo X/genética
10.
PLoS Biol ; 18(3): e3000663, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203540

RESUMO

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as 'suicidal' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.


Assuntos
Espermatozoides/fisiologia , Receptores Toll-Like/metabolismo , Cromossomo X , Animais , Evolução Biológica , Humanos , Masculino , Transporte de RNA , Razão de Masculinidade , Espermatogênese , Espermatozoides/citologia , Espermatozoides/metabolismo , Receptores Toll-Like/genética
11.
Nat Struct Mol Biol ; 27(3): 297-304, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32157249

RESUMO

Understanding the targeting and spreading patterns of long non-coding RNAs (lncRNAs) on chromatin requires a technique that can detect both high-intensity binding sites and reveal genome-wide changes in spreading patterns with high precision and confidence. Here we determine lncRNA localization using biotinylated locked nucleic acid (LNA)-containing oligonucleotides with toehold architecture capable of hybridizing to target RNA through strand-exchange reaction. During hybridization, a protecting strand competitively displaces contaminating species, leading to highly specific RNA capture of individual RNAs. Analysis of Drosophila roX2 lncRNA using this approach revealed that heat shock, unlike the unfolded protein response, leads to reduced spreading of roX2 on the X chromosome, but surprisingly also to relocalization to sites on autosomes. Our results demonstrate that this improved hybridization capture approach can reveal previously uncharacterized changes in the targeting and spreading of lncRNAs on chromatin.


Assuntos
Cromatina/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Oligonucleotídeos/química , RNA Longo não Codificante/química , Proteínas de Ligação a RNA/genética , Cromossomo X/química , Animais , Pareamento de Bases , Sítios de Ligação , Biotinilação , Cromatina/metabolismo , Mapeamento Cromossômico , Cromossomos de Insetos/química , Cromossomos de Insetos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Resposta ao Choque Térmico , Nanotecnologia/métodos , Hibridização de Ácido Nucleico , Oligonucleotídeos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Cromossomo X/metabolismo
12.
Am Nat ; 195(3): 561-568, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32097044

RESUMO

Most population genetic theory assumes that populations adapt to an environmental change without a change in population size. However, environmental changes might be so severe that populations decline in size and, without adaptation, become extinct. This "evolutionary rescue" scenario differs from traditional models of adaptation in that rescue involves a race between adaptation and extinction. While most previous work has usually focused on models of evolutionary rescue in haploids, here we consider diploids. In many species, diploidy introduces a novel feature into adaptation: adaptive evolution might occur either on sex chromosomes or on autosomes. Previous studies of nonrescue adaptation revealed that the relative rates of adaptation on the X chromosome versus autosomes depend on the dominance of beneficial mutations, reflecting differences in effective population size and the efficacy of selection. Here, we extend these results to evolutionary rescue and find that, given equal-sized chromosomes, there is greater parameter space in which the X is more likely to contribute to adaptation than the autosomes relative to standard nonrescue models. We also discuss how subtle effects of dominance can increase the chance of evolutionary rescue in diploids when absolute heterozygote fitness is close to 1. These effects do not arise in standard nonrescue models.


Assuntos
Adaptação Biológica/genética , Evolução Biológica , Diploide , Cromossomo X/genética , Animais , Genética Populacional , Modelos Genéticos , Mutação , Densidade Demográfica
13.
Proc Natl Acad Sci U S A ; 117(8): 4262-4272, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32041873

RESUMO

Long thought to be dispensable after establishing X chromosome inactivation (XCI), Xist RNA is now known to also maintain the inactive X (Xi). To what extent somatic X reactivation causes physiological abnormalities is an active area of inquiry. Here, we use multiple mouse models to investigate in vivo consequences. First, when Xist is deleted systemically in post-XCI embryonic cells using the Meox2-Cre driver, female pups exhibit no morbidity or mortality despite partial X reactivation. Second, when Xist is conditionally deleted in epithelial cells using Keratin14-Cre or in B cells using CD19-Cre, female mice have a normal life span without obvious illness. Third, when Xist is deleted in gut using Villin-Cre, female mice remain healthy despite significant X-autosome dosage imbalance. Finally, when the gut is acutely stressed by azoxymethane/dextran sulfate (AOM/DSS) exposure, both Xist-deleted and wild-type mice develop gastrointestinal tumors. Intriguingly, however, under prolonged stress, mutant mice develop larger tumors and have a higher tumor burden. The effect is female specific. Altogether, these observations reveal a surprising systemic tolerance to Xist loss but importantly reveal that Xist and XCI are protective to females during chronic stress.


Assuntos
Neoplasias Gastrointestinais/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/microbiologia , RNA Longo não Codificante/genética , Cromossomo X/genética , Animais , Feminino , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Trato Gastrointestinal/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Masculino , Camundongos , RNA Longo não Codificante/metabolismo , Estresse Fisiológico , Carga Tumoral , Inativação do Cromossomo X
14.
Nature ; 578(7795): 455-460, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025035

RESUMO

Xist represents a paradigm for the function of long non-coding RNA in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Several proteins that bind to Xist RNA have recently been identified, including the transcriptional repressor SPEN1-3, the loss of which has been associated with deficient XCI at multiple loci2-6. Here we show in mice that SPEN is a key orchestrator of XCI in vivo and we elucidate its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells. SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI. We show that SPEN is immediately recruited to the X chromosome upon the upregulation of Xist, and is targeted to enhancers and promoters of active genes. SPEN rapidly disengages from chromatin upon gene silencing, suggesting that active transcription is required to tether SPEN to chromatin. We define the SPOC domain as a major effector of the gene-silencing function of SPEN, and show that tethering SPOC to Xist RNA is sufficient to mediate gene silencing. We identify the protein partners of SPOC, including NCoR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in the regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for the initiation of XCI, bridging Xist RNA with the transcription machinery-as well as with nucleosome remodellers and histone deacetylases-at active enhancers and promoters.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Inativação Gênica , Proteínas de Ligação a RNA/metabolismo , Transcrição Genética , Inativação do Cromossomo X/genética , Cromossomo X/genética , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Cromatina/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/química , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos/genética , Feminino , Histona Desacetilases/metabolismo , Masculino , Metilação , Camundongos , Regiões Promotoras Genéticas/genética , Domínios Proteicos , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/química
15.
Nature ; 578(7795): 365-366, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32066915
16.
PLoS One ; 15(2): e0228631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017800

RESUMO

With the objective of assisting in the understanding of the chromosome evolution of Pentatomomorpha and in the quest to understand how the genome organizes/reorganizes for the chromosomal position of the 45S rDNA in this infraorder, we analyzed 15 species (it has being 12 never studied before by FISH) of Pentatomomorpha with the probe of 18S rDNA. The mapping of the 45S gene in the Coreidae family demonstrated that the species presented markings on the autosomes, with the exception of Acanthocephala parensis and Leptoglossus gonagra that showed markers on m-chromosomes. Most species of the Pentatomidae family showed marking in the autosomes, except for two species that had 45S rDNA on X sex chromosome (Odmalea sp. and Graphosoma lineatum) and two that showed marking on the X and Y sex chromosomes. Species of the Pyrrhocoridae family showed 18S rDNA markers in autosomes, X chromosome as well as in Neo X. The Largidae and Scutelleridae families were represented by only one species that showed marking on the X sex chromosome and on a pair of autosomes, respectively. Based on this, we characterized the arrangement of 45S DNAr in the chromosomes of 12 new species of Heteroptera and discussed the main evolutionary events related to the genomic reorganization of these species during the events of chromosome and karyotype evolution in Pentatomomorpha infraorder.


Assuntos
Cromossomos de Insetos/genética , Evolução Molecular , Heterópteros/genética , Animais , Mapeamento Cromossômico , DNA Ribossômico/genética , Hemípteros/genética , Hibridização in Situ Fluorescente , Filogenia , Ribossomos/genética , Cromossomo X , Cromossomo Y
17.
PLoS Genet ; 16(2): e1008300, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092051

RESUMO

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse mutant models to elucidate mechanisms underlying CFNS pathogenesis. By generating EPHRIN-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. EPHRIN-B1 can bind and signal with EPHB1, EPHB2, and EPHB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EPHB2 and EPHB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EPHB1-3 does not fully recapitulate the severity of CFNS-like Efnb1 heterozygosity. Finally, by generating Efnb1+/Δ; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EPHB2 and EPHB3 play an important role in craniofacial cell segregation, EPHB1 is more important for cell segregation in the brain; surprisingly, complete loss of EPHB1-EPHB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the etiology and signaling interactions underlying CFNS dysmorphology.


Assuntos
Movimento Celular/genética , Anormalidades Craniofaciais/genética , Efrina-B1/genética , Crista Neural/embriologia , Crânio/anormalidades , Animais , Anormalidades Craniofaciais/diagnóstico , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Efrina-B1/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Mosaicismo , Mutação , Crista Neural/citologia , Fenótipo , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Índice de Gravidade de Doença , Fatores Sexuais , Crânio/embriologia , Cromossomo X/genética
18.
Proc Natl Acad Sci U S A ; 117(9): 4864-4873, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071206

RESUMO

In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X, SEPT6, NKRF, CX0rf57, NAA10, and FLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.


Assuntos
Dosagem de Genes , Regulação da Expressão Gênica , Genômica , Síndrome de Klinefelter/genética , Síndrome de Turner/genética , Cromossomo X , Animais , Cromatina/química , Cromossomos Humanos X , Metilação de DNA , Feminino , Filaminas , Humanos , Cariótipo , Masculino , Mamíferos/genética , Acetiltransferase N-Terminal A , Acetiltransferase N-Terminal E , Proteínas Serina-Treonina Quinases/genética , Receptor PAR-2 , Proteínas Repressoras/genética , Septinas , Transcriptoma/genética , Inativação do Cromossomo X
19.
Mol Genet Genomics ; 295(2): 357-371, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31776761

RESUMO

Females and males differ substantially in various neuronal functions in divergent, sexually dimorphic animal species, including humans. Despite its developmental, physiological and medical significance, understanding the molecular mechanisms by which sex-specific differences in the anatomy and operation of the nervous system are established remains a fundamental problem in biology. Here, we show that in Caenorhabditis elegans (nematodes), the global sex-determining factor TRA-1 regulates food leaving (mate searching), male mating and adaptation to odorants in a sex-specific manner by repressing the expression of goa-1 gene, which encodes the Gα(i/o) subunit of heterotrimeric G (guanine-nucleotide binding) proteins triggering physiological responses elicited by diverse neurotransmitters and sensory stimuli. Mutations in tra-1 and goa-1 decouple behavioural patterns from the number of X chromosomes. TRA-1 binds to a conserved binding site located in the goa-1 coding region, and downregulates goa-1 expression in hermaphrodites, particularly during embryogenesis when neuronal development largely occurs. These data suggest that the sex-determination machinery is an important modulator of heterotrimeric G protein-mediated signalling and thereby various neuronal functions in this organism and perhaps in other animal phyla.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Animais , Sítios de Ligação/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Masculino , Mutação/genética , Processos de Determinação Sexual/genética , Cromossomo X/genética
20.
Anim Genet ; 51(1): 122-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691328

RESUMO

A GWAS was performed for inborn X-linked facial dysmorphia with severe growth retardation in Labrador Retrievers. This lethal condition was mapped on the X chromosome at 17-21 Mb and supported by eight SNPs in complete LD. Dams of affected male puppies were heterozygous for the significantly associated SNPs and male affected puppies carried the associated alleles hemizygously. In the near vicinity to the associated region, RPS6KA3 was identified as a candidate gene causing facial dysmorphia in humans and mice known as Coffin-Lowry syndrome. Haplotype analysis showed significant association with the phenotypes of all 18 animals under study. This haplotype was validated through normal male progeny from a dam with the not-associated haplotype on both X chromosomes but male affected full-sibs with the associated haplotype.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Genes Letais , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Craniossinostoses/genética , Feminino , Estudos de Associação Genética/veterinária , Haplótipos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética
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