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1.
Science ; 372(6542): 592-600, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958470

RESUMO

The mammalian sex chromosome system (XX female/XY male) is ancient and highly conserved. The sex chromosome karyotype of the creeping vole (Microtus oregoni) represents a long-standing anomaly, with an X chromosome that is unpaired in females (X0) and exclusively maternally transmitted. We produced a highly contiguous male genome assembly, together with short-read genomes and transcriptomes for both sexes. We show that M. oregoni has lost an independently segregating Y chromosome and that the male-specific sex chromosome is a second X chromosome that is largely homologous to the maternally transmitted X. Both maternally inherited and male-specific sex chromosomes carry fragments of the ancestral Y chromosome. Consequences of this recently transformed sex chromosome system include Y-like degeneration and gene amplification on the male-specific X, expression of ancestral Y-linked genes in females, and X inactivation of the male-specific chromosome in male somatic cells. The genome of M. oregoni elucidates the processes that shape the gene content and dosage of mammalian sex chromosomes and exemplifies a rare case of plasticity in an ancient sex chromosome system.


Assuntos
Cariótipo Anormal , Arvicolinae/genética , Processos de Determinação Sexual/genética , Cromossomo X/genética , Animais , Sequência de Bases , Feminino , Amplificação de Genes , Genes sry , Haplótipos , Masculino , Herança Materna , Inativação do Cromossomo X , Cromossomo Y/genética
2.
Mol Cell ; 81(8): 1598-1600, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33861949

RESUMO

Yu et al. (2021) demonstrate that a subset of X-linked immune genes is repressed on the inactive X chromosome (Xi) in a manner dependent on XIST RNA in B cells, and derepression of these genes upon XIST depletion could bias differentiation of naive B cells and be involved in etiology of female-biased autoimmune diseases.


Assuntos
RNA Longo não Codificante , Inativação do Cromossomo X , Linfócitos B , Diferenciação Celular , Feminino , Humanos , RNA Longo não Codificante/genética , Cromossomo X/genética , Inativação do Cromossomo X/genética
3.
Biochem Biophys Res Commun ; 553: 25-29, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33756342

RESUMO

The current COVID-19 pandemic is caused by infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A sex-bias has been observed, with increased susceptibility and mortality in male compared to female patients. The gene for the SARS-CoV-2 receptor ACE2 is located on the X chromosome. We previously generated TP53 mutant pigs that exhibit a sex-specific patho-phenotype due to altered regulation of numerous X chromosome genes. In this study, we explored the effect of p53 deficiency on ACE2 expression in pigs. First, we identified the p53 binding site in the ACE2 promoter and could show its regulatory effect on ACE2 expression by luciferase assay in porcine primary kidney fibroblast cells. Later, quantitative PCR and western blot showed tissue- and gender-specific expression changes of ACE2 and its truncated isoform in p53-deficient pigs. We believe these findings will broaden the knowledge on ACE2 regulation and COVID-19 susceptibility.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Regulação da Expressão Gênica , Especificidade de Órgãos , Caracteres Sexuais , Sus scrofa/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Animais , Sequência de Bases , Sítios de Ligação , COVID-19/metabolismo , COVID-19/virologia , Modelos Animais de Doenças , Feminino , Fibroblastos , Deleção de Genes , Masculino , Regiões Promotoras Genéticas/genética , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Cromossomo X/genética
4.
EMBO Rep ; 22(3): e51989, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33605056

RESUMO

During X chromosome inactivation (XCI), in female placental mammals, gene silencing is initiated by the Xist long non-coding RNA. Xist accumulation at the X leads to enrichment of specific chromatin marks, including PRC2-dependent H3K27me3 and SETD8-dependent H4K20me1. However, the dynamics of this process in relation to Xist RNA accumulation remains unknown as is the involvement of H4K20me1 in initiating gene silencing. To follow XCI dynamics in living cells, we developed a genetically encoded, H3K27me3-specific intracellular antibody or H3K27me3-mintbody. By combining live-cell imaging of H3K27me3, H4K20me1, the X chromosome and Xist RNA, with ChIP-seq analysis we uncover concurrent accumulation of both marks during XCI, albeit with distinct genomic distributions. Furthermore, using a Xist B and C repeat mutant, which still shows gene silencing on the X but not H3K27me3 deposition, we also find a complete lack of H4K20me1 enrichment. This demonstrates that H4K20me1 is dispensable for the initiation of gene silencing, although it may have a role in the chromatin compaction that characterises facultative heterochromatin.


Assuntos
Histonas , RNA Longo não Codificante , Animais , Feminino , Inativação Gênica , Histonas/genética , Histonas/metabolismo , Placenta/metabolismo , Gravidez , RNA Longo não Codificante/genética , Cromossomo X/genética , Inativação do Cromossomo X/genética
5.
Proc Biol Sci ; 288(1945): 20202244, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33622136

RESUMO

X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala (Phascolarctos cinereus), and present the first whole-genome, multi-tissue marsupial 'methylome atlas'. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.


Assuntos
Phascolarctidae , Animais , Metilação de DNA , Epigênese Genética , Epigenoma , Feminino , Masculino , Phascolarctidae/genética , Cromossomo X/genética
6.
Mol Biol Rep ; 48(2): 1667-1676, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33479828

RESUMO

Accurate species and sex identification of non-invasive and forensic samples of the tiger and leopard is still confusing when using the allele-specific methods. We designed allele-specific methods with penultimate nucleotide mismatch in a nested manner for the exact identification and double-checking of forensic samples. The mismatch design is a novel concept in species and sex identification, making the allele-specific targeting precise. We developed three sets of markers, a 365 bp outer and a 98 bp inner marker for nested tiger species identification assay, 136 bp leopard specific marker, and carnivore sex identification markers. We validated the method with tissue/blood forensic samples of various felids and herbivorous available in our lab and on known fecal samples from Vandalur Zoo. We also collected 37 scat samples at diverse stages of deterioration from the Mudumalai Tiger Reserve, Tamil Nadu, India. The 365 bp targeted markers resulted in 70.2% (n = 22; 22/37) amplification success, while the 98 bp FAM-labelled marker amplified 89% (n = 33; 33/37) scat samples independently. The 136 bp leopard markers answered four scat samples (11%) unrequited by the tiger specific markers. We evaluated species and the sex identification with these markers in another 190 non-invasive samples provided by the Mudumalai Tiger Reserve authorities. Among which 56.3% (n = 107) of samples were recognized as tiger (64 male and 43 female) and 38.9% (n = 74) as leopard (41 male and 33 female). The method supersedes any other previous methods in this regard by its high accuracy and simplicity.


Assuntos
Genética Forense/métodos , Panthera/genética , Reação em Cadeia da Polimerase/métodos , Tigres/genética , Alelos , Animais , Biomarcadores , Primers do DNA , Espécies em Perigo de Extinção , Feminino , Identidade de Gênero , Índia , Masculino , Panthera/sangue , Panthera/metabolismo , Sensibilidade e Especificidade , Especificidade da Espécie , Tigres/sangue , Tigres/metabolismo , Cromossomo X/genética , Cromossomo Y/genética
7.
Science ; 371(6527): 396-400, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479152

RESUMO

Sexual dimorphism in animals results from sex-biased gene expression patterns. These patterns are controlled by genetic sex determination hierarchies that establish the sex of an individual. Here we show that the male-biased wing expression pattern of the Drosophila biarmipes gene yellow, located on the X chromosome, is independent of the fly sex determination hierarchy. Instead, we find that a regulatory interaction between yellow alleles on homologous chromosomes (a process known as transvection) silences the activity of a yellow enhancer functioning in the wing. Therefore, this enhancer can be active in males (XY) but not in females (XX). This transvection-dependent enhancer silencing requires the yellow intron and the chromatin architecture protein Mod(mdg4). Our results suggest that transvection can contribute more generally to the sex-biased expression of X-linked genes.


Assuntos
Proteínas de Drosophila/genética , Drosophila/genética , Regulação da Expressão Gênica , Genes Ligados ao Cromossomo X , Caracteres Sexuais , Cromossomo X/genética , Alelos , Animais , Elementos Facilitadores Genéticos , Feminino , Masculino , Fatores Sexuais , Asas de Animais/metabolismo
8.
Nat Commun ; 12(1): 41, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397980

RESUMO

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.


Assuntos
Drosophila melanogaster/genética , Genoma de Inseto , Conformação de Ácido Nucleico , Animais , Biopolímeros/metabolismo , Cromatina/genética , Bases de Dados Genéticas , Epigênese Genética , Haploidia , Modelos Genéticos , Processos Estocásticos , Cromossomo X/genética
9.
Methods Mol Biol ; 2254: 251-257, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33326080

RESUMO

Immunofluorescence and fluorescence in situ hybridization (FISH) are widely used cytogenetic techniques for visualization of protein and RNA/DNA molecules. Here, we describe an experimental procedure for quick sequential immunofluorescence and RNA FISH (immuno-FISH), which enables the simultaneous detection of proteins, chromatin modifications, and RNAs on the inactive X-chromosome (Xi) using female mouse embryonic fibroblast (MEF) and tail-tip 3T3 cell lines. Using a pooled array of oligonucleotides labeled with a single fluorophore as an RNA FISH probe, we can reduce the time for RNA FISH from an overnight process to 1-2 h without losing its sensitivity. This protocol could be applied to visualization of various protein and RNA molecules, and chromatin modifications.


Assuntos
Cromatina/genética , Histonas/metabolismo , Hibridização in Situ Fluorescente/métodos , RNA Longo não Codificante/genética , RNA/genética , Animais , Células Cultivadas , Montagem e Desmontagem da Cromatina , Feminino , Imunofluorescência , Camundongos , Células NIH 3T3 , Cromossomo X/genética
10.
Elife ; 92020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33372658

RESUMO

We demonstrate how RNA binding protein FOX-1 functions as a dose-dependent X-signal element to communicate X-chromosome number and thereby determine nematode sex. FOX-1, an RNA recognition motif protein, triggers hermaphrodite development in XX embryos by causing non-productive alternative pre-mRNA splicing of xol-1, the master sex-determination switch gene that triggers male development in XO embryos. RNA binding experiments together with genome editing demonstrate that FOX-1 binds to multiple GCAUG and GCACG motifs in a xol-1 intron, causing intron retention or partial exon deletion, thereby eliminating male-determining XOL-1 protein. Transforming all motifs to GCAUG or GCACG permits accurate alternative splicing, demonstrating efficacy of both motifs. Mutating subsets of both motifs partially alleviates non-productive splicing. Mutating all motifs blocks it, as does transforming them to low-affinity GCUUG motifs. Combining multiple high-affinity binding sites with the twofold change in FOX-1 concentration between XX and XO embryos achieves dose-sensitivity in splicing regulation to determine sex.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/fisiologia , Proteínas de Ligação a RNA/fisiologia , Cromossomo X/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Íntrons/genética , Íntrons/fisiologia , Masculino , Proteínas de Ligação a RNA/metabolismo , Processos de Determinação Sexual
11.
Nucleic Acids Res ; 48(18): 10500-10517, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986830

RESUMO

The Xist lncRNA requires Repeat A, a conserved RNA element located in its 5' end, to induce gene silencing during X-chromosome inactivation. Intriguingly, Repeat A is also required for production of Xist. While silencing by Repeat A requires the protein SPEN, how Repeat A promotes Xist production remains unclear. We report that in mouse embryonic stem cells, expression of a transgene comprising the first two kilobases of Xist (Xist-2kb) causes transcriptional readthrough of downstream polyadenylation sequences. Readthrough required Repeat A and the ∼750 nucleotides downstream, did not require SPEN, and was attenuated by splicing. Despite associating with SPEN and chromatin, Xist-2kb did not robustly silence transcription, whereas a 5.5-kb Xist transgene robustly silenced transcription and read through its polyadenylation sequence. Longer, spliced Xist transgenes also induced robust silencing yet terminated efficiently. Thus, in contexts examined here, Xist requires sequence elements beyond its first two kilobases to robustly silence transcription, and the 5' end of Xist harbors SPEN-independent transcriptional antiterminator activity that can repress proximal cleavage and polyadenylation. In endogenous contexts, this antiterminator activity may help produce full-length Xist RNA while rendering the Xist locus resistant to silencing by the same repressive complexes that the lncRNA recruits to other genes.


Assuntos
Proteínas de Ligação a DNA/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Transcrição Genética , Inativação do Cromossomo X/genética , Animais , Cromatina/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Inativação Gênica , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Poliadenilação/genética , Sequências Repetitivas de Ácido Nucleico/genética , Cromossomo X/genética
12.
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
13.
Nat Biotechnol ; 38(9): 1054-1060, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32393821

RESUMO

Only female insects transmit diseases such as malaria, dengue and Zika; therefore, control methods that bias the sex ratio of insect offspring have long been sought. Genetic elements such as sex-chromosome drives can distort sex ratios to produce unisex populations that eventually collapse, but the underlying molecular mechanisms are unknown. We report a male-biased sex-distorter gene drive (SDGD) in the human malaria vector Anopheles gambiae. We induced super-Mendelian inheritance of the X-chromosome-shredding I-PpoI nuclease by coupling this to a CRISPR-based gene drive inserted into a conserved sequence of the doublesex (dsx) gene. In modeling of invasion dynamics, SDGD was predicted to have a quicker impact on female mosquito populations than previously developed gene drives targeting female fertility. The SDGD at the dsx locus led to a male-only population from a 2.5% starting allelic frequency in 10-14 generations, with population collapse and no selection for resistance. Our results support the use of SDGD for malaria vector control.


Assuntos
Anopheles/genética , Tecnologia de Impulso Genético/métodos , Malária/transmissão , Mosquitos Vetores/genética , Processos de Determinação Sexual/genética , Animais , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Feminino , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Malária/prevenção & controle , Masculino , Controle de Mosquitos , Cromossomo X/genética , Cromossomo X/metabolismo
14.
Am Nat ; 195(4): 743-751, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32216661

RESUMO

Selfish genetic elements that gain a transmission advantage through the destruction of sperm have grave implications for drive male fertility. In the X-linked meiotic drive system (SR) of a stalk-eyed fly, we found that SR males have greatly enlarged testes and maintain high fertility despite the destruction of half of their sperm, even when challenged with fertilizing large numbers of females. Conversely, we observed reduced allocation of resources to the accessory glands that probably explains the lower mating frequency of SR males. Body size and eye span were also reduced, which are likely to impair viability and precopulatory success. We discuss the potential evolutionary causes of these differences between drive and standard males.


Assuntos
Dípteros/genética , Dípteros/fisiologia , Fertilidade/genética , Meiose , Animais , Tamanho Corporal , Copulação/fisiologia , Feminino , Masculino , Razão de Masculinidade , Espermatozoides , Testículo/anatomia & histologia , Cromossomo X/genética
15.
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
16.
Sci Rep ; 10(1): 5625, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221341

RESUMO

Human sperm protein associated with the nucleus on the X chromosome (SPANX) genes encode a protein family (SPANX-A, -B, -C and -D), whose expression is limited to the testis and spermatozoa in normal tissues and to a wide variety of tumour cells. Present only in hominids, SPANX-A/D is exclusively expressed in post-meiotic spermatids and mature spermatozoa. However, the biological role of the protein family in human spermatozoa is largely unknown. Combining proteomics and molecular approaches, the present work describes the presence of all isoforms of SPANX-A/D in human spermatozoa and novel phosphorylation sites of this protein family. In addition, we identify 307 potential SPANX-A/D interactors related to nuclear envelop, chromatin organisation, metabolism and cilia movement. Specifically, SPANX-A/D interacts with fumarate hydratase and colocalises with both fumarate hydratase and Tektin 1 proteins, involved in meeting energy demands for sperm motility, and with nuclear pore complex nucleoporins. We provide insights into the molecular features of sperm physiology describing for the first time a multifunctional role of SPANX-A/D protein family in nuclear envelope, sperm movement and metabolism, considered key functions for human spermatozoa. SPANX-A/D family members, therefore, might be promising targets for sperm fertility management.


Assuntos
Proteínas Nucleares/metabolismo , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/genética , Células HEK293 , Células HeLa , Hominidae/metabolismo , Humanos , Masculino , Membrana Nuclear/metabolismo , Fosforilação/genética , Isoformas de Proteínas/metabolismo , Proteômica/métodos , Homologia de Sequência de Aminoácidos , Espermátides/metabolismo , Testículo/metabolismo , Fatores de Transcrição/metabolismo , Cromossomo X/genética
17.
Sci Rep ; 10(1): 4276, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152354

RESUMO

Turtles demonstrate variability in sex determination and, hence, constitute an excellent model for the evolution of sex chromosomes. Notably, the sex determination of the freshwater turtles from the family Chelidae, a species-rich group with wide geographical distribution in the southern hemisphere, is still poorly explored. Here we documented the presence of an XX/XY sex determination system in seven species of the Australasian chelid genera Chelodina, Emydura, and Elseya by conventional (karyogram reconstruction, C-banding) and molecular cytogenetic methods (comparative genome hybridization, in situ hybridization with probes specific for GATA microsatellite motif, the rDNA loci, and the telomeric repeats). The sex chromosomes are microchromosomes in all examined species of the genus Chelodina. In contrast, the sex chromosomes are the 4th largest pair of macrochromosomes in the genera Emydura and Elseya. Their X chromosomes are submetacentric, while their Y chromosomes are metacentric. The chelid Y chromosomes contain a substantial male-specific genomic region with an accumulation of the GATA microsatellite motif, and occasionally, of the rDNA loci and telomeric repeats. Despite morphological differences between sex chromosomes, we conclude that male heterogamety was likely already present in the common ancestor of Chelodina, Emydura and Elseya in the Mesozoic period.


Assuntos
Evolução Molecular , Genoma , Cromossomos Sexuais/genética , Cromossomo X/genética , Cromossomo Y/genética , Animais , Feminino , Cariótipo , Masculino , Repetições de Microssatélites , Processos de Determinação Sexual , Tartarugas
18.
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
19.
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
20.
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
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